Cancer Biology Course
Tuesdays, 12 noon, Holden Auditorium
All students,Postdocs, faculty, staff welcome
WebSite: http:siteman.wustl.edu/physicianh/prof.education_online
Format: 45-55 min didactic/30 min discussion
Schedule for 2014 Course
Jan 21 Ratner Introduction
Jan 28 Ravi Salgia Novel targets in lung cancer
Feb 4 Shaw - BRAF
Feb 11 Wartman – personalized medicine
Feb 18 Romee-NK therapy
Feb 25 Charles Rudin – Lung treatments
Mar 4 Obi Griffith-druggable genome
Mar 11 Sleckman - DNA repair
Mar 18 Bose – HER 2
Mar 25 Frederick Appelbaum-AML
Apr 1 Uy – bispecific antibodies
Apr 8 Lim Cell signaling in lymphoma
Apr 15 Pearse –T cell metabolism in cancer
Apr 22 ? Guest Lecturer
Attendance of all sessions & active discussion esp during presentation classic paper
1.6 million new cases this year
21% decrease in cancer-related deaths in men
vs 1990s
12% decline in women
13 million cancer survivors alive in US
Cancer-related death rates decline 1.5%/yr
580,000 Americans died of cancer in 2013
Introduction
 History
 Principles of Cancer Biology
 Advances in Treatment
 Advances in Prevention
 Current Social Issues
See Perspectives in Nature Reviews in Cancer
JCO Jan 2014, Clinical Cancer Advances
deVita NEJM 2012 History of Cancer
Hanahan & Weinberg Cell, 2011
Cancer – Historical Perspective
1600 BC Egyptian physician record 1st description of breast cancer
460 BC
Hippocrates uses “carcinos” to describe tumors (Greek – crab)
129 AD
Galen attributes cancer to black bile
1660 Mastectomy for breast cancer
1713 Ramazzini noted lack of cervical ca but increased breast ca in nuns
1775 Pott describes scrotal cancer in chimney sweeps
1838 Muller describes cancer as abnormalities of cells
Boveri’s Predictions (1902)
Cell-cycle checkpoints (Hemmungseinrichtung: inhibitory
mechanism) that would allow cell division only when a specific
external stimulus is experienced by the cell.
The clonal origin of tumours.
.
Tumour-suppressor genes (Teilungshemmende Chromosomen), the
effects of which can be overcome by external signals, and which are
physically lost in progressively growing tumours.
Oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im
permanenten Übergewicht) during tumour development.
Tumour progression from benign to malignant, involving sequential changes of
increased growth-stimulatory chromosomes & loss of growth-inhibitory chromosomes.
Cancer predisposition through inheritance of chromosomes (genes) that are less able
to suppress malignancy.
Cancer predisposition through inheritance of genes that cause aberrant mitoses.
The role of wounding and inflammation in tumour promotion.
Loss of cell adhesion in metastasis.
Sensitivity of malignant cells to radiation therapy.
