Dose Escalation of Topical Curcumin

1. Dose Escalation ofTopical Curcumin Christopher D. Lao, MD, MPH University of Michigan October 22, 2006 -Proposal was drafted and reviewed. -Interest but needed revisions. This is still ongoing -the final model may change depending on continued feedback from �you all� and others. -This was proposed because of my interest in melanoma prevention �but it was pointed out that this really could be used for skin cancer in general (I believe that is true). What we�re trying to do is establish the safety and absorption etc of a topical curcuminoid formulation. -THC was previously proposed, and although more potent antioxidant� there much less data compared to curcumin for its potential to adffect carcinogenesis -was less attractive to many reviewers -The concern was simply the yellow color. But anecdotally it appears that low concentrations of curcumin may be tolerable and preclinical data supports it�s potential effectiveness even at low doses. So- curcuminoid product is being pursued. I am meeting with the company Monday to discuss these issues. They own a cosmetic company that has experience in formulating cosmetically elegant products �and have offered in writing to produce and provide the drug in whatever formulation we need or want. -Proposal was drafted and reviewed. -Interest but needed revisions. This is still ongoing -the final model may change depending on continued feedback from �you all� and others. -This was proposed because of my interest in melanoma prevention �but it was pointed out that this really could be used for skin cancer in general (I believe that is true). What we�re trying to do is establish the safety and absorption etc of a topical curcuminoid formulation. -THC was previously proposed, and although more potent antioxidant� there much less data compared to curcumin for its potential to adffect carcinogenesis -was less attractive to many reviewers -The concern was simply the yellow color. But anecdotally it appears that low concentrations of curcumin may be tolerable and preclinical data supports it�s potential effectiveness even at low doses. So- curcuminoid product is being pursued. I am meeting with the company Monday to discuss these issues. They own a cosmetic company that has experience in formulating cosmetically elegant products �and have offered in writing to produce and provide the drug in whatever formulation we need or want.

2. Melanoma rates: increased compared other cancers Background & Significance MELANOMA 54,000 cases/yr Nearly 8000 deathsBackground & Significance MELANOMA 54,000 cases/yr Nearly 8000 deaths

3. Melanoma: Survival by Stage Defn Presentation Stage 0 in situ 15% Stage I 1mm2 48% Stage II 0 LN3 23% Stage III LN+ 9% Stage IV Mets 5% 5y Survival1 >97% 93% 65% 50% <10% Moajority present in early stage However �when advance dx is presen the outcomes are miserable Talking about a stage III patient �just has LN involved �often young person that has a 50% chance of living 5 years!! Attempting to make advances in metastatic dx Likely going to cure people in earlier stage / microscopic dx stage Potentially preventing disease from occuring in the first place Early Diagnosis My research is in chemoprevention but growing interest in molecularly targeted agents the Moajority present in early stage However �when advance dx is presen the outcomes are miserable Talking about a stage III patient �just has LN involved �often young person that has a 50% chance of living 5 years!! Attempting to make advances in metastatic dx Likely going to cure people in earlier stage / microscopic dx stage Potentially preventing disease from occuring in the first place Early Diagnosis My research is in chemoprevention but growing interest in molecularly targeted agents the

5. Non-melanoma issues Non-melanoma skin cancer Basal cell carcinoma Squamous cell carcinoma Low mortality High morbidity Health care cost Risk of metastasis Merkel cell carcinoma

6. Non-cancer issues Other skin disorders Psoriasis Aging Health of our youth

7. Risk factors for melanoma Family history Personal history Dysplastic nevi Multiple congenital nevi Immunosuppression Light skin, eyes (sun-sensitivity) UV RADIATION ALL above constitute a genetic predisposition UV radiation is likely involved in most melanomasALL above constitute a genetic predisposition UV radiation is likely involved in most melanomas

8. Ultraviolet Radiation Damages DNA Signature mutations have been seen in genes known to be associated with melanoma Induction of FREE RADICALS Impairs IMMUNE system Induces GROWTH FACTORs Damages surrounding keratinocytes LOSS of CONTROL melanocyte growth and function

