Conquer Cancer Foundation

Conquer Cancer Foundation of ASCO Grant Recipients supported by WWWW Foundation, Inc.

Articles published January 1, 2013 – August 12, 2015

Recipients:

Steven DuBois (2007 YIA)

Jason Yustein (2008 YIA)

Alexei Morozov (2009 YIA)

Aimee Crago (2010 YIA)

Fernanda Arnaldez (2011 YIA)

Breelyn Wilky (2012 YIA)

Wendy Allen-Rhoades (2013 YIA)

Christine Heske (2014 YIA)

Steven DuBois (2007 YIA):

Second malignant neoplasms among children, adolescents and young adults with Wilms tumor

By: Lee, Jean S.; Padilla, Benjamin; DuBois, Steven G.; et al.

PEDIATRIC BLOOD & CANCER Volume: 62 Issue: 7 Pages: 1259-1264 Published: JUL 2015

Abstract

BACKGROUND:

The goal of this study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMN) in survivors of Wilms tumor.

PROCEDURES:

Patients who were 0-20 years of age at time of primary diagnosis with Wilms tumor and reported to the Surveillance, Epidemiology, and End Results [SEER] program between

1973 and 2011 were eligible for inclusion in the cohort. We used competing risks methods to estimate the cumulative incidence of SMNs and assess contributing factors for developing SMN. We estimated standardized incidence ratios (SIR), absolute excess risk and overall survival after SMN using standard methods.

RESULTS:

Within the SEER database, 2,851 patients were diagnosed with Wilms tumor as their first malignancy. Of these, 34 patients were reported to have a SMN. Cumulative incidence of for a secondary malignancy was 0.6% (95% confidence interval [95% CI]

0.3-1.0%) at 10 years, 1.6% (95% CI 1.0-2.3%) at 20 years, and 3.8% (95% CI 2.4-

5.9%) at 30 years. Median time from primary diagnosis to SMN diagnosis was 12.5 years. SIR for SMN for survivors of Wilms tumor was 3.4 (95% CI 2.2-4.9) with an absolute excess risk of 7.6 per 10,000 persons per year. Exposure to radiation did not significantly increase risk for development of second malignancy. Overall survival for patients with SMN was 64.5% at 5 years.

CONCLUSION:

Survivors of Wilms tumor are at an increased risk of SMN compared to the general population, but the added risk is relatively small compared to other pediatric cancers.

Steven DuBois (2007 YIA) Page 1



Phase I Study of Vorinostat as a Radiation Sensitizer with I-131-Metaiodobenzylguanidine (I-

131-MIBG) for Patients with Relapsed or Refractory Neuroblastoma

By: DuBois, Steven G.; Groshen, Susan; Park, Julie R.; et al.

CLINICAL CANCER RESEARCH Volume: 21 Issue: 12 Pages: 2715-2721 Published: JUN 15

2015

Abstract

PURPOSE:

(131)I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and

MIBG in combination.

EXPERIMENTAL DESIGN:

Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible.

Patients received oral vorinostat (dose levels 180 and 230 mg/m(2)) daily days 1 to 14.

MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.

RESULTS:

Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation.

No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4

(15 mCi/kg MIBG/230 mg/m(2) vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m(2) vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg

MIBG/180 mg/m(2) vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.

CONCLUSIONS:

Vorinostat at 180 mg/m(2)/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing.




Patient-Specific Dosimetry Using Pretherapy [I-124]m-iodobenzylguanidine ([I-124]mIBG)

Dynamic PET/CT Imaging Before [I-131]mIBG Targeted Radionuclide Therapy for

Neuroblastoma

By: Huang, Shih-ying; Bolch, Wesley E.; Lee, Choonsik; et al.

MOLECULAR IMAGING AND BIOLOGY Volume: 17 Issue: 2 Pages: 284-294 Published: APR

2015

Abstract

PURPOSE:

Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG)-targeted radionuclide therapy (TRT) is a standard treatment for recurrent or refractory neuroblastoma with response rates of

30-40 %. The aim of this study is to demonstrate patient-specific dosimetry using quantitative [(124)I]mIBG positron emission tomography/X-ray computed tomography

(PET/CT) imaging with a GEometry ANd Tracking 4 (Geant4)-based Monte Carlo method for better treatment planning.

PROCEDURES:

A Monte Carlo dosimetry method was developed using the Geant4 toolkit with voxelized anatomical geometry and source distribution as input. The presegmented hybrid computational human phantoms developed by the University of Florida and the National

Cancer Institute (UF/NCI) were used as a surrogate to characterize the anatomy of a given patient. S values for I-131 were estimated by the phantoms coupled with Geant4 and compared with those estimated by OLINDA|EXM and MCNPX for the newborn model. To obtain patient-specific biodistribution of [(131)I]mIBG, a 10-year-old girl with relapsed neuroblastoma was imaged with [(124)I]mIBG PET/CT at four time points prior to the planned [(131)I]mIBG TRT. The organ- and tumor-absorbed doses of the clinical case were estimated with the Geant4 method using the modified UF/NCI 10-year-old phantom with tumors and the patient-specific residence time.

RESULTS:

For the newborn model, the Geant4 S values were consistent with the MCNPX S values. The S value ratio of the Geant4 method to OLINDA|EXM ranged from 0.08 to

6.5 of all major organs. The [(131)I]mIBG residence time quantified from the pretherapy

[(124)I]mIBG PET/CT imaging of the 10-year-old patient was mostly comparable to those previously reported. Organ-absorbed dose for the salivary glands was 98.0 Gy, heart wall 36.5 Gy, and liver 34.3 Gy, while tumor-absorbed dose ranged from 143.9 to

1,641.3 Gy in different sites.

CONCLUSIONS:

Patient-specific dosimetry for [(131)I]mIBG TRT was accomplished using pretherapy

[(124)I]mIBG PET/CT imaging and a Geant4-based Monte Carlo dosimetry method. The

Geant4 method with quantitative pretherapy imaging can provide dose estimates to normal organs and tumors with more realistic simulation geometry, and thus may improve treatment planning for [(131)I]mIBG TRT.




Phase II Study of Cixutumumab in Combination With Temsirolimus in Pediatric Patients and

Young Adults With Recurrent or Refractory Sarcoma: A Report From the Children's Oncology

Group

By: Wagner, Lars M.; Fouladi, Maryam; Ahmed, Atif; et al.

PEDIATRIC BLOOD & CANCER Volume: 62 Issue: 3 Pages: 440-444 Published: MAR 2015

Abstract

BACKGROUND:

The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-

IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.

METHODS:

Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to

10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable firstcycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response.

RESULTS:

Forty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks.

Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers.

CONCLUSIONS:

Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.




Phase I/II study of I-131-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

By: DuBois, S. G.; Allen, S.; Bent, M.; et al.

BRITISH JOURNAL OF CANCER Volume: 112 Issue: 4 Pages: 644-649 Published: FEB 17

2015

Abstract

BACKGROUND:

(131)I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.

METHODS:

Patients 1-30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days 1 to +6, irinotecan (50 mg m(-2) per dose IV) on days 0-4, vincristine

(2 mg m(-2)) on day 0, MIBG (555 or 666 MBq kg(-1)) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.

RESULTS:

Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg(-1). Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37%; P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.

CONCLUSIONS:

MIBG (666 MBq kg(-1)) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.




Comparative Evaluation of Local Control Strategies in Localized Ewing Sarcoma of Bone A

Report From the Children's Oncology Group

By: DuBois, Steven G.; Krailo, Mark D.; Gebhardt, Mark C.; et al.

CANCER Volume: 121 Issue: 3 Pages: 467-475 Published: FEB 1 2015

Abstract

BACKGROUND:

Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear.

METHODS:

Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included

(n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type.

RESULTS:

Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR,

1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure

(HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS

(HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups.

CONCLUSIONS:

In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.




Growth Plate Abnormalities in Pediatric Cancer Patients Undergoing Phase 1 Anti-Angiogenic

Therapy: A Report From the Children's Oncology Group Phase I Consortium

By: Voss, Stephan D.; Glade-Bender, Julia; Spunt, Sheri L.; et al.

PEDIATRIC BLOOD & CANCER Volume: 62 Issue: 1 Pages: 45-51 Published: JAN 2015

Abstract

BACKGROUND:

Pre-clinical studies suggest that anti-angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti-angiogenic therapy.

PROCEDURE:

Targeted radiographic studies from 53 subjects enrolled on six separate Children's

Oncology Group Phase 1 and Pilot Consortium clinical trials evaluating new anti-cancer agents interfering with angiogenesis were reviewed. Subjects received tyrosine kinase inhibitors with anti-angiogenic effects (n = 35), monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (n = 13), or angiopoietin (n = 5). Radiographs of their distal femur/proximal tibia were obtained at baseline. Follow-up radiographs were obtained after odd-numbered treatment cycles in patients with open growth plates who did not experience disease progression prior to cycle 3.

