Metastatic melanoma is one of the fastest growing tumor types in the US, especially in Veterans, and also is one of the most challenging malignancies to treat. While there has been some recent success for melanoma tumors that carry the BRAFV600 mutation, the response is transient and treatment is complicated by development of resistance as well as secondary tumors. Both BRAFWT and BRAFV600 melanoma tumors are eligible for treatment with CTLA-4 or PD1 antibody to boost the T cell response to tumor, only 20-30 percent of the tumors respond with the 2-4 month increase in overall survival. Our preclinical experiments have focused on stopping tumor growth by blocking cell cycle with the Aurora kinase A (AURKA) inhibitor, MLN8237. Most human melanoma tumors implanted into immune deficient mice respond strongly to therapy with MLN8237, but the drug largely induces senescence and slows tumor growth, but does not cause regression. We now have strong preliminary data showing that combining the AURKA inhibitor with inhibitors of MDM2 or activators of death receptors 4 or 5 (DR4, DR5) pushes the tumor cells rendered senescent by MLN8237 into apoptosis and causes tumor regression. We now want to carryout advanced pre-clinical studies using these combinations of therapy to treat human melanoma tumor implants into mice to test the hypothesis that combining AURKA inhibitor therapy with agents that stabilize p53 by inhibition its ubiquitination by MDM2 or agents that activate DRs will provide improved therapy for late BRAFWT melanoma or melanomas that develop resistance to BRAF inhibitors. There are 3 specific aims:
Aim I A: To characterize the effectiveness of combined therapy with the MDM antagonist, Nutlin-3a, and the AURKA inhibitor, MLN8237, for treatment of BRAFWT/p53WT, NRasmutant/p53WT, NRasWT/p53WT melanoma.
Aim I B. To examine the effect of the Nutlin-3a and MLN8237 combination treatment on the growth of BRAFV600 /p53WT melanoma tumor implants from patients that have developed resistance to BRAF inhibitors.
Aim II A. To characterize the effects of combined treatment with MDM2 antagonist Nutlin-3a and AURKA inhibitor MLN8237 on tumor microenvironment an on melanoma metastasis.
Aim II B. To evaluate the potential for boosting the antitumor response of myeloid cells to enhance melano-ma tumor cell death in association with MLN8237 and Nutlin-3a. We will express constitutively active IKK? in myeloid cells to push them into an antitumor phenotype. Melanoma tumors growing in mice with WT or constitutively active IKK? in myeloid cells will be treated with MLN8237 and Nutlin-3a and growth of tumor and metastatic properties of tumor will be evaluated.
Aim III A. To characterize the effectiveness of combining treatment with agonist for the death receptors DR4 and DR5 with MLN8237 for treatment of BRAFWT, NRAS WT or NRAS mutant melanoma tumors that are either p53WT or p53mutant.
Aim III B. To evaluate the effectiveness of combined DR5, DR4 agonists with MLN8237 for BRAF inhibitor resistant BRAFV600 melanoma.
Melanoma is one of the fastest growing tumor types in the US and current chemotherapy regimens for advanced metastatic melanoma are usually ineffective for >75% of the patients. Older men with extensive sun exposure are highly represented in the group of Americans comprising the 'melanoma epidemic'. Our Veteran population is increasingly affected due to age, sun and chemical exposure. Surgical intervention prior to the time of tumor invasion is the key factor for reduced fatality for this form of cancer. All current approaches to therapy for advanced metastatic melanoma have significant drawbacks and substantial side effects and toxicity. Aurora kinase inhibitors combined with agents that induce apoptosis may provide an effective therapeutic alternative for patients without BRAF mutation or for those with resistance to BRAF inhibitors. Results from this study will provide key information for better design of futur clinical trials which will provide improved treatment for Veterans experiencing malignant melanoma
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