9. fOdds ratios and 95% CIs for ever use of sunscreen for the 18 studies, sorted by first year of data collection; overall pooled estimate, based on a random-effects dose-response model; and pooled estimate including only studies that adjusted for sun sensitivity (n= 9) fOdds ratios and 95% CIs for ever use of sunscreen for the 18 studies, sorted by first year of data collection; overall pooled estimate, based on a random-effects dose-response model; and pooled estimate including only studies that adjusted for sun sensitivity (n= 9)

10. Sunscreen has not been clearly demonstrated to prevent melanoma in the US May be in the way its used Not reapplied regularly Sunscreen may increase the time spent in the sun. No data to support sun protection to prevent melanoma in the US Maybe it�s the way we use it?Sunscreen has not been clearly demonstrated to prevent melanoma in the US May be in the way its used Not reapplied regularly Sunscreen may increase the time spent in the sun. No data to support sun protection to prevent melanoma in the US Maybe it�s the way we use it?

12. Melanoma Carcinogenesis Genetic instbility 2. deregulated proliferation 3. invasive potential 4. met potential -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and Genetic instbility 2. deregulated proliferation 3. invasive potential 4. met potential -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and

13. Curcuminoids Major Yellow Pigment Extract of Tumeric Derived from Rhizome of Curcuma Longa Active metabolites Topical -> skin wounds and tumors Skin carcinogenesis models Originally used as a topical agent for medicinal purposes Over the last 10 -15 years models of skin carcinogenesis have demonstrated Originally used as a topical agent for medicinal purposes Over the last 10 -15 years models of skin carcinogenesis have demonstrated

14. Curcuminoids Inhibits PGE2, COX, LOX Inhibits NF?-B Inhibits tyrosine kinase and xanthine oxidase MELANOMA Topical curcumin inhibited TPA induced melanoma Inhibited lung metastasis in melanoma mouse model Originally used as a topical agent for medicinal purposes Over the last 10 -15 years models of skin carcinogenesis have demonstrated Originally used as a topical agent for medicinal purposes Over the last 10 -15 years models of skin carcinogenesis have demonstrated

15. Curcumin�s Potential in Melanoma -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and

16. Topical should reach target� still want to demonstrate that. May be more difficult to demonstrated that an agent has biologic effects if can�t confirm that it even reaches tissue. Topical bests demonstrates positive effect of agent � can work on delivery etc if worthwhileTopical should reach target� still want to demonstrate that. May be more difficult to demonstrated that an agent has biologic effects if can�t confirm that it even reaches tissue. Topical bests demonstrates positive effect of agent � can work on delivery etc if worthwhile

17. Background Summary Melanoma (and others) -> health problem Preclinical data and early human data supports curcumin�s anticarcinogenic activity in melanoma No human studies in skin Establishment of topical agent to allow future phase II/III studies to be performed for efficacy Studied extensively inpreclinical models -> active but limited in humans. Topical agent are being produced but no clinical studies have been performed. To determine the maximum tolerated dose and safety profile of topical tetrahydrocurcumin. Secondary Objectives: To determine the depth of absorption of topical tetrahydrocurcumin. To quantify curcumin in the skin after 3 weeks of topical tetrahydrocurcumin use. To determine the optimal topical tetrahydrocurcumin does based on its biologic activity. Studied extensively inpreclinical models -> active but limited in humans. Topical agent are being produced but no clinical studies have been performed. To determine the maximum tolerated dose and safety profile of topical tetrahydrocurcumin. Secondary Objectives: To determine the depth of absorption of topical tetrahydrocurcumin. To quantify curcumin in the skin after 3 weeks of topical tetrahydrocurcumin use. To determine the optimal topical tetrahydrocurcumin does based on its biologic activity.

