MD Anderson – Willie Tichenor Fellowship
Publications
Park MS, Patel SR, Ludwig JA, Trent JC, Conrad CA, Lazar AJ, Wang WL,
Boonsirikamchai P, Choi H, Wang X, Benjamin RS, Araujo DM. Activity of
temozolomide and bevacizumab in the treatment of locally advanced,
recurrent, and metastatic hemangiopericytoma and malignant solitary
fibrous tumor. Cancer, 11/2011. PMID: 21480200.
Abstract
BACKGROUND:
Hemangiopericytomas and malignant solitary fibrous tumors (HPC/SFT) are rare,
closely related sarcomas with unpredictable behavior that respond infrequently to
chemotherapy. An optimal systemic treatment strategy for advanced HPC/SFT
has not yet been identified.
METHODS:
We retrospectively analyzed the records of 14 patients with histopathologically
confirmed HPC/SFT who were treated at The University of Texas MD Anderson
Cancer Center between May 2005 and June 2007. All patients were treated with
temozolomide 150 mg/m(2) orally on days 1-7 and days 15-21 and bevacizumab
5 mg/kg intravenously on days 8 and 22, repeated at 28-day intervals. Computed
tomography assessment of tumor size and density (Choi criteria) was used to
determine the best response to therapy. The Kaplan-Meier method was used to
estimate progression-free survival.
RESULTS:
The median follow-up period was 34 months. Eleven patients (79%) achieved a
Choi partial response, with a median time to response of 2.5 months. Two
patients (14%) had stable disease as the best response, and 1 patient (7%) had
Choi progressive disease as the best response. The estimated median
progression-free survival was 9.7 months, with a 6-month progression-free rate
of 78.6%. The most frequently observed toxic effect was myelosuppression.
CONCLUSION:
Combination therapy with temozolomide and bevacizumab is a generally welltolerated and clinically beneficial regimen for HPC/SFT patients. Additional
investigation in a controlled, prospective trial is warranted.
Min S. Park, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Demicco EG, Park MS, Araujo DM, Fox PS, Bassett RL, Pollock RE, Lazar
AJ, Wang WL. Solitary fibrous tumor: a clinicopathological study of 110
cases and proposed risk assessment model. Modern Pathology 25(9):1298306, 9/2012.
Abstract
Solitary fibrous tumor represents a spectrum of mesenchymal tumors,
encompassing tumors previously termed hemangiopericytoma, which are
classified as having intermediate biological potential (rarely metastasizing) in the
2002 World Health Organization classification scheme. Few series have reported
on clinicopathological predictors with outcome data and formal statistical analysis
in a large series of primary tumors as a single unified entity. Institutional
pathology records were reviewed to identify primary solitary fibrous tumor cases,
and histological sections and clinical records reviewed for canonical prognostic
indicators, including patient age, tumor size, mitotic index, tumor cellularity,
nuclear pleomorphism, and tumor necrosis. Patients (n=103) with resected
primary solitary fibrous tumor were identified (excluding meningeal tumors). The
most common sites of occurrence were abdomen and pleura; these tumors were
larger than those occurring in the extremities, head and neck or trunk, but did not
demonstrate significant outcome differences. Overall 5- and 10-year metastasisfree rates were 74 and 55%, respectively, while 5- and 10-year disease-specific
survival rates were 89 and 73%. Patient age, tumor size, and mitotic index
predicted both time to metastasis and disease-specific mortality, while necrosis
predicted metastasis only. A risk stratification model based on age, size, and
mitotic index clearly delineated patients at high risk for poor outcomes. While
small tumors with low mitotic rates are highly unlikely to metastasize, large
tumors ≥ 15 cm, which occur in patients ≥ 55 years, with mitotic figures ≥ 4/10
high-power fields require close follow-up and have a high risk of both metastasis
and death.
Min S. Park, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Park MS, Ravi V, Conley A, Patel SR, Trent JC, Lev DC, Lazar AJ, Wang WL,
Benjamin RS, Araujo DM. The role of chemotherapy in advanced solitary
fibrous tumors: a retrospective analysis. Clinical Sarcoma Research,
5/2013. e-Pub 5/2013.
Abstract
Background
Patients with advanced solitary fibrous tumors (SFTs) have a poor prognosis; treatment
options for recurrent disease are particularly limited. Several novel targeted agents have
recently shown promise against advanced SFTs, but the relative efficacy of new agents is
difficult to assess because data on the efficacy of conventional chemotherapy for SFTs
are limited. We thus sought to estimate the efficacy of conventional chemotherapy for
SFTs by reviewing data on tumor response to therapy and progression-free survival from
SFT patients who received this therapy.