RESULTS:

Baseline and follow-up growth plate radiographs were acquired in 48/53 (90%) of patients. Five patients (9.4%), all of whom received a specific VEGF/VEGFR blocking agent (sunitinib [n = 1] or pazopanib [n = 4]), had growth plate abnormalities. Four patients had growth plate widening that was apparent on at least two successive radiographs, but was not confirmed by MRI. The fifth patient had progressive growth plate widening and evidence of physeal cartilage hypertrophy on MRI. Subsequent off treatment radiographs showed that the growth plate changes were reversible.

CONCLUSION:

Growth plate abnormalities occur in a small, but relevant number of patients undergoing anti-angiogenic therapy. These results support the need for growth plate monitoring in children with open growth plates who are receiving anti-angiogenic therapy, and for improved methods to assess toxicity of anti-angiogenic agents to the developing skeleton.




Secondary Malignant Neoplasms Among Children, Adolescents, and Young Adults With

Osteosarcoma

By: Lee, Jean S.; DuBois, Steven G.; Boscardin, W. John; et al.

CANCER Volume: 120 Issue: 24 Pages: 3987-3993 Published: DEC 15 2014

Abstract

BACKGROUND:

As patients with osteosarcoma become long-term survivors, increasing attention has turned to the burden of late effects. The goal of the current study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMNs) in this population.

METHODS:

Patients aged birth to 40 years at time of primary diagnosis with osteosarcoma and reported to the Surveillance, Epidemiology, and End Results (SEER) program between

1973 and 2010 were eligible for inclusion in the cohort. Competing risks methods were used to estimate the cumulative incidence of SMNs and potential risk factors for developing an SMN. Standardized incidence ratios (SIR) and overall survival after an

SMN were estimated.

RESULTS:

The SEER database included 3379 patients who were diagnosed with osteosarcoma as their first malignancy. Of these, 89 patients were diagnosed with an SMN. The cumulative incidence of any SMN was 2.1% (95% confidence interval [95% CI], 1.6%-

2.7%) at 10 years, 4.0% (95% CI, 3.1%-5.1%) at 20 years, and 7.4% (95% CI, 5.6%-

9.5%) at 30 years. The median time from the primary diagnosis to an SMN diagnosis was 6.0 years. The SIR for SMNs for survivors of osteosarcoma compared with the general population was 1.6 (95% CI, 1.0-2.5) for patients diagnosed with osteosarcoma from 1973 through 1985 and 4.7 (95% CI, 3.3-6.4) for patients diagnosed with osteosarcoma from 1986 through 2010, with a 34-fold increased risk of leukemia in this most recent era. The overall survival rate at 5 years for patients with SMNs after a diagnosis of osteosarcoma was 44.5%.

CONCLUSIONS:

Survivors of osteosarcoma are at an increased risk of developing SMNs compared with the baseline population, with an increased risk noted in patients treated in the more recent era.




Clinical, Biologic, and Prognostic Differences on the Basis of Primary Tumor Site in

Neuroblastoma: A Report From the International Neuroblastoma Risk Group Project

By: Vo, Kieuhoa T.; Matthay, Katherine K.; Neuhaus, John; et al.

JOURNAL OF CLINICAL ONCOLOGY Volume: 32 Issue: 28 Pages: 3169-+ Published: OCT 1

2014

Abstract

PURPOSE:

Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear.

PATIENTS AND METHODS:

Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the

International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS).

RESULTS:

Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were > 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P < .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to

2.63; P < .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P < .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P < .001 for both comparisons). After controlling for age,

MYCN status, and stage, patients with adrenal tumors had higher risk for events

(hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003).

CONCLUSION:

Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively.

Future studies will need to investigate the biologic origin of these differences.




Pediatric cancer type predicts infection rate, need for critical care intervention, and mortality in the pediatric intensive care unit

By: Zinter, Matt S.; DuBois, Steven G.; Spicer, Aaron; et al.

INTENSIVE CARE MEDICINE Volume: 40 Issue: 10 Pages: 1536-1544 Published: OCT 2014

Abstract

PURPOSE:

Up to 38 % of children with cancer require pediatric intensive care unit (PICU) admission within 3 years of diagnosis, with reported PICU mortality of 13-27 % far exceeding that of the general PICU population. PICU outcomes data for individual cancer types are lacking and may help identify patients at risk for poor clinical outcomes.

METHODS:

We performed a retrospective multicenter analysis of 10,365 PICU admissions of cancer patients no greater than 21 years old among 112 PICUs between 1 January

2009 and 30 June 2012. We evaluated the effect of cancer type, age, gender, genetic syndrome, stem cell transplantation, PRISM3 score, infections, and critical care interventions on PICU mortality.

RESULTS:

After excluding scheduled perioperative admissions, cancer patients represented 4.2 % of all PICU admissions (10,365/246,346), had overall mortality of 6.8 % (708/10,365) vs.

2.4 % (5,485/230,548) in the general PICU population (RR = 2.9, 95 % CI 2.7-3.1, p <

0.001), and accounted for 11.4 % of all PICU deaths (708/6,215). Hematologic cancer patients had greater median PRISM3 score (8 vs 2, p < 0.001), rates of sepsis (27 vs 9

%, RR = 2.9, 95 % CI 2.6-3.1, p < 0.001), and mortality (9.6 vs 4.5 %, RR = 2.1, 95 %

CI 1.8-2.5, p < 0.001) compared to solid cancer patients. Among hematologic cancer patients, stem cell transplantation, diagnosis of acute myeloid leukemia, PRISM3 score, and infection were all independently associated with PICU mortality.

CONCLUSIONS:

Children with cancer account for 4.2 % of PICU admissions and 11.4 % of PICU deaths.

Hematologic cancer patients have significantly higher admission illness severity, rates of infections, and PICU mortality than solid cancer patients. These data may be useful in risk stratification for closer monitoring and patient counseling.




Comparative Evaluation of Strategies for Quantifying Signaling Pathway Proteins in Ewing

Sarcoma

By: Applebaum, Mark A.; Thomas, Dafydd G.; Hembrough, Todd; et al.

APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Volume: 22 Issue: 8

Pages: 593-599 Published: SEP 2014

Abstract

Targeted therapies are increasingly being evaluated for patients with Ewing sarcoma

(EWS). Optimal strategies for quantifying key signaling proteins in EWS remain unclear.

We sought to quantify tumor expression of signaling pathway proteins in EWS using 3 methodologies. A total of 46 blocks of formalin-fixed paraffin-embedded tissue were obtained from 40 patients with EWS. Tumor was evaluated for the expression of proteins in the insulin-like growth factor type 1 receptor (IGF-1R), epithelial growth factor receptor (EGFR), and mTOR pathways using standard immunohistochemical analysis (IHC), automated quantitative analysis (AQUA) immunohistochemical analysis, and mass spectrometry quantification. The mean age at diagnosis was 14 years (range,

1 to 49 y). About 67.5% were male and 57.5% had localized disease. Samples displayed a wide range of expression by AQUA: mean (range) IGF-1R=10,702 (393 to

14,424); EGFR=2750 (672 to 9798); and phosphatase and tensin homolog

(PTEN)=2250 (251 to 6557). Mean IGF-1R expression by AQUA did not differ between standard IHC expression categories (low IHC=11,255; medium IHC=11,070; high

IHC=11,023; P=0.98). Mean PTEN expression by AQUA was higher in the medium and high IHC categories (low IHC=1229; medium IHC=2715; high IHC=2940; P=0.064).

Only 2 samples expressed EGFR by standard IHC. Mass spectrometry trended toward correlation with standard IHC but did not yield interpretable results in the majority of samples. This study demonstrates that the relative quantification of signaling protein expression in EWS is dependent on the methodology used. Optimization and validation of these tools are necessary before clinical application for risk stratification of patients or measurement of biomarker expression.




Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk

Neuroblastoma

By: Polishchuk, Alexei L.; Li, Richard; Hill-Kayser, Christine; et al.

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Volume: 89 Issue: 4

Pages: 839-845 Published: JUL 15 2014

Abstract

PURPOSE/OBJECTIVES:

Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure.

Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy.

METHODS AND MATERIALS:

Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation.

RESULTS:

Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131

(82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites.

CONCLUSIONS:

Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients.

Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities

(external beam radiation or (131)I-MIBG).




Comparison of Latino and Non-Latino Patients With Ewing Sarcoma

By: Sharib, Jeremy; Horvai, Andrew; Hazard, Florette K. Gray; et al.