18. Study Objectives Primary Objective To determine the MTD and safety profile of topical curcumin Secondary Objectives To determine the feasibility of measuring curcumin in human skin after repeated application Establish HPLC assays for curcumin in human skin Studied extensively inpreclinical models -> active but limited in humans. Topical agent are being produced but no clinical studies have been performed. To determine the maximum tolerated dose and safety profile of topical tetrahydrocurcumin. Secondary Objectives: To determine the depth of absorption of topical tetrahydrocurcumin. To quantify curcumin in the skin after 3 weeks of topical tetrahydrocurcumin use. To determine the optimal topical tetrahydrocurcumin does based on its biologic activity. Studied extensively inpreclinical models -> active but limited in humans. Topical agent are being produced but no clinical studies have been performed. To determine the maximum tolerated dose and safety profile of topical tetrahydrocurcumin. Secondary Objectives: To determine the depth of absorption of topical tetrahydrocurcumin. To quantify curcumin in the skin after 3 weeks of topical tetrahydrocurcumin use. To determine the optimal topical tetrahydrocurcumin does based on its biologic activity.

19. Stage 1 Schema Time to event continual reassessement Time to event continual reassessement

21. Phase Ib Schema 

23. Thanks. Questions?

25. Oral vs. Topical Topical directly applied to cells at risk Oral delivered to all tissues in the body Likely need some combination approach Lotions, shampoo, gels, pills, food Need to establish show that agents can reach the target and have an effect If sunscreens application doesn�t work? Why topical approach? If sunscreens application doesn�t work? Why topical approach?

28. Clinical Observation Duration of mutational events -take years adolscence, adult (popln at increased risk -> white males)Duration of mutational events -take years adolscence, adult (popln at increased risk -> white males)

29. Genetic Events of Melanomagenesis 5-25% CDKN2A 25-77% RAS 5-60% 10-80% BRAF Up to 100% 66% PTEN 32-67% CDKN2A 46-73% sporadic MM -> deletions in 9p21 region 25-50% familial MM Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi CDKN2A 46-73% sporadic MM -> deletions in 9p21 region 25-50% familial MM Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi

30. Molecular events in melanomagenesis CDKN2A Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi CDKN2A Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi

31. Possible Interventions CDKN2A Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi CDKN2A Early event 5-25% Dysplastic nevi PTEN 32-67% metastatic MM -> loss of chr10 Chromosomal rearrangements -> early event BRAF 66% MM mutations 80% -> single point mutation (Val599Glu) Up to 100% of RGP 10-80% in melanocytic nevi

33. Melanoma Carcinogenesis -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and -Melanoma histopath model has been proposed which appear to account for a percentage of melanomas - *Curcumin and metabolites: potent scavengers of free radical and ROS formation *Potent inhibitors of TF partipicating in proliferation and cell survival -Caspase 8bid cleavage, decer bcl 2 -MITO loss of mito membr potential ->release of cyt c -> caspase 9 activation -> caspase 3 activation -MAPK pathway �downstream of ras and braf �latter of which has been shown to be mutated in 2/3 of melanomas. Mutations have been shwon in early lesions although small samples. By far the most interesting exciting pathway to target in melanoma �for treatment and prevention. -curcumin has demonstrated farnesul transferase inhibitor activity, and

34. Background & Significance MELANOMA 54,000 cases/yr Nearly 8000 deathsBackground & Significance MELANOMA 54,000 cases/yr Nearly 8000 deaths

35. Melanoma: Survival by Stage Defn Presentation Stage 0 in situ 15% Stage I 1mm2 48% Stage II 0 LN3 23% Stage III LN+ 9% Stage IV Mets 5% 5y Survival1 >97% 93% 65% 50% <10% Moajority present in early stage However �when advance dx is presen the outcomes are miserable Talking about a stage III patient �just has LN involved �often young person that has a 50% chance of living 5 years!! Attempting to make advances in metastatic dx Likely going to cure people in earlier stage / microscopic dx stage Potentially preventing disease from occuring in the first place Early Diagnosis My research is in chemoprevention but growing interest in molecularly targeted agents the Moajority present in early stage However �when advance dx is presen the outcomes are miserable Talking about a stage III patient �just has LN involved �often young person that has a 50% chance of living 5 years!! Attempting to make advances in metastatic dx Likely going to cure people in earlier stage / microscopic dx stage Potentially preventing disease from occuring in the first place Early Diagnosis My research is in chemoprevention but growing interest in molecularly targeted agents the

41. Melanoma Carcinogenesis

42. Risk factors for melanoma Family history Dysplastic nevi Multiple congenital nevi Personal history Immunosuppression Light skin, eyes Sun-sensitivity UV radiation History of sunburns