Methods
We retrospectively analyzed the clinical outcomes of 21 patients with grossly
measurable, advanced SFTs (unresectable metastatic disease or potentially resectable
primary tumors) who received conventional chemotherapy and follow-up at The
University of Texas MD Anderson Cancer Center between January 1994 and June 2007.
Best tumor response to therapy was assessed using the Response Evaluation Criteria In
Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progressionfree survival (PFS) duration.
Results
Of 21 patients, 4 received more than 1 regimen of chemotherapy, for a total of 25
treatments. Doxorubicin-based chemotherapy was given in 15 cases (60%), gemcitabinebased therapy in 5 cases (20%), and paclitaxel in 5 cases (20%). First-line chemotherapy
was delivered in 18 cases (72%). No patients had a complete or partial response, 16
(89%) had stable disease, and 2 (11%) had disease progression. Five patients (28%)
maintained stable disease for at least 6 months after first-line treatment. The median PFS
duration was 4.6 months. The median overall survival from diagnosis was 10.3 years.
Conclusion
Conventional chemotherapy is effective in controlling or stabilizing locally advanced and
metastatic SFTs. Our findings can serve as a reference for tumor response and clinical
outcomes in the assessment of novel treatments for SFTs.
Min S. Park, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Park MS, Araujo DM. New insights into the hemangiopericytoma/solitary
fibrous tumor spectrum of tumors. Current Opinion in Oncology 21(4):32731, 7/2009. PMID: 19444101.
Abstract
PURPOSE OF REVIEW:
This review provides an overview of the hemangiopericytoma/solitary fibrous
tumor (HPC/SFT) spectrum of tumors, focusing on the histopathologic
characteristics, clinical features, diagnosis, and treatment of HPC/SFT.
RECENT FINDINGS:
Due to the relatively insensitive nature of HPC/SFT to radiotherapy and cytotoxic
chemotherapy, new therapies are needed for treatment of advanced disease.
Inhibition of angiogenic pathways may provide a novel therapeutic mechanism
for targeting this malignancy. Combination therapy with temozolomide and
bevacizumab has recently emerged as a potentially promising regimen for
HPC/SFT.
SUMMARY:
With many novel targeted therapies currently in development for soft tissue
sarcomas, a better understanding of the molecular pathogenesis and aberrations
of HPC/SFT is needed to determine optimal therapeutic agents. Identifying
appropriate targets and designing rational prospective clinical trials will not only
improve treatment of HPC/SFT but will also lead to a new paradigm of
personalized, targeted therapy.
Min S. Park, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Park MS, Ravi V, Araujo DM. Inhibiting the VEGF-VEGFR Pathway in
Angiosarcoma, Epithelioid Hemangioendothelioma, and
Hemangiopericytoma/Solitary Fibrous Tumor. Current Opinion in Oncology
22(4):351-355, 7/2010.
Abstract
PURPOSE OF REVIEW:
This review highlights the current body of knowledge regarding the role of the
vascular endothelial growth factor (VEGF) and its receptor (VEGFR) in
angiosarcoma, epithelioid hemangioendothelioma (EHE), and
hemangiopericytoma/solitary fibrous tumor (HPC/SFT). Therapeutic agents that
target this pathway are reviewed.
RECENT FINDINGS:
Several phase II trials in advanced soft tissue sarcoma patients have
investigated the efficacy of bevacizumab, an anti-VEGF antibody, as well as
sunitinib, sorafenib, and pazopanib, VEGFR tyrosine kinase inhibitors (TKIs).
Although response rates and progression-free survival periods were generally
low, several angiosarcoma, EHE, and HPC/SFT patients demonstrated response
or durable disease stabilization on these therapies. Biological mechanisms
underlying the activity of these agents in angiosarcoma, EHE, and HPC/SFT are
poorly understood. Some angiosarcoma tumors, however, harbor specific
activating mutations in VEGFR2, which may be effectively targeted by VEGFR
TKIs.
SUMMARY:
Inhibition of the VEGF/VEGFR pathway may be a rational and effective therapy
for certain patients with angiosarcoma, EHE, and HPC/SFT, but more studies are
needed to confirm these findings and to identify which patients will benefit from
these agents.
Min S. Park, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Reynoso D, Nolden LK, Yang D, Dumont SN, Conley AP, Zhou K, Wang WL,
Duensing A, Trent JC. Synergistic Induction of Apoptosis by the Bcl-2
Inhibitor ABT-737 and Imatinib Mesylate in Gastrointestinal Stromal tumor
Cells. Mol Oncol. 2011 Feb;5(1);93-104. PMID: 21115411
Abstract
BACKGROUND:
Although imatinib mesylate has revolutionized the management of patients with
gastrointestinal stromal tumor (GIST), resistance and progression almost
inevitably develop with long-term monotherapy. To enhance imatinib-induced
cytotoxicity and overcome imatinib-resistance in GIST cells, we examined the
antitumor effects of the pro-apoptotic Bcl-2/Bcl-x(L) inhibitor ABT-737, alone and
in combination with imatinib.
