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Get ready for an exciting announcement for the melanoma community

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Funded Research

Understand metastasis of uveal melanoma in vivo via novel mouse models

Understand metastasis of uveal melanoma in vivo via novel mouse models

Understand metastasis of uveal melanoma in vivo via novel mouse models

Xiaonan Xu, MD, PhD

Award Type Career Development Award
Institution Moffitt Cancer Center

Uveal melanoma (UM) is the most common eye cancer in adults which originates from pigmented cells in the uvea of the eye. The major challenge in UM treatment is the high frequency of metastasis. Even with successful local treatment of the primary tumor in the early stage, up to half of UM patients will eventually develop distant metastasis, primarily to the liver. However, there currently is no available therapy to prevent or treat UM metastasis, and therapies that have proven effective in cutaneous melanoma such as targeted therapy and immunotherapy have little or no success in UM. This is because UM has a unique genetic landscape. Genetically engineered mouse models (GEMM) are among the best tools to recapitulate cancer initiation and progression. Therefore, I developed a novel UM specific GEMM that not only recapitulates human uveal nevus hyperplasia and melanogenesis, but also acts as a versatile platform for gene editing and metastasis tracking. In this project, I aim to unravel the mechanisms underlying UM metastasis using this novel UM mouse model.

Deciphering the role of APRIL/TNFSF13 in melanoma-associated TLS formation

Deciphering the role of APRIL/TNFSF13 in melanoma-associated TLS formation

Deciphering the role of APRIL/TNFSF13 in melanoma-associated TLS formation

Lilit Karapetyan, MD

Award Type Career Development Award
Institution Moffitt Cancer Center
Donor Support Silverstein Family Research Grant Challenge Women in Science Career Development Award and supported by the 3rd Annual GetNakedJax Event

The overall survival of a subset of patients with melanoma drastically improved with a type of treatment called immunotherapy, which activates the body’s immune system to fight cancer more effectively. To better understand which patients are most likely to benefit from such treatments it has become increasingly important to identify biomarkers that may be predictive of clinical outcomes. Our project aims to evaluate biomarkers called tertiary lymphoid structures (TLS) to determine their relationship to survival outcomes in patients with melanoma.

Targeting melanoma with engineered CD4+ T cells

Targeting melanoma with engineered CD4+ T cells

Targeting melanoma with engineered CD4+ T cells

Joshua Veatch, MD, PhD

Award Type Career Development Award
Institution Fred Hutchinson Cancer Center
Donor Support Funded by the Cavan Family Foundation

Both helper CD4 T cells and killer CD8 T cells are known to be involved in immune responses to cancer. Helper CD4 T cells assist immune responses to cancer by enhancing the function of killer CD8 T cells as well as innate immune cells and antibody producing B cells. Growing large numbers of T cells from a patient and re-infusing them can increase the number of tumor specific T cells and can benefit melanoma patients who have failed other treatments in particular variant melanomas, such as mucosal melanomas, that are less immunogenic. This proposal is focused on understanding how helper CD4 T cells function when used as a cellular therapy and trying to develop ways to engineer these cells to be more potent, using a mouse model of melanoma. The first part of the proposal is understanding how infused CD4 T cells function when the interactions between the T cells and their target antigens are weaker, such as is often the case in variant melanomas such as mucosal melanoma, and when they have to see their antigen targets indirectly through other immune cells in the tumor, as this is often the case in many human melanomas. The second part of the proposal is to engineer CD4 T cells to target additional inflammatory signals to tumors, in hopes that this will lead to greater activation of immune cells and destruction of the tumors. The results from these studies in mice will inform the design of clinical trials we are currently planning using CD4 T cells in human melanoma.

Immunogenic landscape and therapeutic targeting of NRAS public Neoantigens

Immunogenic landscape and therapeutic targeting of NRAS public Neoantigens

Immunogenic landscape and therapeutic targeting of NRAS public Neoantigens

Inaki Etxeberria, PhD

Award Type Career Development Award
Institution Memorial Sloan Kettering Cancer Center

Many cancer immunotherapy patients fail to respond or progress after initially experiencing tumor regression. More than 25% of melanomas carry activating mutations in the driver oncogene NRAS. Unlike other genomic variants of melanoma, NRAS mutant patients respond poorly to current immunotherapies and targeted agents; therefore, new therapies are urgently needed. A major gap in knowledge that limits the application of immunotherapy in NRAS mutant cancers is the identification of immunogenic targets selectively expressed by tumor cells and not normal tissues. This proposal seeks to develop new, mechanism-based immunotherapies to target melanoma and other common cancers with specific genetic alterations associated with resistance to current treatments. As part of these studies, new generalizable knowledge will be generated that improves our molecular understanding of how the adaptive immune system can distinguish between normal and transformed tissues.

Targeting an adaptor function of CDK6 to enhance melanoma immunotherapy

Targeting an adaptor function of CDK6 to enhance melanoma immunotherapy

Targeting an adaptor function of CDK6 to enhance melanoma immunotherapy

Poulikos Poulikakos, PhD

Award Type Established Investigator Award
Institution Icahn School of Medicine at Mt. Sinai

Immunotherapy has been remarkably successful in the treatment of melanoma, but not all patients benefit from therapy and its effects is in most cases temporary, followed by development of resistance. Immunotherapy largely relies on active and persistent T cells, and thus elucidating regulatory mechanisms of T cell function is of paramount importance to the development of more effective immune therapies. CDK4 and CDK6 are closely related kinases that are known to control cell cycle progression.  Recent studies reported that CDK4/6 inhibitors unexpectedly stimulate T cells and tumor immunity, but the underlying mechanisms remain incompletely understood. Efforts to translate these findings to the clinic have been disappointing thus far, with the combination of CDK4/6 inhibitors with immune checkpoint blockade showing modest efficacy and increased toxicities in clinical trials. Since CDK4/6 inhibitors both activate certain function of T cells, but they also block their proliferation, the path to clinically exploit the immunostimulatory properties of these drugs remains unclear. The overall objective of this application is to elucidate mechanisms underlying the immunostimulatory properties of CDK4/6 inhibitors, and to leverage those properties to potentiate melanoma immunotherapy.