discover personalized medicine: gordon mills, pd, phd

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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

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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

Targeted Therapy For Cancer

Tumor

Capitalizing on the vulnerabilities (Achilles Heel) of 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

Combination of a PI3Ki and a PARPi

Gerburg Wulf and SU2C PI3K in Women’s Cancer Team

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

Time on Treatment

PI3K Dream Team

http://pi3k.org

On study

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

TP53 is the most commonly mutated gene in the human genome

R273 R248

R175

R220

Ovary

Lung

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