Therapeutic Targeting of the Hallmarks of Cancer
Pearse
Sleckman
AML (NEJM, 2013)
• 200 adult cases
• fewer mutations (13)
than most other adult
cancers
• average of 5 are in
genes that are
recurrently mutated
• 23 genes were
significantly mutated
• at least one driver in
nearly all AMLs
• mutation in one of 9 categories of genes relevant
for pathogenesis, including
transcription-factor fusions
(18% of cases), the gene
encoding nucleophosmin
(NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling
genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesincomplex genes (13%), and spliceosome-complex genes (14%)
• Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among
several of the genes and categories
Wartman, Griffith, Applebaum
Targeting BTK with
Ibrutinib in Relapsed CLL &
Mantle Cell Lymphoma
N Engl J Med 2013; 369:32 & 507,
For CLL, at 26 mos, PFS 75%,
OS 83%, For MCL PFS 13.9
mos
Lim
Ponatinib in Refractory CML
N Engl J Med 2012; 367:2075-2088
Patients who had chronic-phase CML with the T315I
mutation, 100% had a CR
Blinatumomab in patients with
MRD in B-lineage ALL
Blood 2012 120:5185-5187
bispecific single-chain (BiTE) Abs,
engages T cells for redirected lysis of
CD19+ target cells
ALL patients with persistent or
relapsed MRD, 80% MRD RR
Uy
Drug Approvals 2012-3, Heme Malignancies
Newly Approved
Carfilzomib
Pomalidomide
Omacetaxine
mepesuccinate
Ponatinib
Expanded
Indications
Vincristine
liposome
Lenalidomide
Progressive myeloma
For relapsed/refractory myeloma
Accelerated phase CML
CML or PH-pos ALL resistant to
prior TKI
Relapsed ALL
Mantle cell lymphoma
Romee
Drug Approvals 2012-3, Breast Cancer
Newly Approved
Pertuzumab
For HER2+ with trastuzumab +
docetaxel
TrastuzumabFor HER2+ metastatic breast cancer
DM1
Expanded
Indication
Everolimus
ER+ breast cancer with exemestane
Bose
CNS Tumors – mIDH1 Inhibitor
for Glioma, Science, 2013
• Impairs
xenograft
growth
• Promotes
astroglial
differentiation
• Inhibits
histone
methylation
CNS
Tumors 6
GBM
subtypes
Cancer
Cell, 2012
The Lancet, Volume 381, Pages 303 - 312, 26 January 2013
Regorafenib, Multifunctional inhibitor against VEGFR-2 & TIE2
OS 6·4 months in the regorafenib group vs 5·0 months in the placebo group
Nature Volume: 486, Pages: 532–536 (28 June 2012)
KRASm detectable in blood as early as 10 months before disease progression.
Early initiation of a MEK inhibitor as a strategy for delaying or reversing drug resistance
Nature Volume: 483, Pages: 100–103 (01 March 2012)
BRAF(V600E) inhibition causes feedback activation of EGFR
Melanoma cells express low levels of EGFR and not subject to feedback activation.
Might benefit from combination therapy consisting of BRAF and EGFR inhibitors
* TCGA-WNT/bCAT, RAS, PI3K, 2nd line BEV, CET adj not beneficial, ziv-aflibercept
Shaw
Drug Approvals 2012-3, Colorectal Cancer
Newly Approved
Ziv-aflibercept
Resistant colorectal cancer with
FOLFIRI
Regorafenib
Progressive colorectal cancer
Expanded
Indication
Cetuximab
1st line KRASwt colorectal cancer
Enzalutamide (MDV3100): N Engl J Med 2012; 367:1187
AR antagonist, 5x binding affinity vs bicalutamide, blocks nuclear translocation &
coactivator binding, OS 18.4 vs 13.6 months in placebo group
Abiraterone (17-OHase, C17:20-lyase) N Engl J Med 2013; 368:138
PFS 16.5 months with abiraterone–prednisone and 8.3 months with prednisone
Radium 223 (α emitter) N Engl J Med 2013; 369:213
OS 14.0 mos vs 11.2 mos with placebo
2 protons/2 neutrons, T1/2 = 11d, bone-seeking
Cabozantinib, JCO 2013; 31:412
72% regression in soft tissue lesions,
68% improvement on bone scan, 12% CR
PFS 24 weeks vs 6 weeks with placebo
57% had ≥ 50% reduced alk phos and C-terminal telopeptide of collagen I
67% improved bone pain, 56% decreased narcotic use
16% grade 3 fatigue , 12% HBP, 8% hand-foot syndrome.
Nature Genetics 2013;45:747
XAF1, XIAP and SRD5A1 as a predictive and actionable
signature for CRPC.