PEDIATRIC BLOOD & CANCER Volume: 61 Issue: 2 Pages: 233-237 Published: FEB 2014

Abstract

BACKGROUND:

Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults.

Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.

METHODS:

Primary data for 218 ES patients treated at two academic medical centers between

1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.

RESULTS:

Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37;

OS: 77.6% vs. 68.6% P = 0.54).

CONCLUSION:

Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.




Current treatment and outcome for childhood acute leukemia in Tanzania.

Kersten E, Scanlan P, Dubois SG, Matthay KK.

Pediatr Blood Cancer. 2013 Dec;60(12):2047-53. doi: 10.1002/pbc.24576. Epub 2013 Aug 26.

PMID: 24039163

Abstract

BACKGROUND:

In order to understand the disparity in childhood leukemia survival in low-income countries (LICs) compared to high-income countries (HICs), we evaluated the resources available at Tanzania's national pediatric oncology ward, and clinical characteristics, disease course and outcomes of children diagnosed with acute leukemia from 2008 through 2010.

PROCEDURES:

A chart review and assessment of services was performed to assess childhood leukemia diagnoses, treatment, and outcomes in Tanzania at the Ocean Road Cancer

Institute (ORCI) from January 1, 2008 to December 31, 2010. Results were compared to those from a 2005 evaluation that showed only one of 20 children with leukemia surviving at 1 year.

RESULTS:

During the study period, 106 patients presented with leukemia, including 81 patients with acute lymphoblastic leukemia (ALL) and 25 with acute myeloid leukemia (AML).

Forty-nine of 58 (84%) patients with ALL, and six of 17 (35%) with AML who received therapy and had complete data, achieved complete remission. Estimated 2-year eventfree survival for all patients with ALL was 33%; for AML it was 0%. Ten patients died prior to initiation of therapy, 19 died of toxicity, and eight abandoned therapy.

CONCLUSIONS:

Though leukemia survival in Tanzania remains far below that in HICs, survival rates for

ALL have significantly improved in recent years due to standardization of treatment regimens and better staff, though AML outcome remains dismal. Ongoing improvements in pediatric leukemia outcomes will require strategies to improve awareness and early access to treatment coupled with improvements in diagnostic capabilities, supportive care, and training.




Adverse impact of regional lymph node involvement in osteosarcoma.

Thampi S, Matthay KK, Goldsby R, DuBois SG.

Eur J Cancer. 2013 Nov;49(16):3471-6. doi: 10.1016/j.ejca.2013.06.023. Epub 2013 Jul 15.

PMID: 23867123

Abstract

BACKGROUND:

Metastatic dissemination in osteosarcoma occurs haematogenously, though regional lymph node involvement is rarely reported. We investigated incidence, patient characteristics and survival for patients with osteosarcoma and regional lymph node involvement at diagnosis.

METHODS:

We identified 2748 cases of high-grade osteosarcoma with available information regarding regional lymph node involvement in the Surveillance Epidemiology and End

Results database from 1973 to 2009. Demographics were compared using chi-squared tests or t-tests. Overall survival was estimated using Kaplan-Meier method and compared with log-rank tests. Multivariate analysis of overall survival was performed using Cox proportional hazards methods.

RESULTS:

There were 74 patients (2.7%) with regional lymph node involvement at diagnosis of whom 19 (0.7%) were pathologically confirmed. Patients with regional node involvement were more likely to have extraskeletal tumours, distant metastases, tumours arising outside the lower extremity (p<0.0001 for all comparisons) and larger tumours

(p=0.033). Five-year overall survival in those with and without regional node involvement was 10.9% (95% confidence interval (CI) 4.6-20.4) and 54.3% (95% CI

52.2-56.4; p<0.0001). In multivariate analysis, regional node involvement remained predictive of inferior survival after controlling for differences in metastatic status, age, tumour site and extraskeletal origin (hazard ratio 2.05, 95% CI 1.57-2.67; p<0.0001).

Similar survival results were found when the analysis was restricted to patients with pathologically confirmed positive or negative regional lymph nodes.

CONCLUSION:

This analysis confirms that regional node involvement is a significant adverse prognostic factor that is independent of metastatic status, extraskeletal origin, age and tumour site.




Acute changes in blood pressure in patients with neuroblastoma treated with ¹³¹I-metaiodobenzylguanidine (MIBG).

Wong T, Matthay KK, Boscardin WJ, Hawkins RA, Brakeman PR, DuBois SG.

Pediatr Blood Cancer. 2013 Sep;60(9):1424-30. doi: 10.1002/pbc.24551. Epub 2013 Apr 23.

PMID: 23613447

Abstract

BACKGROUND:

Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy for children with neuroblastoma. The aim of our study was to evaluate systematically the acute effects of (131)I-MIBG on blood pressure in patients with neuroblastoma and to identify possible predictors of hypertension.

PROCEDURE:

We conducted a retrospective chart review of neuroblastoma patients who were treated with (131)I-MIBG between January 1, 1999 and June 1, 2012 at the University of

California, San Francisco. Clinical data for 172 patients with neuroblastoma, receiving

218 administrations of (131)I-MIBG, were collected. The primary endpoint was development of systolic blood pressure above the 95th percentile for age. Logistic regression with generalized estimating equations to account for multiple administrations in some subjects was used to identify bivariate and multivariate predictors of hypertension.

RESULTS:

Of the 218 administrations of (131)I-MIBG, 112 (51.3%) were associated with at least one episode of systolic hypertension during or after the (131)I-MIBG infusion. The majority of these acute elevations in blood pressure resolved within 48 hours of the infusion. Only six administrations in five patients required nifedipine administration to lower blood pressure. Younger age (P = 0.012), lower eGFR (P = 0.047), and elevated blood pressure measurements immediately before infusion began (P = 0.010) were all independently associated with risk of treatment-associated hypertension.

CONCLUSIONS:

Acute elevations in blood pressure are common after therapeutic doses of (131) I-

MIBG. Elevations in blood pressure typically occur only within the first 48 hours after

(131)I-MIBG administration. Blood pressure monitoring during this period of risk is recommended.




Substrate and reaction specificity of Mycobacterium tuberculosis cytochrome P450 CYP121: insights from biochemical studies and crystal structures.

Fonvielle M, Le Du MH, Lequin O, Lecoq A, Jacquet M, Thai R, Dubois S, Grach G, Gondry M,

Belin P.

J Biol Chem. 2013 Jun 14;288(24):17347-59. doi: 10.1074/jbc.M112.443853. Epub 2013 Apr

25.

PMID: 23620594

Abstract

Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis.

Studies in vitro show that it can use the cyclodipeptide cyclo(l-Tyr-l-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of

CYP121 involving analysis of the interaction between CYP121 and 14 cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring.

Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in lconfiguration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85),

Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo.

This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.




131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma.

French S, DuBois SG, Horn B, Granger M, Hawkins R, Pass A, Plummer E, Matthay K.

Pediatr Blood Cancer. 2013 May;60(5):879-84. doi: 10.1002/pbc.24351. Epub 2012 Sep 28.

PMID: 23024113

Abstract

BACKGROUND:

(131) I-metaiodobenzylguanidine (MIBG) produces a 37% response rate in relapsed/refractory neuroblastoma, and could be used to improve remission status prior to myeloablative chemotherapy with autologous stem cell transplant (ASCT). The purpose of our report was to evaluate safety and response with MIBG therapy followed by myeloablative busulfan and melphalan (BuMel) with ASCT in patients with refractory neuroblastoma.

METHODS:

Retrospective chart review was done on patients treated with MIBG (18 mCi/kg) on Day

1 and ASCT on day 14. Six to eight weeks after MIBG, patients without progressive disease received IV busulfan on days -6 to -2 (target Css 700-900), melphalan

(140 mg/m2 IV) on day -1, and ASCT on Day 0. Response and toxicity were evaluated after MIBG and again after myeloablative therapy.

RESULTS:

Eight patients completed MIBG/ASCT followed by BuMel/ASCT. MIBG was well tolerated, with grade 3 or 4 non-hematologic toxicity limited to one patient with sepsis.

Grade 3 mucositis occurred in six patients after BuMel/ASCT. One patient developed sinusoidal obstructive syndrome (SOS) and died 50 days post-ASCT following myeloablative conditioning. All patients engrafted neutrophils (median 16.5 days) and platelets (median 32 days) after BuMel, excluding the patient with SOS. After all therapy, there were three complete, two partial, and one minor response in seven evaluable patients.

CONCLUSIONS:

MIBG at doses up to 18 mCi/kg can be safely administered 6 weeks prior to a BuMel consolidative regimen for refractory neuroblastoma. Preceding MIBG did not impair engraftment following BuMel. This regimen is being further evaluated in a Children's

Oncology Group (COG) trial.




