epigenetics (nilofer saba azad, m.d.)

8/7/2019 Epigenetics (Nilofer Saba Azad, M.D.)

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Epigenetics andEpigenetics andCancerCancer

Nilofer Azad, MDNilofer Azad, MDAssistant Professor, Gastrointestinal Oncology/Phase I ProgramAssistant Professor, Gastrointestinal Oncology/Phase I Program

Sidney Kimmel Comprehensive Cancer CenterSidney Kimmel Comprehensive Cancer Center

October 19, 2010October 19, 2010


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CMAJ 2006;174(3):341-8

Simplified Model of Epigenetic Regulation of Gene Expression


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Promoter Coding section Non-coding section Coding section

Protein

Complex

How do genes get turned on and off?

DNAof

Gene X

M M M

Gene is transcribed = ON

Gene blocked from being transcribed = OFF

Histone Histone

Protein

Complex


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DNA Methyltransferase

inhibitors Two currently FDA approved agents

5-azacytidine

(Vidaza)

5-aza-2'-deoxycytidine(decitabine, Dacogen)


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5-azacitidine

FDA approved in 2004 for myelodysplasia

Dose: 75 mg/m2

SQ daily x 7 d / 28 d cycle

Mechanism of action: Incorporated into DNA suicide

inhibitor of DNMT

Induces global hypomethylation

Time to clinical response: Average = 4 months


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Histone deacetylase inhibitors Three currently FDA approved agents

Vorinostat (Pan-HDACi)

(SAHA, Zolinza) Oral agentApproved for cutaneous T-cell lymphoma

Depsipeptide (Pan-HDACi)

(Istodax) Intravenous agent

Approved for cutaneous T-cell lymphoma

Valproic acid (weak inhibitor) anti-seizure


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LUNG CANCER


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Rationale for double epigenetic

blockage in lung cancer Epigenetic gene silencing mediated by DNA

methylation and histone deaceylation is a keycontributor to lung carcinogenesis

Preclinical studies suggest that combiningDMNTi with HDACi synergistically enhancesexpression of silenced tumor suppressor genes

Clinical studies combining DMNTi andHDACi have shown remarkable clinicalactivity in MDS/AML

Hypothesis: similar effect in NSCLC


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Trial Schema

5AC Dosing = 40 mg/m2 SQ daily on days 1-6 and 8-10 SNDX-275 dosing = 7 mg PO (fixed dose) days 3 and 10

Cycle length = 28 days

MS275

5-Aza

Day 1 8 15 22 29 36

SNDX-275

5-AC

Day 1 8 15 22 29 36


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Phase I Toxicity Data

0 2 4 6 8 10

Number of Patients

Injection Site ReactionNausea / Vomiting

ConstipationAnorexia

Lower Extremity EdemaHyperglycemia

Low ElectrolytesFatigue

Neuropathy

NeutropeniaLymphopenia

AnemiaThrombocytopenia

Phase I Toxicities

Grade 1

Grade 2

Grade 3


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Updated Response Data

28 Evaluable Patients 1 Complete Response

On treatment for 14 months

1 Partial Response

Responded for 8 months then new SCLCStill no progression of his NSCLC 9 months off epigenetic therapy

8 Stable DiseaseOne on treatment for 18 months;

Five treated for 4 months

One treated for 3 months then stopped due to schedule

One still being treated (on cycle 12 now)

17 Progressive Disease

8 Not evaluable (finished less than 1 cycle)

5 Actively being treated


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Overall Survival

Median OS: 8.2 months


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Images of patient with

Partial Response

58 year old male treated with 3 prior therapies; Chemotherapy refractorydisease. He completed 8 cycles.


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Images of patient with partial response:

liver metastases

Pre-treatment Cycle 2 Cycle 4 Cycle 8Pre-treatment Cycle 2 Cycle 4 Cycle 8


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Hypotheses for biology of the complete

responder

Fewer number of previous therapies

Higher serum level of 5-azacitidine

Epigenetics Responding patient was a previously resected stage I

NSCLC patient

Analysis of her tumor and mediastinal lymph nodes

found a methylation pattern that predicted she was at

high risk for early recurrence

Response

PD NE SD CR

5ACCmax(ng/mL)

0

500

1000

1500

2000

14500

15000

15500


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0 1 2 3 4 5

0.00

0.25

0.50

0.75

1.00

Negative (U)n=79

Positive (M)N=11

P


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Epigenetic Therapy Study Design: TreatmentEpigenetic Therapy Study Design: Treatment

SchemaSchema

2

1

5-Azacitidine 40 mg/m2 SQ Day 1-5, 8-10

Entinostat 7mg PO Day 3 and 10

Every 28 days, for 6 cycles

Intended Accrual: 172 patients

5-Azacitidine 40 mg/m2 SQ Day 1-5, 8-10

Entinostat 7mg PO Day 3 and 10

Every 28 days, for 6 cycles


Stage IA or IB

NSCLC s/p surgery

with curative intent

Stage IA or IB

NSCLC s/p surgery

with curative intent

R

A

ND

O

M

I

Z

E

R

A

ND

O

M

I

Z

EStandard Care


Standard Care


Within 4-8 weeks of

completing surgery


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Men

294,120

Women

271,530Available at: http://www.cancer.org.

Colorectal Cancer is Common 2009 Estimated U.S. Cancer Deaths

Colorectal cancer represents 2nd

leading cause of death

Lung and bronchus 31%

Prostate 10%

Colon and rectum 8%

Pancreas 6%

Leukemia 4%

Liver/bile duct 4%

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin Lymphoma 3%Kidney 3%

All other sites 24%

26% Lung and bronchus

15% Breast

9% Colon and rectum

6% Pancreas

6% Ovary

4% Non-Hodgkin lymphoma

3% Leukemia

3% Uterine corpus

2% Brain/other nervous system

2% Liver/bile duct

25% All other sites

Available at: http://www.cancer.org.


