In spite of the progress made in the understanding of the biology, genetics and immunology of melanoma, the outcome for patients with advanced-stage disease has remained poor. A step forward toward better therapies was recently provided by the improvement in overall survival observed in melanoma patients treated with an anti-CTLA4 antibody. Attempts to further augment the efficacy of this treatment would still face however a variety of immunosuppressive factors operative in melanoma-bearing hosts. Among those, one that has gained much attention is the ability of melanoma tumors to induce T-cell tolerance. Our studies to date of the epigenetic regulation of T-cell unresponsiveness point to histone deacetylase inhibitors (HDI) as promising immunomodulatory compounds given their dual ability to influence the immunogenicity of melanoma tumors and enhance T-cell function. These observations together with our additional findings that HDAC6 and HDAC11 regulates melanoma immunogenicity and T-cell responsiveness respectively, provided the rationale to mechanistically address the role of HDACs in melanoma immunobiology. The hypothesis to be tested is therefore whether epigenetic manipulation of specific HDACs might augment the immunogenicity of melanoma cells and/or augment T-cell responses leading to breaking of immune tolerance and enhancement of the efficacy of CTLA4 blockade. The animal models, molecular and pharmacological tools we have in hands together with the access (through the Pathology Core of this SPORE) to human melanoma samples would allow us to gain insights into the role of HDAC6 in melanoma proliferation, survival and immunogenicity (Aim 1), and the role of HDAC11 in T-cell anti-melanoma immunity (Aim 2). In addition, the expertise provided by the Clinical Core will allow the successful completion of a Phase I clinical trial aimed to assess the safety and immunologic effects of HDAC inhibition in combination with an anti-CTLA4 antibody in patients with stage IV melanoma (Aim 3). The new knowledge to be generated by this team effort would lead to novel epigenetic-based immunotherapy that by overcoming the remarkable barrier of melanoma-induced T-cell tolerance would improve the efficacy of CTLA4 blockade.

Public Health Relevance

In 2012, metastatic melanoma remains largely incurable. As such, innovative therapies based in a better mechanistic understanding of melanoma immunobiology are greatly needed. We strongly believe that our project would lead to novel epigenetic-based approaches to overcome T-cell tolerance and potentiate further the efficacy of CTLA4 blockade in patients with metastatic melanoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
H. Lee Moffitt Cancer Center & Research Institute
United States
Zip Code
Rebecca, Vito W; Wood, Elizabeth; Fedorenko, Inna V et al. (2014) Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. Mol Cell Proteomics 13:1844-54
Kim, Sungjune; Ramakrishnan, Rupal; Lavilla-Alonso, Sergio et al. (2014) Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice. Cancer Immunol Immunother 63:1009-21
Smyth, Tomoko; Paraiso, Kim H T; Hearn, Keisha et al. (2014) Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models. Mol Cancer Ther 13:2793-804
Haarberg, H Eirik; Smalley, Keiran S M (2014) Resistance to Raf inhibition in cancer. Drug Discov Today Technol 11:27-32
Rebecca, Vito W; Smalley, Keiran S M (2014) Change or die: targeting adaptive signaling to kinase inhibition in cancer cells. Biochem Pharmacol 91:417-25
Johnson, Douglas B; Smalley, Keiran S M; Sosman, Jeffrey A (2014) Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin Cancer Res 20:4186-92
Rebecca, Vito W; Alicea, Gretchen M; Paraiso, Kim H T et al. (2014) Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma. Pigment Cell Melanoma Res 27:1154-8
Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53
Rebecca, Vito W; Massaro, Renato R; Fedorenko, Inna V et al. (2014) Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. Pigment Cell Melanoma Res 27:465-78
Fedorenko, Inna V; Fang, Bin; Koomen, John M et al. (2014) Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma. Melanoma Res 24:448-53