XAF1 = XIAP-associated factor
SRD5A1 = 3-oxo-5-alpha-steroid 4-dehydrogenase 1
Cell 2013; 155:1309
Induction of glucocorticoid receptor expression as a
common feature of drug-resistant tumors
Drug Approvals 2012-3, GU Cancers
Newly Approved
Enzalutamide
Docetaxel refractory prostate cancer
Ra223
For bone metastases of prostate
cancer
Axitinib
Renal cell carcinoma
Expanded
Indication
Abiraterone
Castration-resistant prostate cancer
 Cabozantinib delays
MTC progression
 Sorafenib reverses RAI resistance of DTC
 Panitumumab improves survival of HPV-neg
squamous cell cancers
 Freq abnormalities in squamous cell carcinomas in FGFR1, 2,
DDR2, EPHA2, PI3K pathways
 Adeno-p53 plus chemotherapy increases survival
in late-stage oral cancer
3 yr OS 88% vs 60%
Salgia, Rudin
Adenocarcinoma
Cell. 2012 Sep 14;150:1121-34
EFGRm and KRASm in founder clones
14 fusions, including RET, ROS1 and ALK &
novel metabolic enzymes
Cell-cycle and JAK-STAT pathways
altered with perturbations in 54 genes that
may be targetable with available drugs
Squamous Cell
Nature 489: 519–525 (27
September 2012)
Alterations in targetable
oncogenic pathways:
FGFR, DDR2, PI3K
Melanoma - Anti–PD-1 Antibody
N Engl J Med 2012; 366:2443-2454
RR 28% Melanoma ,27% Renal,
18% NSCLC
Additive to CTLA4 blockade
PTCHm, Vismodegib – SMOi,
fatigue
Weight loss, dysgeusia, m
spasms
ANG,
CYCD1,
Antiapoptosis
Drug Approvals 2012-3, Skin Cancers
Newly Approved
Vismodegib
Advanced basal cell ca
Dabrafenib,
BRAFm metastatic melanoma
Trametinib
Pazopanib for refractory soft tissue
sarcoma
Lancet 379:1879-1886, May 2012
OS 12·5 mos with pazopanib vs 10·7
months
multitargeted tyrosine kinase
inhibitor, with activity against
VEGFR1,2,3 & PDGFR
PD0332991 in Patients With
Advanced CDK4-Amplified WellDifferentiated or
Dedifferentiated Liposarcoma
JCO 2013 31:2024-2028
CDK4 is amplified in > 90% of welldifferentiated (WDLS) and
dedifferentiated liposarcomas
(DDLS); PFS 18 weeks, 1 PR
Regorafenib for refractory
GIST
Lancet 381:295-302, 2013
PFS was 4·8 months for
regorafenib and 0·9 months
for placebo
Circulating DNA instead
of bx
Drug Approvals 2012-3, Sarcomas
Expanded
Indications
Imatinib
Regorafenib
Pazopanib
Denosumab
Adjuvant GIST
Treatment-resistant GIST
Advanced soft tissue sarcoma
For giant cell bone tumor
Low-Dose CT Screening for Lung
Cancer (NEJM 2013)
 A total of 53,439 eligible participants were
randomly assigned to a study group (26,715 to lowdose CT and 26,724 to chest radiography)
 Lung cancer was diagnosed in 292 participants
(1.1%) in the low-dose CT group versus 190 (0.7%)
in the radiography group (stage 1 in 158 vs. 70
participants)
 Sensitivity and specificity were 93.8% and 73.4%
for low-dose CT and 73.5% and 91.3% for chest
radiography, respectively.
• NIH cut existing grants by 10%
• Eliminated 700 viable projects that
would otherwise have been
considered
• NIH budget declined 22% over last
decade
• Number of new
grants at lowest level
since 1998
• If sequester not
reversed, budget cuts
will continue until
2021
• LOBBY CONGRESS
Drug Shortages
Notify FDA re drug withdrawals
Economic incentives
Emphasis on Quality and Value in Cancer Care
Therapy only for pts who will benefit
Avoid imaging/biomarkers in early stage prostate &
breast ca
Avoid CSFs if <20% likelihood of febrile neutropenia
 Continued progress depends on access to clinical
trials and quality care
 Faster and smarter clinical trials utilizing
information technology
 Revitalize federal funding of clinical trials
 Examine potential impact of health care reform on
cancer disparities
 Assist FDA in addressing cancer drug shortages
 Improve advanced cancer care planning
 Highlight potential solutions for oncology
workforce shortages
 Assist UN in addressing cancer crisis in developing
counties