Clinical features and outcomes in patients with secondary Ewing sarcoma.

Applebaum MA, Goldsby R, Neuhaus J, DuBois SG.

Pediatr Blood Cancer. 2013 Apr;60(4):611-5. doi: 10.1002/pbc.24251. Epub 2012 Jul 27.

PMID: 22847990

Abstract

BACKGROUND:

Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).

METHODS:

Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results

Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using

Fisher exact tests. Overall survival was estimated via the Kaplan-Meier method and compared using log-rank tests and Cox proportional hazard models.

RESULTS:

Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61-3.44) beyond 24 months from initial diagnosis.

CONCLUSIONS:

Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care.




Characteristics and outcomes of patients with Ewing sarcoma over 40 years of age at diagnosis.

Karski EE, Matthay KK, Neuhaus JM, Goldsby RE, Dubois SG.

Cancer Epidemiol. 2013 Feb;37(1):29-33. doi: 10.1016/j.canep.2012.08.006. Epub 2012 Sep 5.

PMID: 22959474

Abstract

BACKGROUND:

The peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥40 years at diagnosis. We describe the clinical characteristics and survival of this rare group.

METHODS:

This retrospective cohort study utilized the Surveillance Epidemiology and End Results da tabase. 2780 patients were identified; including 383 patients diagnosed ≥40 years.

Patient characteristics between age groups were compared using chi-squared tests.

Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer.

RESULTS:

Patients ≥40 years of age were more likely to have extra-skeletal tumors (66.1% vs.

31.7%; p < 0.001), axial tumors (64.0% vs. 57.2%; p = 0.01), and metastatic disease at diagnosis (35.5% vs. 30.0%; p = 0.04) compared to younger patients. Five-year survival for those age ≥40 and age <40 were 40.6% and 54.3%, respectively (p < 0.0001). A

Cox multivariable model controlling for differences between groups confirmed inferior survival for older patients (hazard ratio for death of 2.04; 95% CI 1.63-2.54; p < 0.0001); though treatment data were unavailable and not controlled for in the model. A competing risks analysis confirmed increased risk of cancer-related death in older patients.

CONCLUSION:

Patients ≥40 years at diagnosis with EWS are more likely to have extra-skeletal tumors, metastatic disease, and axial primary tumors suggesting a difference in tumor biology.

Independent of differences in these characteristics, older patients also have a lower survival rate.




Superselective intra-arterial melphalan therapy for newly diagnosed and refractory retinoblastoma: results from a single institution.

Thampi S, Hetts SW, Cooke DL, Stewart PJ, Robbins E, Banerjee A, Dubois SG, Char D, Halbach

V, Matthay K.

Clin Ophthalmol. 2013;7:981-9. doi: 10.2147/OPTH.S43398. Epub 2013 May 27.

PMID: 23818751

Abstract

BACKGROUND:

Intra-arterial administration of melphalan chemotherapy has shown promise in the treatment of retinoblastoma. This report describes our results using superselective intraarterial melphalan in patients with newly diagnosed retinoblastoma and those who were treated for progression after systemic chemotherapy.

METHODS:

This is a retrospective review of all retinoblastoma patients treated with intra-arterial melphalan at the University of California, San Francisco from March 2010 to August

2012. Twenty eyes (16 patients) underwent 40 intra-arterial melphalan infusions, and dose was determined by age. Patients were treated at monthly intervals and received a range of 1-5 treatments. Response to therapy, toxicity, and procedural radiation exposure was assessed.

RESULTS:

All patients are alive without metastatic disease at a median follow-up of 14.5 (1-29) months. Treatment with enucleation or external beam radiation was avoided in 11/20 eyes (55%) overall [6/12 (50%) in newly diagnosed eyes and 5/8 (63%) in refractory/relapsed eyes]. Response rates (per the International Classification of

Retinoblastoma) were as follows: 6/7 (86%) in groups A-C and 5/13 (38%) in groups D and E. Nonhematologic and hematologic toxicities were minimal and comparable with those in previous reports. The mean procedural radiatio n dose was 20.2 ± 11.9 mGy per eye per procedure.

CONCLUSION:

Superselective intra-arterial melphalan therapy is effective for less advanced eyes but further modifications to therapy are required to improve results in eyes with advanced retinoblastoma.




Jason Yustein (2008 YIA)

Cross-species identification of a plasma microRNA signature for detection, therapeutic monitoring, and prognosis in osteosarcoma

By: Allen-Rhoades W, Kurenbekova L, Satterfield L, Parikh N, Fuja D, Shuck RL, Rainusso N,

Trucco M, Barkauskas DA, Jo E, Ahern C, Hilsenbeck S, Donehower LA, Yustein JT

CANCER MEDICINE Volume: 4 Issue: 7 Pages: 977-988 Published: JUL 2015

Abstract

Osteosarcoma (OS) is the primary bone tumor in children and young adults. Currently, there are no reliable, noninvasive biologic markers to detect the presence or progression of disease, assess therapy response, or provide upfront prognostic insights.

MicroRNAs (miRNAs) are evolutionarily conserved, stable, small noncoding RNA molecules that are key posttranscriptional regulators and are ideal candidates for circulating biomarker development due to their stability in plasma, ease of isolation, and the unique expressions associated with specific disease states. Using a qPCR-based platform that analyzes more than 750 miRNAs, we analyzed control and diseasedassociated plasma from a genetically engineered mouse model of OS to identify a profile of four plasma miRNAs. Subsequent analysis of 40 human patient samples corroborated these results. We also identified disease-specific endogenous reference plasma miRNAs for mouse and human studies. Specifically, we observed plasma miR-

205-5p was decreased 2.68-fold in mice with OS compared to control mice, whereas, miR-214, and miR-335-5p were increased 2.37- and 2.69-fold, respectively. In human samples, the same profile was seen with miR-205-5p decreased 1.75-fold in patients with OS, whereas miR-574-3p, miR-214, and miR-335-5p were increased 3.16-, 8.31- and 2.52-fold, respectively, compared to healthy controls. Furthermore, low plasma levels of miR-214 in metastatic patients at time of diagnosis conveyed a significantly better overall survival. This is the first study to identify plasma miRNAs that could be used to prospectively identify disease, potentially monitor therapeutic efficacy and have prognostic implications for OS patients.

Jason Yustein (2008 YIA) Page 22



NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma

By: S Zhao, L Kurenbekova, Y Gao, A Roos, C J Creighton, P Rao, J Hicks, T-K Man, C Lau, A M C

Brown, S N Jones, A J Lazar, D Ingram, D Lev, L A Donehower and J T Yustein

Oncogene (online advance publication, 12 January 2015)

Abstract

Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.




Mouse models to study cancer stem cells in osteosarcoma.

By: Rainusso, Nino Carlo; Kurenbekova, Lyazat; Donehower, Lawrence; Rosen, Jason; Yustein,

Jason

JOURNAL OF CLINICAL ONCOLOGY Volume: 32 Issue: 15 Supplement: S Meeting Abstract:

10543 Published: MAY 20 2014

Abstract

Background: Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Many patients suffer disease recurrence and eventually die from metastatic disease that has spread to the lungs. Clearly, more research is needed to understand the biology and molecular mechanisms driving OS metastasis and chemoresistance. The identification of cancer stem cells (CSCs) in solid tumor malignancies, mainly carcinomas and brain tumors, has expanded our knowledge about tumor heterogeneity and its role in tumorigenesis, metastasis and therapy resistance.

However, similar research accomplishments have not been established in sarcomas.

Methods: We performed our experiments aimed to identify OS stem cells using two distinct mouse models: a genetically engineered mouse model that carries an osteoblast-specific p53 mutation and a syngenic (DLM8 tumor cells orthotopically injected in C3H mice) mouse model.

Results: We observed that murine tumor cells obtained from freshly isolated tumors developed sphere-like structures (sarcospheres). Sarcophere forming capacity was significantly increased in tumor cells obtained from metastatic lesions. We found that both OS models contain ALDH Hi (stem-like) cells. The high expression of ALDH ranged from 0.7 to 17%. Further analysis showed that distal metastases contained up to

10 times more ALDH Hi cells than the primary bone tumors. Moreover, we performed microarray analysis of primary bone tumors, pulmonary nodules and CSCs in both primary and metastatic sites, and found that 159 genes were differently expressed between bone and metastatic lung OS tumors. Our preliminary data showed that genes involved in the biologic processes of bone development, mesenchymal differentiation and skeletal morphogenesis were enriched in ALDH Hi cells in primary bone tumors, and genes involved in immune response, inflammatory response and cytokines/chemotaxis were up-regulated in ALDH Hi cells in metastatic tumors.