METHODS:
We treated imatinib-sensitive, GIST-T1 and GIST882, and imatinib-resistant cells
with ABT-737 alone and with imatinib. We determined the anti-proliferative and
apoptotic effects by cell viability assay, flow cytometric apoptosis and cell cycle
analysis, immunoblotting, and nuclear morphology. Synergism was determined
by isobologram analysis.
RESULTS:
The IC(50) of single-agent ABT-737 at 72 h was 10 μM in imatinib-sensitive
GIST-T1 and GIST882 cells, and 1 μM in imatinib-resistant GIST48IM cells. ABT737 and imatinib combined synergistically in a time- and dose-dependent manner
to inhibit the proliferation and induce apoptosis of all GIST cells, as evidenced by
cell viability and apoptosis assays, caspase activation, PARP cleavage, and
morphologic changes. Isobologram analyses revealed strongly synergistic drug
interactions, with combination indices <0.5 for most ABT-737/imatinib
combinations. Thus, clinically relevant in vitro concentrations of ABT-737 have
single-agent antitumor activity and are synergistic in combination with imatinib.
CONCLUSION:
We provide the first preclinical evidence that Bcl-2/Bcl-x(L) inhibition with ABT737 synergistically enhances imatinib-induced cytotoxicity via apoptosis, and that
direct engagement of apoptotic cell death may be an effective approach to
circumvent imatinib-resistance in GIST.
Anthony P. Conley, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Wang WL, Conley A, Reynoso D, Nolden L, Lazar A, George S, Trent JC.
Mechanisms of Resistance to Imatinib and Sunitinib in Gastrointestinal
Stromal Tumor. Cancer Chemother Pharmacol. 2011 Jan;67 Suppl 1:S15-24.
Epub 2010 Dec 24. PMID: 21181476
Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal
neoplasm of the GI tract and one of the most common sarcomas, is dependent
on the expression of the mutated KIT or platelet-derived growth factor receptor in
most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by
directly binding into the ATP-binding pocket of the kinase. It is becoming
increasingly apparent that the binding affinity of imatinib for the receptor is
dependent on the type and location of mutation. Within KIT, patients whose
tumor has an exon 9 mutation are treated by many clinicians with higher doses of
imatinib than those patients with mutations within exon 11. Additionally, there are
over 400 unique mutations within exon 11 that may have distinctly different
binding affinity for imatinib as well as other kinases. Secondary KIT mutations
generally occur at a codon where imatinib binds resulting in KIT reactivation and
resistance. Sunitinib malate, a second-generation KIT inhibitor is active in
imatinib-resistant disease and is FDA-approved for use in this setting. In this
review, we describe the biology of the genes and gene mutations responsible for
GIST and discuss known and potential clinical implications.
Anthony P. Conley, MD (2010 – 2011)
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MD Anderson – Willie Tichenor Fellowship
Publications
Abstracts
Conley AP, Reynoso D, Yoo SY, Bloom G, Wang WL, Dumont A, Dumont S,
Gonzalez R, Reed D, Ravi V, Wang J, Pledger WJ, Zhang W, Trent
J. Paper #31 MicroRNA expression characteristics in imatinib-treated,
paired human GIST samples: a correlative study of ID03-0023. CTOS,
Chicago, IL, October 26-29, 2011. (Oral presentation)
Reynoso D, Alicie BM, Yang D, Wang WL, Dumont AG, Conley AP, Rubin BP,
Zhang W, Trent JC. Paper #28 BIM upregulation and downregulation of prosurvival Bcl-2 family members, correlate with apoptosis and disease-free
survival in GIST patients treated with imatinib. CTOS, Chicago, IL, October
26-29, 2011. (Oral presentation)
Park MS, Patel S, Ravi V, Conley AP, Trent JC, Lazar JF, Lev D, Wang X,
Benjamin RS, Araujo DM. The role of chemotherapy in advanced
hemangiopericytoma/solitary fibrous tumor. 2011 Annual ASCO Meeting.
A. Grand'Maison, J. M. Meis, R. S. Benjamin, S. Patel, V. RAV
TITLE: IMPACT OF CHEMOTHERAPY ON SURVIVAL IN PRIMARY
GASTROINTESTINAL ANGIOSARCOMAS, Scheduled for CTOS 2016, Salt
Lake City, UT
Min S. Park, MD and Anthony P. Conley, MD (2010 – 2011)
A. Grand Maison (2014 – 2015)
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