Options for melanoma prevention: Is there a role for sulforaphane?

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Herbert Norris
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Cancer Institute Perspectives in Melanoma XV September 16-17, 2011 New York,

Chemoprevention for Melanoma: What s it going to take? II.

1 Options for melanoma prevention: Is there a role for sulforaphane? Sancy Leachman Director, Melanoma and Cutaneous Oncology Program, Huntsman Cancer Institute Perspectives in Melanoma XV September 16-17, 2011 New York, New York I have no conflicts of interest to declare. A Roadmap I. Chemoprevention for Melanoma: What s it going to take? II. Where do we currently stand along the pathway to prevention? III. Is sulforaphane a candidate p chemoprevention agent? 1

2 Chemoprevention for Melanoma: What s it going to take? How do we get here? 2

3 Without going through here? Systematic, rigorous pre-clinical evaluation. 3

4 Essential milestones before a large clinical trial: Targetable pathway of melanoma predisposition Relevant biomarkers of response to the agent Epidemiological support of the hypothesis Pre-clinical animal studies for toxicity AND efficacy in melanoma Ex vivo evaluation of the agent in human skin or nevi using biomarkers Early-phase human studies demonstrating bioavailability and efficacy (with biomarkers) in skin/nevi Cohort of high-risk patients; defined risk Use of risk stratification in final study design Where do we currently stand Where do we currently stand along the pathway to prevention? 4

Microarray analysis of MC1R response in melanocytes suggests a mechanism for activation of antioxidant genes Results indicated that expression of genes

5 Targetable pathway of melanoma predisposition #1: MC1R ligand binding (MSH) cytosol (activation domain) Schaffer and Bologna Arch Dermatol 2001;137: Microarray analysis of MC1R response in melanocytes suggests a mechanism for activation of antioxidant genes Results indicated that expression of genes controlled by the transcription factor Nrf2 was elevated in melanocytes treated with MSH Kadekaro et al., FASEB J Marrot L. et al., Pigment Cell Melanoma Res., 2008, 21, Song X. et al., Pigment Cell Melanoma Res., 2009, 22, Kokot A. et al., Endocrinology, 2009, 50,

6 The MC1R Pathway is Targetable MSH UVR camp MC1R Increased DNA Binding Nrf2 Decreased ROS Sulforaphane ARE Antioxidant gene expression -Decreased DNA damage -Decreased cell death Targetable pathway of melanoma predisposition #2: CDKN2A/p16 ARF DNA Damage HDM2 CHK1 CHK2 ATM ATR p53 p21, p27 Cyclin E CDK2 Cyclin A CDK2 S G2 DNA-PK DNA Damage ATM ATR Cyclin A CDK1 ARF p16 P-Rb CDK4/6 Cyclin D E2F G 1 M Cyclin B CDK1 Rb-E2F G 0 6

Novel oxidative Stress function for p16 identified RNAi knockdown of p16 leads to increased oxidative stress and reversed by an antioxidant RNAi knockdown of p16 results in increased oxidative DNA

7 Novel oxidative Stress function for p16 identified RNAi knockdown of p16 leads to increased oxidative stress and reversed by an antioxidant RNAi knockdown of p16 results in increased oxidative DNA damage Jenkins et al. Oncogene, July 2011 Melanoma: Where do we stand? MC1R variants confer 2-4 fold increased risk for melanoma 1 p16 mutation carriers have about a 76% lifetime risk for melanoma development 2 p16 mutation carriers that also have an MC1R variant are at even higher risk 3 Epidemiological support of the target pathway: Yes Cohort of high-risk patients: Yes, MC1R and p16 1. Palmer et al., Am J. Hum. Genet Bishop, et al., JNCI, Box et al., Am. J. Hum. Genet

8 Is sulforaphane a candidate chemoprevention agent? Isolation and characterization of sulforaphane (SF) - SF was isolated from broccoli sprouts in an effort to identify cancer chemoprevention agents that began with the observation that individuals who consumed cruciferous vegetables had lower incidence of cancer - A classic medicinal chemistry study of the medicinal utility of natural products; grind it up, chemically fractionate, and assay fractions for biological activity of interest Paul Talalay, Johns Hopkins 8

9 Sulforaphane recapitulates the pro apoptotic effects of MSH in melanocytes Antioxidant gene expression is a biomarker of response 7 Expressio on (Relative to co ontrol) Control SF FSK UV UV+SF UV+FSK Hmox1 TrxR1 Prdx1 9

Antioxidant gene expression in human epidermis ex-vivo ntrol) ion (Relative to co Express 7 6 5 4 3 2 1 0 2 MED blistering sunburn Con UV 2min UV 8min SF/UV SF Prdx1 Hmox1 Gpx2 TrxR1 UV

10 Antioxidant gene expression in human epidermis ex-vivo ntrol) ion (Relative to co Express MED blistering sunburn Con UV 2min UV 8min SF/UV SF Prdx1 Hmox1 Gpx2 TrxR1 UV = 2000 J/m 2 8 min SF/UV = 8 min UV Sulforaphane decreases human melanoma tumor volume in mice SK-Mel 31 athymic mouse xenografts STAT 3 Expression Courtesy of John Kirkwood 10

11 Essential milestones before a large clinical trial: Targetable pathway of melanoma predisposition Relevant biomarkers of response to the agent Epidemiological support of the hypothesis Pre-clinical animal studies for efficacy in melanoma Ex vivo evaluation of the agent in human skin or nevi using biomarkers Cohort of high-risk patients Early-phase human studies demonstrating bioavailability and efficacy (with biomarkers) in skin/nevi Use of risk stratification in final study design Summary I. Chemoprevention for Melanoma: What s it going to take? SCIENTIFIC RIGOR II. Where do we currently stand along the pathway to prevention? PHASE I (PILOT) III. Is sulforaphane a candidate p chemoprevention agent? YES 11

12 10/5/11 Acknowlegements Genotyping and qpcr analysisjennifer Campbell, Brad Graham, John Quakenbush Donor recruitment and tissue acquisitioncandace Larsen, Jeremy Sunseri MD, Jason Hawkes, Sally Tran Biomarker Bi k Pamela P l Cassidy C id MC1R - Ana-Luisa Kadekaro PhD, Zalfa Abdel-Malek PhD Funding- U of U Cancer Center Support Grant, Melanoma Research Alliance and the Huntsman Cancer Foundation Snake River Canyon near Jackson, WY 12

Prevention. Skin cancer is the most common cancer in the. The Science of. by Laura Brockway-Lunardi, Ph.D.

Prevention. Skin cancer is the most common cancer in the. The Science of. by Laura Brockway-Lunardi, Ph.D. 66 DERMASCOPE June 2012 The Science of Prevention by Laura Brockway-Lunardi, Ph.D. Skin cancer is the most common cancer in the U.S. with more than two million Americans diagnosed annually. Basal cell