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Funded Research

Identification of molecular pathways that drive uveal melanoma metastasis

Identification of molecular pathways that drive uveal melanoma metastasis

Identification of molecular pathways that drive uveal melanoma metastasis

Bruce Ksander, PhD

Co-PI Rizwan Haq MD, PhD, Margarete Karg, PhD
Award Type Team Awards
Institution The Schepens Eye Research Institute, Inc., Dana-Farber Cancer Institute, Massachusetts Eye and Ear Infirmary
Donor Support This research award is made in honor of OM patient and advocate, Lindsay Zubeck, and is generously funded by the Family and Friends of the Zubeck and Miller families along with the fantastic OM community.

Uveal melanoma (UM) is a type of aggressive eye cancer that often spreads to the liver and has a poor prognosis. We don’t fully understand how UM spreads, which makes it difficult to develop targeted treatments. In this study, we created a new model of UM by injecting human cancer cells into the eyes of mice. This model consistently led to large liver metastasis, whereas other organs were not as strongly affected, mimicking how UM behaves in humans.

Our goal is to figure out the main factors that drive UM to spread and specifically target the liver. Firstly, we think a protein called hepatocyte growth factor (HGF) and its receptor c-Met might be important for the cancer cells to colonize the liver. We will use a gene editing technique called CRISPR to turn off c-Met and see if it affects the cancer’s ability to spread to the liver. Secondly, we believe that a pathway called NRF2, which is activated by a protein called MITF, is crucial for UM metastasis. We will use genetic methods and a new drug called DF-52A to investigate the role of NRF2 in the cancer’s ability to spread. We will monitor tumor growth and metastasis using imaging techniques and flow cytometry.

If successful, these studies could provide evidence for targeting c-Met and NRF2 as potential therapies to prevent UM from spreading. Additionally, our experimental model allows us to identify other pathways involved in the spread of UM. The findings from this research will improve our understanding of how UM spreads and help develop better treatments.

Evaluation of cutaneous immune related adverse events by morphotype

Evaluation of cutaneous immune related adverse events by morphotype

Evaluation of cutaneous immune related adverse events by morphotype

Kristen Richards, MD

Co-PI Noah Hornick, MD, PhD and Kristen Pauken, MD
Mentor Anisha Patel, MD, Padmanee Sharma, MD, PhD and Amy Moran, PhD
Award Type Team Awards
Institution M.D. Anderson Cancer Center and Oregan Health and Science
Donor Support MRF Breakthrough Consortium-Bristol Myers Squibb Young Investigator Research Team Award to Advance the Field of Translational Immuno-Oncology

The treatment of melanoma with checkpoint inhibitor (CPI) therapy has produced rapid and substantial gains in survival, and as a result, the indications for its use have steadily increased. As CPIs are used in more patients, and particularly as part of a neoadjuvant therapeutic strategy, the significance of the challenge presented by toxicities has also increased. Immune-related adverse events (irAEs), always a meaningful concern in the use of CPIs, can present with increased severity in the neoadjuvant setting, and can delay timely progression to surgery in addition to their impacts on morbidity, mortality, and the ability to maintain an uninterrupted course of CPI treatment. irAE in the skin, the most frequently affected organ, can present with a variety of morphologies that mimic a collection of naturally-occurring inflammatory dermatoses. The management strategies of these irAE is built on the treatment of their naturally-occurring namesakes. Much about the immunologic mechanisms of the irAE remains poorly understood, and as a result, management decisions are made empirically, to mixed results. Here, we propose to address this challenge by leveraging the distinct strengths of our team’s institutions and laboratories to compile a thorough characterization of the immune infiltrates across morphologies of cutaneous irAE, and compare these to the corresponding naturally-occurring dermatoses. Beginning with a substantial existing repository of patient samples, we will use sequential-slice tissue sections to generate paired single-cell and spatial transcriptomic analyses of both irAE and morphologically-matched dermatoses occurring outside the context of CPIs. This strategy will allow us to combine the power of single-cell resolution to generate information about population shifts and transcriptional program activation with the tissue-level context and cell-cell interaction mapping that spatial sequencing makes possible, generating in the process a first-of-its-kind library of transcriptional data across a class of immune-mediated skin disease. We will then interrogate this library to reveal features that connect irAE to (or distinguish them from) their naturally-occurring counterparts, along with those features that define cutaneous irAE as a class of toxicities to melanoma therapeutics. Building on these results, we will utilize multiplex RNA in situ hybridization, quantitative RT-PCR, and protein-level cytokine arrays to validate significant driver genes, while assessing the relationship between in-skin inflammatory response and patient-level shifts in circulating cytokine levels. Collectively, this work will represent a foundational step toward the understanding of the breakdown of selftolerance that is commonly a feature of the treatment of melanoma patients with CPI, and will provide mechanistic support for what are currently empiric treatment decisions that can determine the success of multiple CPI delivery strategies.

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.