Conclusions: We have identified putative OS stem cells in two immunocompetent mouse models of metastatic OS. Our preliminary data have shown that CSC content seems to be increased in metastases.




The Adolescent and Young Adult with Cancer: State of the Art - Bone Tumors

By: Rainusso, Nino; Wang, Lisa L.; Yustein, Jason T.

CURRENT ONCOLOGY REPORTS Volume: 15 Issue: 4 Pages: 296-307 Published: AUG 2013

Abstract

Primary malignant bone tumors in the pediatric to young adult populations are relatively uncommon and account for about 6 % of all cancers in those less than 20 years old [1] and 3 % of all cancers in adolescents and young adults (AYA) within the age range of

15 to 29 years [2]. Osteosarcoma (OS) and Ewing's sarcoma (ES) comprise the majority of malignant bone tumors. The approach to treatment for both tumors consists of local control measures (surgery or radiation) as well as systemic therapy with high-dose chemotherapy. Despite earlier advances, there have been no substantial improvements in outcomes over the past several decades, particularly for patients with metastatic disease. This review summarizes the major advances in the treatment of OS and ES and the standard therapies available today, current active clinical trials, and areas of investigation into molecularly targeted therapies.

ChIP-PED enhances the analysis of ChIP-seq and ChIP-chip data

By: Wu, George; Yustein, Jason T.; McCall, Matthew N.; et al.

BIOINFORMATICS Volume: 29 Issue: 9 Pages: 1182-1189 Published: MAY 1 2013

Abstract

MOTIVATION : Although chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) or tiling array hybridization (ChIP-chip) is increasingly used to map genome-wide-binding sites of transcription factors (TFs), it still remains difficult to generate a quality ChIPx (i.e. ChIP-seq or ChIP-chip) dataset because of the tremendous amount of effort required to develop effective antibodies and efficient protocols. Moreover, most laboratories are unable to easily obtain ChIPx data for one or more TF(s) in more than a handful of biological contexts. Thus, standard ChIPx analyses primarily focus on analyzing data from one experiment, and the discoveries are restricted to a specific biological context.

RESULTS: We propose to enrich this existing data analysis paradigm by developing a novel approach, ChIP-PED, which superimposes ChIPx data on large amounts of publicly available human and mouse gene expression data containing a diverse collection of cell types, tissues and disease conditions to discover new biological contexts with potential TF regulatory activities. We demonstrate ChIP-PED using a number of examples, including a novel discovery that MYC, a human TF, plays an important functional role in pediatric Ewing sarcoma cell lines. These examples show that ChIP-PED increases the value of ChIPx data by allowing one to expand the scope of possible discoveries made from a ChIPx experiment.

Oncogenic role of Runx2 in the development of osteosarcoma.

By: Roos, Alison; Yustein, Jason T.; Donehower, Larry

CANCER RESEARCH Volume: 73 Issue: 8 Supplement: 1 Meeting

Abstract: 5036 Published: APR 15 2013




Abstract not available

Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma

By: Yustein, Jason; Zhao, Shuying; Satterfield, Laura; et al.

PEDIATRIC BLOOD & CANCER Volume: 58 Issue: 7 Special Issue: SI Pages: 1019-

1019 Published: JUL 2012

Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma

By: Zhao, Shuying; Kurenbekova, Lyazat; Donehower, Lawrence A.; et al.

CANCER RESEARCH Volume: 73 Issue: 8 Supplement: 1 Meeting

Abstract: 3867 Published: APR 15 2013

Abstracts not available




Proteoglycan 4 Expression Protects Against the Development of Osteoarthritis

By: Ruan MZ , Erez A , Guse K , Dawson B , Bertin T , Chen Y , Jiang MM , Yustein J , Gannon F , Lee BH

SCIENCE TRANSLATIONAL MEDICINE Volume: 5 Issue:176 Article

Number: 176ra34 Published: MAR 13 2013

Proteoglycan 4 Expression Protects Against the Development of Osteoarthritis

By: Ruan MZ , Erez A , Guse K , Dawson B , Bertin T , Chen Y , Jiang MM , Yustein J , Gannon F , Lee BH

OSTEOARTHRITIS AND CARTILAGE Volume: 21 Supplement: S Pages: S18-

S18 Published: APR 2013

Abstract

Osteoarthritis (OA) is a common degenerative condition that afflicts more than 70% of the population between 55 and 77 years of age. Although its prevalence is rising globally with aging of the population, current therapy is limited to symptomatic relief and, in severe cases, joint replacement surgery. We report that intra-articular expression of proteoglycan 4 (Prg4) in mice protects against development of OA. Long-term Prg4 expression under the type II collagen promoter (Col2a1) does not adversely affect skeletal development but protects from developing signs of age-related OA. The protective effect is also shown in a model of posttraumatic OA created by cruciate ligament transection. Moreover, intra-articular injection of helper-dependent adenoviral vector expressing Prg4 protected against the development of posttraumatic OA when administered either before or after injury. Gene expression profiling of mouse articular cartilage and in vitro cell studies show that Prg4 expression inhibits the transcriptional programs that promote cartilage catabolism and hypertrophy through the up-regulation of hypoxiainducible factor 3α. Analyses of available human OA data sets are consistent with the predictions of this model. Hence, our data provide insight into the mechanisms for OA development and offer a potential chondroprotective approach to its treatment.




Multiple Target-Specific Molecular Agents for Detection and Image Analysis of Breast Cancer

Characteristics in Mice

By: Ke S, Wang W, Qiu X, Zhang F, Yustein JT, Cameron AG, Zhang S, Yu D, Zou C, Gao X, Lin J,

Yallampalli S, Li M.

CURRENT MOLECULAR MEDICINE Volume: 13 Issue: 3 Pages: 446-458 Published: MAR

2013

Abstract

Breast cancer is a heterogenetic tumor at the cellular level with multiple factors and components. The inconsistent expression of molecular markers during disease progression reduces the accuracy of diagnosis and efficacy of target-specific therapy.

Single target-specific imaging agents can only provide limited tumor information at one time point. In contrast, multiple target-specific imaging agents can increase the accuracy of diagnosis. The aim of this study was to demonstrate the ability of multiagent imaging to discriminate such differences in single tumor. Mice bearing human cancer cell xenografts were tested to determine individual differences under optimal experimental conditions. Neovasculature agent (RGD peptide), tumor stromal agent

(matrix metalloproteinase), and tumor cell markers (epidermal growth factor, Her-2, interleukin 11) imaging agents were labeled with reporters. 18F-Fluorodeoxyglucose was used to evaluate the tumor glucose status. Optical, X-ray, positron emission tomography, and computer tomography imaging modalities were used to determine tumor characteristics. Tumor size and imaging data demonstrated that individual differences exist under optimal experimental conditions. The target-specific agents used in the study bind to human breast cancer cell lines in vitro and xenografts in vivo. The pattern of binding corresponds to that of tumor markers. Multi-agent imaging had complementary effects in tumor detection. Multiple noninvasive imaging agents and modalities are complementary in the interrogation of unique biological information from each individual tumor. Such multi-agent approaches provide methods to study several disease components simultaneously. In addition, the imaging results provide information on disease status at the molecular level.

Tumor Suppressive Function of MicroRNA34c in Osteosarcoma

By: Bae, Yangjin; Zeng, Huan-Chang; Tao, Jianning; et al.

JOURNAL OF BONE AND MINERAL RESEARCH Volume: 28 Supplement: 1 Meeting

Abstract: SA0467 Published: FEB 2013

Abstract not available




High ALDH Activity Identifies Chemotherapy-Resistant Ewing's Sarcoma Stem Cells That

Retain Sensitivity to EWS-FLI1 Inhibition

By: Awad, Ola; Yustein, Jason T.; Shah, Preeti; et al.

PLOS ONE Volume: 5 Issue: 11 Article Number: e13943 Published: NOV 11 2010

Abstract

BACKGROUND:

Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model - remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal.

METHODOLOGY/PRINCIPAL FINDINGS:

We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDH(high)) activity and are enriched for clonogenicity, sphereformation, and tumor initiation. The ALDH(high) cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo.

CONCLUSIONS/SIGNIFICANCE:

Ewing's sarcoma contains an ALDH(high) stem-like population of chemotherapyresistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.




Abdominal Undifferentiated Small Round Cell Tumor With Unique Translocation

(X;19)(q13;q13.3)

By: Yustein, Jason T.; Rednam, Surya; Bertuch, Alison A.; et al.

