Principal Investigator/Program Director (Last, first, middle): Robertson, Gavin, P RESEARCH & RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3045-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 9750-Project_Summary.pdf Mime Type: application/pdf 7. * Project Narrative 488-Project_Narrative.pdf Mime Type: application/pdf 8. Bibliography & References Cited 9018-Bibliography_Ref_Cited.pdf Mime Type: application/pdf 9. Facilities & Other Resources 525-Facilities.pdf Mime Type: application/pdf 10. Equipment 8287-Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Robertson, Gavin, P Project Summary/Abstract Malignant melanoma is the most invasive and deadly form of skin cancer with no effective therapy to treat advanced disease, leading to poor survival rates. Targeted combinatorial therapeutics is needed that inhibit proteins or pathways causing melanoma. Regrettably, relatively few targets have been identified or no therapeutic agents are available to inhibit them. Recently, we identified elevated Akt3 activity occurring in ~70% of sporadic melanomas compared to normal cells. Functionally, active Akt3 reduces responsiveness of melanomas to agents that would normally kill via apoptosis, thereby promoting tumorigenesis and development of chemoresistance. Unfortunately, no agents are available to inhibit this important pathway in melanomas. Furthermore, it is unknown whether targeting Akt3 signaling would be therapeutically sufficient or whether a combinatorial approach targeting other melanoma causing proteins, such as V600EB-Raf, would be necessary for an effective therapeutic. Based on these important unanswered questions, the central hypothesis for this proposal is that targeting Akt3 signaling alone or in combination with V600EB-Raf inhibition would be an effective targeted approach for inhibiting melanoma. The hypothesis will be tested by: (1) characterizing the utility of novel synthetic isothiocyanate and isoselenocyanate derivatives that inhibit Akt3 signaling to reduce melanoma tumorigenesis and metastasis; and (2) determining the therapeutic potential of a combinatorial approach targeting Akt3 and V600EB-Raf signaling in melanomas. We are prepared to undertake the proposed research, having demonstrated that the Akt3 and V600EB-Raf pathways are |