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Epigenetics and Cancer + Nilofer Azad, MD Assistant Professor, Gastrointestinal Oncology/Phase I Program Sidney Kimmel Comprehensive Cancer Center October 19, 2010. Simplified Model of Epigenetic Regulation of Gene Expression. CMAJ 2006;174(3):341-8. How do genes get turned on and off?.

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slide1

Epigenetics and

Cancer

+

Nilofer Azad, MD

Assistant Professor, Gastrointestinal Oncology/Phase I Program

Sidney Kimmel Comprehensive Cancer Center

October 19, 2010

slide3

How do genes get turned on and off?

Protein

Complex

Protein

Complex

M

M

M

DNA

of

Gene X

Promoter

Coding section

Non-coding section

Coding section

Histone

Histone

Gene is transcribed = ON

Gene blocked from being transcribed = OFF

dna methyltransferase inhibitors
DNA Methyltransferase inhibitors
  • Two currently FDA approved agents
      • 5-azacytidine(Vidaza)
      • 5-aza-2'-deoxycytidine (decitabine, Dacogen)
5 azacitidine
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 DNMTInduces global hypomethylation
  • Time to clinical response: Average = 4 months
histone deacetylase inhibitors
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
rationale for double epigenetic blockage in lung cancer
Rationale for double epigenetic blockage in lung cancer
  • Epigenetic gene silencing mediated by DNA methylation and histonedeaceylation is a key contributor to lung carcinogenesis
  • Preclinical studies suggest that combining DMNTi with HDACi synergistically enhances expression of silenced tumor suppressor genes
  • Clinical studies combining DMNTi and HDACi have shown remarkable clinical activity in MDS/AML
  • Hypothesis: similar effect in NSCLC
trial schema

MS275

SNDX-275

5

5

-

-

Aza

AC

Day 1 8 15

Day 1 8 15

22 29 36

22 29 36

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
updated response data 28 evaluable patients
Updated Response Data 28 Evaluable Patients
  • 1 Complete Response – On treatment for 14 months
  • 1 Partial Response

Responded for 8 months – then new SCLC

Still no progression of his NSCLC 9 months off epigenetic therapy

  • 8 Stable Disease One 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
overall survival
Overall Survival

Median OS: 8.2 months

images of patient with complete response
Images of Patient with Complete Response

56 year old woman with stage I lung cancer that was resected and treated with adjuvant chemotherapy.

She progressed after salvage chemotherapy with radiation at relapse.

She had a response after 2 cycles, continued improvement after 4;

14 cycles were given. She had 3 prior therapies for advanced disease.

images of patient with partial response
Images of patient withPartial Response

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

images of patient with partial response liver metastases
Images of patient with partial response: liver metastases

Pre-treatment Cycle 2 Cycle 4 Cycle 8

hypotheses for biology of the complete responder
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
slide17

Gene DNA Hypermethylation Markers Are Better for Prognosis than Standard Staging

p16 and H-cadherin

1.00

P<0.0001

Negative (U)

n=79

0.75

Stage 1

Proportion Disease-Free

0.50

OR = 25 fold

Positive (M)

N=11

0.25

Stage 3

Molecular Re-staging

0.00

0

1

2

3

4

5

Brock et al, 2008

Years After Surgery

epigenetic therapy study design treatment schema
Epigenetic Therapy Study Design: Treatment Schema

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

R

A

N

D

O

M

I

Z

E

2

Stage IA or IB NSCLC s/p surgery with curative intent

Standard Care

Intended Accrual: 86 patients

1

Within 4-8 weeks of completing surgery

slide20

Colorectal Cancer is Common

2009 Estimated U.S. Cancer Deaths

Men294,120

Women271,530

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

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

Colorectal cancer represents 2nd leading cause of death

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

slide21

Stage I-II

Colorectal Cancer Staging

Adenoma

Pre-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

IV

slide22

Disease Stage at Time of Diagnosis

Stage I 15%

Stage II 20%–30%

Stage III 30%–40%

Stage IV 20%–25%

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

slide23

Risk of recurrence after primary resection in Stage II and III Colon Cancer

85% recur within 3 years

85%

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

slide25

History 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 of Cetuximab (Erbitux) & Bevacizumab (Avastin)
  • 2006: Approval of Panitumumab (Vectibix)
  • 2008: KRAS mutations predict lack of benefit of EGFR mAb’s
incremental survival advantage in first line metastatic colorectal cancer

No active drug

~4-6 mo

5-FU/LV

12-14 mo

IFL

~ 15-16 mo

FOLFOX4

~ 20 mo

IFL + bevacizumab

20.3 mo

FOLFOX/FOLFIRI

21.5 mo

FOLFOX/FOLFIRI

+ biologics

?

0

6

12

18

24

Median OS (mo)

Incremental Survival Advantage in First-LineMetastatic Colorectal Cancer

Are we hitting a wall with current drugs?

slide27

Therapy for Advanced Colorectal Cancer:

Response rates and survival

First LineSecond LineThird 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

slide28

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.

slide29

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
slide30

Study Schema

28 days

C1d1

C1d3

entinostat

C1d10

entinostat

C2d1

C2d3

entinostat

C2d10

entinostat

C3d1

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

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

= plasma sampling for research purposes

= tumor sampling for research purposes

ongoing and upcoming studies
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
conclusions
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-stage colon cancer an treating them with epigenetic agents, 5-azacitidine and entinostat
epigenetics and breast cancer
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.

principal investigator vered stearns md fellow roisin connolly mb bch

SKCCC J0785/TBCRC 008A Multi-Institutional Randomized Phase II Study Evaluating Response and Surrogate Biomarkers to Carboplatin and nab-Paclitaxel (CP) with or without Vorinostat (SAHA) in HER2- Negative Breast Cancer

Principal Investigator: Vered Stearns, MD

Fellow: Roisin Connolly, MB.BCh

study schema

Eligible patients with locally advanced or metastatic breast cancer (up to 60)

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

Cohort A (up to 30)Triple-negative5-AZA + entinostat

Disease Progression at Any Time

Cohort A or Cohort B

5-AZA + etinostat + hormonal therapy

MD discretion

Event Monitoring

Study schema
conclusions39
Conclusions
  • Epigenetics is a new way to look at cancer biology and therapy
  • Ongoing trials in major tumor types in the metastatic setting
  • Plans to move therapy into earlier stage disease may be even more successful
acknowledgements
Acknowledgements
  • First and foremost, our patients
  • SU2C researchers
  • Research support staff at all our institutions