PEDIATRIC BLOOD & CANCER Volume: 54 Issue: 7 Pages: 1041-1044 Published: JUL 1 2010

Abstract

We describe a male with a large abdominal mass, most likely originating from the liver, with capsule rupture and tumor dissemination into the abdominal cavity. Adherence of the tumor to the diaphragm and lower right colon also were noted. A comprehensive evaluation of the mass revealed no tumor-defining histopathologic, immunocytochemical, ultrastructural, cytogenetic, or translocation features. The malignant tumor was found to have a novel translocation (X;19)(q13;13.3), which has not been reported in small round cell tumors of childhood or adults. The final diagnosis rendered was an undifferentiated small round cell tumor of uncertain cell of origin.

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

By: Yustein, Jason T.; Liu, Yen-Chun; Gao, Ping; et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF

AMERICA Volume:107 Issue: 8 Pages: 3534-3539 Published: FEB 23 2010

Abstract

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dosedependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible

Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the gamma-secretase Notch inhibitor

N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that

Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.




Hypoxia and metabolism - Opinion - The interplay between MYC and HIF in cancer

By: Dang, Chi V.; Kim, Jung-whan; Gao, Ping; Yustein, Jason

NATURE REVIEWS CANCER Volume: 8 Issue: 1 Pages:51-56 Published: JAN 2008

Abstract

The interaction of MYC and hypoxia inducible factors (HIFs) under physiological, nontumorigenic conditions provides insights into normal homeostatic cellular responses to low oxygen levels (hypoxia). Many tumours contain genetic alterations, such as MYC activation, that can collaborate with HIF to confer metabolic advantages to tumour cells, which tend to exist in a hypoxic microenvironment. This Perspective emphasizes the differences between the transcriptional network that operates under normal homeostatic conditions and the network in a tumorigenic milieu.




Alexei Morozov (2009 YIA)

Rap1 signaling prevents L-type calcium channel-dependent neurotransmitter release.

Subramanian J, Dye L, Morozov A.

J Neurosci. 2013 Apr 24;33(17):7245-52. doi: 10.1523/JNEUROSCI.5963-11.2013.

PMID: 23616533

Abstract

The small GTPase Rap1 contributes to fear learning and cortico-amygdala plasticity by inhibiting glutamate release from cortical neurons, but mechanisms of this inhibition remain unknown. Conversely, L-type calcium channels (LTCCs) become involved in glutamate release after fear learning and LTP induction. Here, we show that Rap1 deletion in mouse primary cortical neurons increases synaptic vesicle exocytosis without altering endocytosis or vesicle pool size in an LTCC-dependent manner. We identify Erk1/2 as the downstream effector of Rap1 and show that its inhibition increases plasma membrane expression of LTCCs near presynaptic terminals. We propose that the Rap1 signaling enables plasticity and fear learning by regulating

LTCCs at cortico-amygdala synapses.

Alexei Morozov (2009 YIA) Page 32



Talin1 and Rap1 are critical for osteoclast function.

Zou W, Izawa T, Zhu T, Chappel J, Otero K, Monkley SJ, Critchley DR, Petrich BG, Morozov A,

Ginsberg MH, Teitelbaum SL.

Mol Cell Biol. 2013 Feb;33(4):830-44. doi: 10.1128/MCB.00790-12. Epub 2012 Dec 10.

PMID: 23230271

Abstract

To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells.

Absence of TLN1 impairs macrophage colony-stimulating factor (M-CSF)-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts.

Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-

CSF and receptor activator of nuclear factor κB (RANK) ligand but attach to substrate and migrate poorly, arresting their development into mature resorptive cells.

In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼ 5-fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-

Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-

TLN1 and CtsK-Rap1 mice is substantially more severe tha n that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss.

Alexei Morozov (2009 YIA) Page 33



Aimee Crago (2010 YIA)

MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition

By: Kovatcheva, Marta; Liu, David D.; Dickson, Mark A.; et al.

ONCOTARGET Volume: 6 Issue: 10 Pages: 8226-8243 Published: APR 10 2015

Abstract

CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using welldifferentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.

Aimee Crago (2010 YIA) Page 34



Comparison of Local Recurrence With Conventional and Intensity-Modulated Radiation

Therapy for Primary Soft-Tissue Sarcomas of the Extremity

By: Folkert, Michael R.; Singer, Samuel; Brennan, Murray F.; et al.

JOURNAL OF CLINICAL ONCOLOGY Volume: 32 Issue: 29 Pages: 3236-+ Published: OCT 10

2014

Abstract

Purpose: The use of intensity-modulated radiation therapy (IMRT) in the treatment of soft tissue sarcoma (STS) of the extremity is increasing, but no large-scale direct comparison has been reported between conventional external-beam radiation therapy

(EBRT) and IMRT.

Results: Treatment groups were comparable in terms of tumor location, histology, tumor size, depth, and use of chemotherapy. Patients treated with IMRT were older (P =.08), had more high-grade lesions (P =.05), close (< 1 mm) or positive margins (P =.04), preoperative radiation (P <.001), and nerve manipulation (P =.04). Median follow-up was 90 months for patients treated with conventional EBRT and 42 months for patients treated with IMRT. On multivariable analysis adjusting for patient age and tumor size,

IMRT retained significance as an independent predictor of reduced LR (hazard ratio =

0.46; 95% CI, 0.24 to 0.89; P =.02)

Methods: Between January 1996 and December 2010, 319 consecutive adult patients with primary nonmetastatic extremity STS were treated with limb-sparing surgery and adjuvant radiotherapy (RT) at a single institution. Conventional EBRT was used in 154 patients and IMRT in 165 with similar dosing schedules. Median follow-up time for the cohort was 58 months.

Conclusion: Despite a preponderance of higher-risk features (especially close/positive margin) in the IMRT group, IMRT was associated with significantly reduced local recurrence compared with conventional EBRT for primary STS of the extremity.




Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.

Miller ML, Molinelli EJ, Nair JS, Sheikh T, Samy R, Jing X, He Q, Korkut A, Crago AM, Singer S,

Schwartz GK, Sander C.

Sci Signal. 2013 Sep 24;6(294):ra85. doi: 10.1126/scisignal.2004014.

PMID: 24065146

Abstract

Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway.

Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.




A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.

Crago AM, Denton B, Salas S, Dufresne A, Mezhir JJ, Hameed M, Gonen M, Singer S,

Brennan MF.

Ann Surg. 2013 Aug;258(2):347-53. doi: 10.1097/SLA.0b013e31828c8a30.

PMID: 23532110

Abstract

OBJECTIVE:

To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors.

BACKGROUND:

The standard management of desmoid tumors is resection, but many recur locally.

Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment.

METHODS:

Patients undergoing resection during 1982-2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set.

RESULTS:

Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of

439 patients undergoing complete gross resection, 100 (23%) had recurrence. Fiveyear local recurrence-free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence-free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence-free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707).

CONCLUSIONS:

A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions.




Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified welldifferentiated or dedifferentiated liposarcoma.

Dickson MA, Tap WD, Keohan ML, D'Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX,

Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK.

J Clin Oncol. 2013 Jun 1;31(16):2024-8. doi: 10.1200/JCO.2012.46.5476. Epub 2013 Apr 8.

PMID: 23569312

Abstract

PURPOSE:

CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor

PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.

PATIENTS AND METHODS:

Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival

(PFS) at 12 weeks, with 12week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.

RESULTS:

We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive).

Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to

4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.

CONCLUSION:

Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.




Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors.

Chmielecki J, Crago AM, Rosenberg M, O'Connor R, Walker SR, Ambrogio L, Auclair D,

McKenna A, Heinrich MC, Frank DA, Meyerson M.

Nat Genet. 2013 Feb;45(2):131-2. doi: 10.1038/ng.2522. Epub 2013 Jan 13.

PMID: 23313954

Summary

In summary, we have identified a novel NAB2-STAT6 fusion in at least half of SFT tumors from whole exome sequencing data. Although most fusions are identified from whole genome or whole transcriptome sequencing, this finding validates the use of exome data for the discovery of fusions that occur mid-exon. The NAB2-STAT6 fusion appears to be unique to SFT samples as fusion analysis of approximately 713 unique tumor-normal pairs from 5 tumor types analyzed by whole genome, exome, or transcriptome sequencing, or a combination of these techniques, 11 15 failed to identify any fusions involving these genes. As such, this fusion represents the first molecular feature unique to SFTs. These data also suggest that small molecule inhibitors of

STAT6 may be efficacious in this tumor type. Further experiments investigating the functional behavior of this fusion protein are ongoing. Our estimates of the frequency of

NAB2-STAT6 fusions should be considered a lower bound because whole exome sequencing would fail to identify intronic breaks, and because our RT-PCR approach is limited to the regions covered.




Oncologic outcomes of sporadic, neurofibromatosis-associated, and radiation-induced malignant peripheral nerve sheath tumors.