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Colorectal Cancer Staging

AdenomaPre-cancer lesion

Stage I

localized, not through muscularis

(muscle wall in the colon)

Stage II

through muscularis, but no lymph nodes

Stage III

cancer in nodes, but not other organs

Stage IV

metastatic (liver, lung, etc)

Stage III

Stage I-II

IV


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Stage I 15%

Stage II 20%30%

Stage III 30%40%

Stage IV 20%25%

Disease Stage at Time ofDiagnosis

Hamilton IM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;157.


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Copyright American Society of Clinical Oncology

Sargent, D. et al. J Clin Oncol; 27:872-877 2009

Risk of recurrence after primary

resection in Stage II and III Colon

Cancer

85% recur within 3

years

85%


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Metastatic Disease


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History of Treatment for Colorectal CancerHistory of Treatment for Colorectal Cancer

~1960: 5-FU is a cornerstone of first-line therapy; bolus/infusion

~1985: Addition of LV (biomodulator) to 5-FU bolus regimens

1998: Irinotecan as single agent approved as second-line

2000: Irinotecan approved as first-line in CRC (bolus IFL)

2001: Capecitabine approved as first-line in CRC in selected pts

2002: Oxaliplatin approved as second-line agent (FOLFOX)

2004: Oxaliplatin approved as first-line agent in infusional regimen

2004: Approval ofCetuximab (Erbitux) & Bevacizumab (Avastin)

2006: Approval of Panitumumab (Vectibix)

2008: KRAS mutations predict lack of benefit of EGFR mAbs


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Incremental Survival Advantage in First-Line

Metastatic Colorectal Cancer

No active drug

0 6 12 18 24

Median OS (mo)

~4-6 mo

12-14 mo

~ 15-16 mo

20.3 mo

?

~ 20 mo

5-FU/LV

FOLFOX4

IFL + bevacizumab

IFL

21.5 moFOLFOX/FOLFIRI

FOLFOX/FOLFIRI

+ biologics

Are we

hitting

a wallwith

current

drugs?


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Therapy for Advanced Colorectal Cancer:

Response rates and survivalFirst Line Second Line Third Line

- FOLFOX or - FOLFOX or - Irinotecan +

- CAPOX or - FOLIRI or Cetuximab

- FOLFIRI - Irinotecan alone - Cetuximab+/- Bevacizumab - Irinotecan/Cetuximab - Panitumumab

+/- Bevacizumab

Response Rates in Randomized Trials:

50-60% 15% 10%

Survival Benefit in Randomized Trials:

Yes Yes Yes


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Epigenetics in CRC

Many genes have silenced expression due to epigenetic

changes

Targeting epigenetically abnormal tumors may be more

effective than targeting abnormal mutations in genes

CRC may be uniquely appropriate for this strategy

A subset of colon cancer have more gene promoter

methylation

Ahuja et al.


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Combination Epigenetic Therapy

First study of epigenetic therapy in CRC

Primary Objective:

To determine the preliminary efficacy via tumor

shrinkage rate of the combination of 5-azacitadine

and entinostat in patients with metastatic colorectal

cancer

Secondary Objective:

To see what is happening in the tumor itself and

circulating cells in blood before and after treatment

with these drugs


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Study Schema28 days

C2d1C1d3entinostat

C1d1 C1d10entinostat

C2d3entinostat

C2d10entinostat

C3d1

= plasma sampling for research purpos

= tumor sampling for research purpos

5-aza days 1-5 and 8-10 q cycle5-aza days 1-5 and 8-10 q cycle


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Ongoing and Upcoming Studies

Lung Cancer

New schedule

Adjuvant treatment of early stage disease

Breast

Same schedule in triple negative and hormone

resistant metastatic cancer


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Conclusions

Despite progress, colon cancer is a still leading source of death

Epigenetic therapy offers a novel way to approach treating

cancer, based on the abnormal gene expression seen in cancers

compared to normal cells

We are presently enrolling a trial of patients with late-stagecolon cancer an treating them with epigenetic agents, 5-

azacitidine and entinostat


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BREAST CANCER


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Epigenetics and breast cancer

Multiple genes are methylated and thus

silenced in breast cancer1

ER, RAR beta, cyclin D, Twist,

RASSF1A, and HIN-1

1 Pu RT. Mod Pathol 2003;16(11):1095-101.


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Zebularine inhibits growth of

MDA-MB-231 cell lines aloneor in combination

Billam M.


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Clinical studies: Vorinostat in

MBC Phase 2


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SKCCC J0785/TBCRC 008

A Multi-Institutional Randomized Phase II Study

Evaluating Response and Surrogate Biomarkers to

Carboplatin and nab-Paclitaxel (CP) with or withoutVorinostat (SAHA) in HER2- Negative Breast

Cancer

Principal Investigator: Vered Stearns, MD

Fellow: Roisin Connolly, MB.BCh


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Eligible patients withlocally advanced or

metastatic breast cancer(up to 60)

Cohort A (up to 30)Triple-negative

5-AZA + entinostat

Cohort B (up to 30)Hormone-resistant5-AZA + entinostat

Disease

Progression atAny TimeCohort A or CohortB

5-AZA + etinostat +

hormonal therapy

Event Monitoring

MD discretion

Study schema


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Conclusions

Epigenetics is a new way to look at cancer

biology and therapy

Ongoing trials in major tumor types in themetastatic setting

Plans to move therapy into earlier stage

disease may be even more successful


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Acknowledgements

First and foremost, our patients

SU2C researchers

Research support staff at all our institutions

epigenetics (nilofer saba azad, m.d.)

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