discover personalized medicine: gordon mills, pd, phd
TRANSCRIPT
Sheikh Khalifa bin Zayed Al
Nahyan Institute for
Personalized Cancer Therapy John Mendelsohn Gordon Mills
Funda Meric-Bernstam Kenna Mills Shaw
DELIVERING ON THE PROMISE OF PERSONALIZED
MOLECULAR MEDICINE IN OVARIAN CANCER
Ovarian Cancer
Karst and Drapkin et al Faculty 1000 Medicine
High Grade Serous Ovarian Cancer
Is Probably Fallopian Tube Cancer
• 22,000 new cases and 15,500 deaths in the USA • Low grade and high grade tumors have distinct genomic
aberrations • Low grade and high grade tumors do not interconvert • HGSEOC is the most common and aggressive form of
ovarian cancer
DIFFERENT HISTOLOGICAL SUBTYPES OF OVARIAN CANCER INDICATE DIFFERENT THERAPEUTIC
OPPORTUNITIES
Serous
Endometrioid
Mucinous
Clear cell
High grade low grade
High grade low grade
Low grade serous
KRAS
Clear Cell
PIK3CA mutations
Endometrioid
ARID1A mutation and deletion
PARP inhibitors
Mucinous
Probably metastatic colon
High grade serous
p53, BRCA1/2 copy number
long tail of actionable mutations
Targeted agents
Bevaczumib
PARP inhibitors have now been
FDA approved
Interstrand crosslink Double-strand break
DNA alkylation O
6-alkylguanine Uracil
Abasic site 8-Oxoguanine
Single-strand break
Ionising radiation Antitumour agents Alkylating agents
Ionising radiation Oxygen radicals
Spontaneous reactions Antitumour agents
(6-4)PP Bulky adduct
CPD
UV light Polycyclic aromatic
hydrocarbons Replication
errors
A-G mismatch T-C mismatch
Insertion Deletion
Me
Recombinational repair (HR, NHEJ)
Direct reversal (AGT, MGMT)
Base excision repair
Nucleotide excision repair
Mismatch repair
Modified from Hoeijmakers, J. H. (2001) Nature 114, 366-374.
MAJOR MECHANISMS OF DNA DAMAGE AND REPAIR
O6BG PaTrin
PARPi DNA PKi ATMi
Normal Cells
DNA Damage
HR mediated-repair
BRCA1
Unknown factors
Rad51
RPA
Others factors
Death
DSB SSB
PARP mediated repair
BRIT1
ATM
PARP
Others factors
HR-deficient Cancer Cells
x
x
BRCA1
BRCA2
PARP inhibitors induce synthetic lethality in HR-deficient cancer cells
PARPness: Can we identify patients likely to benefit from PARP inhibitors
BRCA1/BRCA2 mutations Germline Somatic BRCA1/2 loss Other members of complex PTEN loss? ARID1A
HRD genomic scaring assay regional loss of heterozygosity CLIA assay in development HRD RNA predictor HRD protein predictor
PARP inhibitors
x
x
PARP inhibitors
x
x
DNA Damage
HR
mediated-repair
BRCA1
BRIT1
ATM
Unknown factors
Rad51
RPA
Others factors
Survival
DSB SSB
PARP mediated repair
BRCA2
PARP
Others factors
Aberrations in BRCA1/2 HR pathway in HGSOC (86% of 574 cases)
ATR, ATM, BRCA1/2 are needed for efficient repair
Loss of TP53BP1 reverses HR defect induced by BRCA1
deficit and protects from effects of DNA damage
TP53BP1 is downregulated by PI3K pathway inhibition
(RPPA arrays)
C11ORF30 = EMSY EMSY decreases BRCA2
PTEN contributes to HR and PARP sensitivity
0 50 100 150
02
040
60
80
100
Months Survival
% S
urviv
ing
Gene Set Not Altered
Gene Set Altered
Logrank test p−value: 0.000042
BRCA1, BRCA2, ATR ATM: homdel exp<-1 mut
C11ORF30: amp exp>1
PTEN: homdel, exp<-1 prot<-1 mut
TP53BP1: homdel mut exp<-1 prot<-1
Samples with BRCA1, BRCA2, or RAD51C deficiency
Samples with BRCA1 mutations
Samples with BRCA2 mutations
Samples with BRCA1 low expression or promoter methylation
Samples with RAD51C promoter methylation
Samples with intact BRCA1, BRCA2, and RAD51C
HRD-LOH score
HRD genomic scarring LOH Loss of heterozygosity Telomeric Allelic Imbalance
Large scale transitions
Myriad Hennessey
Abkevich et al, BJC, 2012
4.1 years
3.1 years
TCGA dataset median dicotomized p = 0.00006
HRD prognosticates overall survival
HRD score predicts PARPi response ARIEL2 Rucaparib
HRD Subgroup
Median PFS, mo (90% CI)
BRCAmut 9.4 (7.3, Not Reached)
HRD positive 7.1 (3.7, 10.8)
Biomarker Negative
3.7 (3.5, 5.5)
Subgroup Comparison
Hazard Ratio (90% CI)
BRCAmut vs Biomarker Negative
0.47 (0.35, 0.64)
HRD vs Biomarker Negative
0.61 (0.41, 0.92)
PFS by HRD biomarker status
Biomarker Negative
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (months)
PF
S
McNeish and colleagues ARIEL2
HRD positive
BRCAmut
UNEXPECTED HIGH RATE
OF FAILURE OF TARGETED
THERAPEUTICS Even for patients with the
biomarker only subpopulations of
patients benefit:
Usually short term
Three resistance mechanisms
Intrinsic (Genetic)
Selected (Genetic)
Adaptive (Homeostatic loops, cross talk
and bypass)
Rationale combinatorial therapy
Systems are robust to single
perturbations. Tumors exhibit
decreased robustness and may
be more sensitive to multiple
perturbations
Yarden and Lander
CHALLENGES TO
PERSONALIZED
TARGETED THERAPY
Ovarian Cancer
Breast Cancer
PI3K Dream Team
http://pi3k.org
77% OvCa gBRCA
57% BrCa gBRCA
Non mutant BRCA1/2 2 PR
One biopsy: ATR mutant
N=46
N=24
BKM and Olaparib
demonstrate marked
responses
15 COTI-2: A novel and effective p53 normalizing agent
N
NNH
S
N
N
N
• Novel small molecule
o Formula = C19H24N6S
o 3rd generation Thiosemicarbazone
• Discovered in a NSCLC screen
• Simple 3 step synthesis
• Active in >10 xenografts
• IND Approved
• Phase I trial pending
• NSC319726 p53 normalizer is a
thiosemicarbazone
• NSC319726 is a Zn chelator and transporter allowing refolding of a subset of p53 mutations
COTI-2 is active in naturally occurring p53 mutant lines in vivo
Intravenous Oral Established OVAR3 Ovarian Cancer Cell Line (R248Q)
75-100mm3 3xper week
COTI2 TP53 mutations in ovarian cancer
R248
G245
R273
Y220C
I195F R175H
C242
R273P/G
G245C/V
R175H/L
R248Q/W
C275S/F
C275