LaFemina J, Qin LX, Moraco NH, Antonescu CR, Fields RC, Crago AM, Brennan MF, Singer S.

Ann Surg Oncol. 2013 Jan;20(1):66-72. doi: 10.1245/s10434-012-2573-2. Epub 2012 Aug 10.

PMID: 22878618

Abstract

BACKGROUND:

Malignant peripheral nerve sheath tumors (MPNSTs) occur sporadically, after prior radiation therapy (RT), or in association with neurofibromatosis type 1 (NF1). It is controversial whether patients with NF1-associated MPNST have worse outcomes. We investigated the prognostic significance of sporadic, NF1-associated, and RT-induced

MPNST.

METHODS:

Patients with primary high-grade MPNST from 1982 to 2011 were identified from a prospectively maintained database. Patients with sporadic MPNST were included only if the MPNST was not associated with NF1 or a neurofibroma or if it was immunohistochemically S100-positive.

RESULTS:

We studied 105 patients; 42 had NF1-associated tumors, 49 sporadic, and 14 RTinduced. Median age at diagnosis was 38 years. Median follow-up for surviving patients was 4 years. Mean tumor diameter was 5.5 cm for RT-induced tumors and 9.7 cm for

NF1-associated and sporadic tumors (P=0.004). In multivariate analysis, factors associated with worse disease-specific survival (DSS) were larger size (HR 1.08; 95%

CI 1.04-1.13; P<0.001) and positive margin (HR 3.30; 95% CI 1.74-6.28; P<0.001). Age, gender, site of disease, and S100 staining were not associated with DSS. The 3-year and median DSS were similar for NF1 and sporadic cases; combined 3-year DSS was

64% and median DSS was 8.0 years. For RT-induced tumors, 3-year DSS was 49% and median DSS was 2.4 years. The relationship between RT association and DSS approached statistical significance (HR 2.29; 95% CI 0.93-5.67; P=0.072).

CONCLUSIONS:

Margin status and size remain the most important predictors of DSS in patients with

MPNST. NF1-associated and sporadic MPNSTs may be associated with improved DSS compared with RT-induced tumors.




Desmoid fibromatosis in children and adolescents: a conservative approach to management.

Honeyman JN, Theilen TM, Knowles MA, McGlynn MM, Hameed M, Meyers P, Crago AM, La

Quaglia MP.

J Pediatr Surg. 2013 Jan;48(1):62-6. doi: 10.1016/j.jpedsurg.2012.10.017.

PMID: 23331794

Abstract

PURPOSE:

Desmoid fibromatosis is associated with frequent recurrence and significant morbidity, but no metastases. To examine the impact of initial non-operative management on event-free survival (EFS) in children, we reviewed our institutional experience with this tumor.

METHODS:

We retrospectively reviewed our institutional database for pediatric cases of desmoid fibromatosis treated between 1970 and 2010. Survival was analyzed using the Kaplan-

Meier method and log-rank test.

RESULTS:

Ninety-three patients were identified, with a median follow-up of 6 years. Median age at diagnosis was 16 years. Forty-seven patients presented with primary tumors, and fortysix had recurrent or progressing disease. Five-year OS was 100%, and 5-year EFS was

31.8%, with a median time to event of 1.48 years. There was no significant difference in

5-year EFS between patients who were managed expectantly and those who initially received treatment (21% versus 34%, P=.09). Sex, race, history of trauma, or familial adenomatous polyposis, multifocality, tumor size, tumor location, and resection status did not correlate with EFS.

CONCLUSION:

Our findings support a conservative initial approach in the management of desmoid fibromatosis. In patients at risk for morbid procedures, upfront resection should be reserved for select tumors that demonstrate aggressive growth or cause serious symptoms.




Fernanda Arnaldez (2011 YIA)

New Strategies in Ewing Sarcoma: Lost in Translation?

By: Arnaldez, Fernanda I.; Helman, Lee J.

CLINICAL CANCER RESEARCH Volume: 20 Issue: 12 Pages: 3050-3056 Published: JUN 15

2014

Abstract

Ewing sarcoma is the second most common pediatric malignant bone tumor.

Aggressive multimodality therapy has led to an improvement in outcomes, particularly in patients with localized disease. However, therapy-related toxicities are not trivial, and the prognosis for patients with relapsed and/or metastatic disease continues to be poor.

In this article, we outline some of the promising therapies that have the potential to change the Ewing sarcoma therapeutic paradigm in the not-too-distant future: insulinlike growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, PARP inhibitors, and immunotherapy.

Fernanda Arnaldez (2011 YIA) Page 42



Loss-of-function screen in rhabdomyosarcoma identifies CRKL-YES as a critical signal for tumor growth.

Yeung CL, Ngo VN, Grohar PJ, Arnaldez FI, Asante A, Wan X, Khan J, Hewitt SM, Khanna C,

Staudt LM, Helman LJ.

Oncogene. 2013 Nov 21;32(47):5429-38. doi: 10.1038/onc.2012.590. Epub 2013 Jan 14.

PMID: 23318429

Abstract

To identify novel signaling pathways necessary for rhabdomyosarcoma (RMS) survival, we performed a loss-of-function screen using an inducible small hairpin RNA (shRNA) library in an alveolar and an embryonal RMS cell line. This screen identified CRKL expression as necessary for growth of alveolar RMS and embryonal RMS both in vitro and in vivo. We also found that CRKL was uniformly highly expressed in both RMS cell lines and tumor tissue. As CRKL is a member of the CRK adapter protein family that contains an SH2 and two SH3 domains and is involved in signal transduction from multiple tyrosine kinase receptors, we evaluated CRKL interaction with multiple tyrosine kinase receptor signaling pathways in RMS cells. While we saw no interaction of CRKL with IGFIR, MET or PI3KAKT/mTOR pathways, we determined that CRKL signaling was associated with SRC family kinase (SFK) signaling, specifically with YES kinase.

Inhibition of SFK signaling with dasatinib or another SFK inhibitor, sarcatinib, suppressed RMS cell growth in vitro and in vivo. These data identify CRKL as a novel critical component of RMS growth. This study also demonstrates the use of functional screening to identify a potentially novel therapeutic target and treatment approach for these highly aggressive pediatric cancers.




Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis

By: Darbari, Deepika S.; Desai, Devarshi; Arnaldez, Fernanda; et al.

BRITISH JOURNAL OF HAEMATOLOGY Volume: 159 Issue: 3 Pages: 376-U11 Published:

NOV 2012

No abstract available

Targeting the Insulin Growth Factor Receptor 1

By: Arnaldez, Fernanda I.; Heiman, Lee J.

HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Volume: 26 Issue: 3 Pages: 527-+

Published: JUN 2012

Abstract

The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation.

Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the

IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool.




Breelyn Wilky (2012 YIA)

Immunotherapy in Sarcoma: A New Frontier

By: Wilky, Breelyn A.; Goldberg, John M.

DISCOVERY MEDICINE Volume: 94 Pages: 201-206 Published: APR 2014

Abstract

Sarcomas are rare cancers of soft tissue and bone, and remain incurable when refractory to standard multimodality treatments. With the recent advances in immunotherapy for other solid tumors, there is heightened interest in the potential link of the immune system with sarcoma physiology. This review aims to summarize the ongoing laboratory and clinical research investigating the applications of immunotherapy in the treatment of sarcomas. With ongoing opportunities in vaccine therapy, adoptive transfer of immune cells, biochemotherapy, and immune checkpoint inhibitors, enrollment in immunotherapy clinical trials is an appealing option for sarcoma patients either in conjunction with traditional treatment modalities, or for those with few standard treatment options.

Breelyn Wilky (2012 YIA) Page 45



Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates

Checkpoint Adaptation in Rhabdomyosarcoma

By: Kikuchi, Ken; Hettmer, Simone; Aslam, M. Imran; et al.

PLOS GENETICS Volume: 10 Issue: 1 Article Number: e1004107 Published: JAN 2014

Abstract

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood.

Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene.

Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.




Extrathoracic Location and "Borderline" Histology are Associated with Recurrence of Solitary

Fibrous Tumors After Surgical Resection.

Wilky BA, Montgomery EA, Guzzetta AA, Ahuja N, Meyer CF.

Ann Surg Oncol. 2013 Dec;20(13):4080-9. doi: 10.1245/s10434-013-3241-x. Epub 2013 Sep 18.

PMID: 24046107

Abstract

BACKGROUND:

Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England's pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology.

METHODS:

With IRB approval, we retrieved patient pathology reports from the Johns Hopkins

Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan-Meier method.

RESULTS:

Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed

1 or more of England's criteria but to an insufficient degree for malignant classification.

These "borderline" SFTs were more likely to recur than benign SFTs without these features.

