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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
4P50CA168536-04
Application #
9134704
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Phadke, Manali; Remsing Rix, Lily L; Smalley, Inna et al. (2018) Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Mol Oncol 12:74-88
Saglam, Ozlen; Naqvi, Syeda M H; Zhang, Yonghong et al. (2018) Female genitourinary tract melanoma: mutation analysis with clinicopathologic correlation: a single-institution experience. Melanoma Res 28:586-591
Eroglu, Zeynep; Chen, Y Ann; Gibney, Geoffrey T et al. (2018) Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAFV600E-Mutant Melanoma. Clin Cancer Res 24:5516-5524
Verduzco, Daniel; Kuenzi, Brent M; Kinose, Fumi et al. (2018) Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS-Wild-Type Melanoma Cell Lines. Mol Cancer Ther 17:73-83
Prieto-Granada, Carlos; Castner, Nicholas; Chen, Ann et al. (2018) Behavior of Cutaneous Adnexal Malignancies: a Single Institution Experience. Pathol Oncol Res :
Abate-Daga, Daniel; Ramello, Maria C; Smalley, Inna et al. (2018) The biology and therapeutic management of melanoma brain metastases. Biochem Pharmacol 153:35-45
Konno, Hiroyasu; Yamauchi, Shota; Berglund, Anders et al. (2018) Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 37:2037-2051
Eroglu, Zeynep; Ozgun, Alpaslan (2018) Updates and challenges on treatment with BRAF/MEK-inhibitors in melanoma. Expert Opin Orphan Drugs 6:545-551
Zhu, Genyuan; Brayer, Jason; Padron, Eric et al. (2018) OMIP-049: Analysis of Human Myelopoiesis and Myeloid Neoplasms. Cytometry A 93:982-986
Zhu, Genyuan; Nemoto, Satoshi; Mailloux, Adam W et al. (2018) Induction of Tertiary Lymphoid Structures With Antitumor Function by a Lymph Node-Derived Stromal Cell Line. Front Immunol 9:1609

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