CONCLUSIONS:

Extrathoracic and "borderline" SFTs with any of England's criteria have a higher risk of recurrence.




A Novel Chordoma Xenograft Allows In Vivo Drug Testing and Reveals the Importance of NF-

κB Signaling in Chordoma Biology.

Trucco MM, Awad O, Wilky BA, Goldstein SD, Huang R, Walker RL, Shah P, Katuri V, Gul N,

Zhu YJ, McCarthy EF, Paz-Priel I, Meltzer PS, Austin CP, Xia M, Loeb DM.

PLoS One. 2013 Nov 6;8(11):e79950. doi: 10.1371/journal.pone.0079950.

PMID: 24223206

Abstract

Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed highthroughput screening of 2,816 compounds using two established chordoma cell lines,

U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an

NFκB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.




Pazopanib in sarcomas: expanding the PALETTE.

Wilky BA, Meyer CF, Trent JC.

Curr Opin Oncol. 2013 Jul;25(4):373-8. doi: 10.1097/CCO.0b013e3283622d3a. Review.

PMID: 23666473

Abstract

PURPOSE OF REVIEW:

After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year.

Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials?

RECENT FINDINGS:

Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo.

Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit.

SUMMARY:

Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit.




LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/β-Catenin Signaling.

Scannell CA, Pedersen EA, Mosher JT, Krook MA, Nicholls LA, Wilky BA, Loeb DM, Lawlor ER.

Front Oncol. 2013 Apr 15;3:81. doi: 10.3389/fonc.2013.00081. eCollection 2013.

PMID: 23596566

Abstract

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPOmediated activation of LGR5 potentiates Wnt/β-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that

LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of

ES cells of origin. LGR5-high ES cells showed nuclear localization o f β-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/β-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-

LGR5-Wntβ-catenin axis is present and active in ES and may contribute to tumor pathogenesis.




Wendy Allen-Rhoades (2013 YIA)

Cross-species identification of a plasma microRNA signature for detection, therapeutic monitoring, and prognosis in osteosarcoma

By: Allen-Rhoades, Wendy; Kurenbekova, Lyazat; Satterfield, Laura; et al.

CANCER MEDICINE Volume: 4 Issue: 7 Pages: 977-988 Published: JUL 2015

Abstract

Osteosarcoma (OS) is the primary bone tumor in children and young adults. Currently, there are no reliable, noninvasive biologic markers to detect the presence or progression of disease, assess therapy response, or provide upfront prognostic insights.

MicroRNAs (miRNAs) are evolutionarily conserved, stable, small noncoding RNA molecules that are key posttranscriptional regulators and are ideal candidates for circulating biomarker development due to their stability in plasma, ease of isolation, and the unique expressions associated with specific disease states. Using a qPCR-based platform that analyzes more than 750 miRNAs, we analyzed control and diseasedassociated plasma from a genetically engineered mouse model of OS to identify a profile of four plasma miRNAs. Subsequent analysis of 40 human patient samples corroborated these results. We also identified disease-specific endogenous reference plasma miRNAs for mouse and human studies. Specifically, we observed plasma miR-

205-5p was decreased 2.68-fold in mice with OS compared to control mice, whereas, miR-214, and miR-335-5p were increased 2.37- and 2.69-fold, respectively. In human samples, the same profile was seen with miR-205-5p decreased 1.75-fold in patients with OS, whereas miR-574-3p, miR-214, and miR-335-5p were increased 3.16-, 8.31- and 2.52-fold, respectively, compared to healthy controls. Furthermore, low plasma levels of miR-214 in metastatic patients at time of diagnosis conveyed a significantly better overall survival. This is the first study to identify plasma miRNAs that could be used to prospectively identify disease, potentially monitor therapeutic efficacy and have prognostic implications for OS patients.

Wendy Allen-Rhoades (2013 YIA) Page 51



Radiation Therapy to the Primary and Postinduction Chemotherapy MIBG-Avid Sites in High-

Risk Neuroblastoma

By: Mazloom, Ali; Louis, Chrystal U.; Nuchtern, Jed; et al.

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Volume: 90 Issue: 4

Pages: 858-862 Published: NOV 15 2014

Abstract

PURPOSE:

Although it is generally accepted that consolidation therapy for neuroblastoma includes irradiation of the primary site and any remaining metaiodobenzylguanidine (MIBG)-avid metastatic sites, limited information has been published regarding the efficacy of this approach.

METHODS AND MATERIALS:

Thirty patients with high-risk neuroblastoma were treated at 1 radiation therapy (RT) department after receiving 5 cycles of induction chemotherapy and resection. All patients had at least a partial response after induction therapy, based upon international neuroblastoma response criteria. The primary sites were treated with 24 to 30 Gy whereas the MIBG-avid metastatic sites were treated with 24 Gy. RT was followed by high-dose chemotherapy with autologous stem cell rescue and 6 months of cis-retinoic acid.

RESULTS:

The 5-year progression-free survival (PFS) and overall survival (OS) rates were 48% and 59%, respectively. The 5-year locoregional control at the primary site was 84%.

There were no differences in locoregional control according to degree of primary surgical resection. The 5-year local control rate for metastatic sites was 74%. The 5year PFS rates for patients with 0, 1, 2, and >3 postinduction MIBG sites were 66%,

57%, 20%, and 0% (P<.0001), respectively, whereas 5-year OS rates were 80%, 57%,

50%, and 0%, respectively (P<.0001).

CONCLUSIONS:

RT to the primary site and postinduction MIBG-positive metastatic sites was associated with 84% and 74% local control, respectively. The number of MIBG-avid sites present after induction chemotherapy and surgery was predictive of progression-free and overall survival.




Allen-Rhoades, Wendy and Steuber, Philip C. “Clinical Assessment and Differential Diagnosis of the Child with Suspected Cancer” in Principles and Practice of Pediatric Oncology, 7th edition, edited by Philip A. Pizzo and David G. Poplack.




Christine Heske (2014 YIA)

IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-

Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma

By: Wan, Xiaolin; Yeung, Choh; Heske, Christine; et al.

NEOPLASIA Volume: 17 Issue: 4 Pages: 358-366 Published: APR 2015

Abstract

The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody,

R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti–IGF-

1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition–induced activation of

YES/SFK and displayed advantageous antitumor activity in vitro and in vivo . Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo . This may be of particular clinical relevance since both

Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of

IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS.

Christine Heske (2014 YIA) Page 54



Role of IGF-1R inhibition on an Src-family kinase bypass resistance pathway: A rational basis for cotargeting IGF-1R and Src kinase in pediatric sarcomas?

By: Wan, Xiaolin; Yeung, Choh L.; Heske, Christine; et al.

JOURNAL OF CLINICAL ONCOLOGY Volume: 31 Issue: 15 Supplement: S Meeting Abstract:

10025 Published: MAY 20 2013

Abstract

Background: Dysregulation of IGF signaling plays a fundamental role in oncogenesis in pediatric sarcomas. We recently completed a Phase II study targeting the IGFI receptor signaling pathway in refrac tory Ewing’s and other sarcomas. We demonstrated an objective response rate of 16 percent, but most responses were transient lasting less than 18 weeks. The majority of patients, even those with initial responses, do not have long term benefit from IGFIR blockade, indicating the presence of an innately resistant tumor mass or the recruitment of compensatory pathways allowing for continued growth. To improve on these responses, we have been probing these tumors to identify other critical pathways that might allow combined targeting approaches.

Methods: Multiple RMS and ES cell lines were treated with IGF1R kinase inhibitors and assayed for up-regulation of various signaling pathways. Combination treatment with

IGF1R inhibitors and inhibitors of additional signaling pathways were then tested in vitro and in vivo using standard techniques. For in vivo xenograft studies, treatments began

11 days following orthotopic injection of tumor cells.

Results: We have identified repid up-regulation of Src family kinase (SFK) signaling within 4 hours of IGF1R blockade in both RMS and ES cell lines. Of note, combined treatment with IGF1R Ab plus IGF1R kinase inhibitors most potently upregulated SFK signaling. Based on these findings, we tested combined IGF1R blockade with SFK inhibition using the commercially available drug, dasatinib. We show that dual blockade of IGF1R and SFK pathways were synergistic in vitro. Furthermore, in xenograft models of RMS, the combination IGF1R and SFK inhibition led to long-term disease free status for at least 90 days in some mice, never seen in our hands previously using these models.

Conclusions: This work identified that IGF-1R inhibition induced activation of Src kinase that may act as a by-pass pathway. Synergistic activity of IGF-1R and SFK kinase inhibitors was observed in vitro and in vivo. Dual IGFI and SFK kinase inhibition may lead to improved therapeutic outcomes.

Christine Heske (2014 YIA) Page 55

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