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Funded Research

Biomarkers to Predict Melanoma Patient Immunotherapy Outcomes

Biomarkers to Predict Melanoma Patient Immunotherapy Outcomes

Biomarkers to Predict Melanoma Patient Immunotherapy Outcomes

David Soto-Pantoja, PhD

Award Type Established Investigator Award
Institution Wake Forest University

 

Our immune system operates on a balance of cells that that can destroy infected or cancerous tissue with those that prevent attacking healthy tissue. This equilibrium is affected during cancer where cells that attack the tumor become inefficient allowing further growth, cancer spread (metastasis) and eventual demise of the patient. To address this problem researchers have developed drugs known as immune checkpoint inhibitors. These drugs re-invigorate cells known as T cells to attack the tumor. In patients with advanced melanoma treated with monoclonal antibodies targeting these immune checkpoints, 3-year survival increased by about 20%. However due to these drugs tipping the balance to a more hyperactive immune system it can cause side effects that are detrimental to the patient causing disruptions in treatment plans and efficacy. Currently methods are limited to predict or treat these side effects without limiting efficacy of the drugs therefore there is a great need to understand how these side effects emerge. The tumor microenvironment consumes aberrant levels of nutrients and release factors that can be felt by circulating cells. We believe that these changes can be sense by mitochondria which is the organelle in cells that regulates energy consumption. With new technological advancements we can measure how this organelle changes in function in patients. Our approach allows the bulk analysis of patient cells to test how their metabolism is affected as a consequence of immunotherapy. We theorize that patients that will develop side effects will also have a lower bioenergetic status. Our analysis will provide a marker to predict side effects before they develop and study genes that regulate metabolism to design clinical trials aimed at reducing the onset of side effects providing a personalized approach to improve outcomes in melanoma patients undergoing immune checkpoint therapy while preserving their quality of life.

Role of Core Fucosylation in the Resistance to Immunotherapy of Melanoma

Role of Core Fucosylation in the Resistance to Immunotherapy of Melanoma

Role of Core Fucosylation in the Resistance to Immunotherapy of Melanoma

Praveen Agrawal, PhD

Mentor Julio Aguirre-Ghiso, PhD
Award Type Career Development Award
Institution Albert Einstein College of Medicine

 

Despite recent therapeutic advances, melanoma remains a major burden that is expected to rise faster than any other cancer in the coming decades. Surgery is frequently curative when tumors are confined to the skin, however long-lasting and/or curative treatments are currently lacking for patients diagnosed with metastatic disease, that is, those whose tumors have spread to other organs. Novel-approved targeted agents have impressive initial efficacy in a subset of melanoma patients; however, therapeutic resistance has been almost universal. In contrast, immunomodulatory therapies can produce durable responses, but these occur rather infrequently and are often associated with significant toxicity, generate resistance to immunotherapy eventually, and are ineffective against melanoma with low immune-infiltrates. Collectively, these treatments have been unable to substantively reduce the mortality of metastatic melanoma patients, Thus, there is a clear need for new therapeutic targets and approaches. Proteins in the cell membrane often acquire sugar modifications, which shape the interactions between a tumor cell and its environment. For instance, these sugar branches modify the recognition of tumor cells by the immune system and their ability to invade and colonize other organs. We have found that certain enzymes that modify those sugar branches (called glycosyltransferases) are altered in melanoma patient tissues during melanoma dissemination in various organs. We plan to elucidate how those sugar structures and the enzymes in particular a specific type of glycosyltransferases known (FUT8) is responsible for interaction with immune cells in the tumor microenvironment and plays a role in immune escape. Elucidating the novel mechanisms of action by a-1,6 fucosyltransferase in melanoma will be of prime importance not only for our understanding of cancer biology but also to developing novel therapies for personalized medicine.

Applicability of the research. Inhibitors designed against specific glycosylation enzymes and glycosidases are already being used in the treatment of metabolic disorders (Zavesca for Gaucher’s disease) and infectious diseases (i.e. Relenza) and Tamiflu)). However, they remain relatively unexploited as anti-cancer agents, in part due to our partial understanding of the mechanism of action in various cancer. Our proposal will address this issue by identifying the mechanism of action of FUT8 against resistance to immunotherapy in melanoma. In addition, because sugar branches can be highly specific to tumor cells and trigger an immune response, they are ideal candidates for the development of small-molecule inhibitors. Therefore, our studies have the potential to open an unexplored avenue for melanoma therapy, alternative or complementary to current immunomodulatory strategies.

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Raquel Buj, PhD

Mentor Katherine Aird, PhD; John Kirkwood, MD
Award Type Career Development Award
Institution University of Pittsburgh

 

About 40% of melanoma patients have decreased p16, a tumor suppressor protein that inhibits cell proliferation. However, our laboratory and others have found that p16 can regulate other processes besides cell proliferation. Among them, recent indirect evidence suggests that loss of p16 is linked with resistance to immune checkpoint blockade (ICB) therapies, a current standard-of-care for melanoma patients. However, no study has directly demonstrated this relationship nor investigated a molecular reason. Understanding this link is critical to design efficient therapeutic regimens for the large subset of melanoma patients with decreased p16.

Our preliminary data using mouse models has shown for the first time, and in a direct manner, that melanoma tumors with decreased p16 are resistant to ICB therapies. Comprehensive analysis of these mouse tumors, as well as human melanoma tumors, showed that melanoma with decreased p16 increases the secretion of a protein called IGFBP-2. In some cancer models, IGFBP-2 has been shown to modify macrophages. Macrophages are a cell type that reside inside the tumor to help the body’s immune system fight tumor progression. Interestingly, we found that both human and mouse tumors with decreased p16 accumulate a specific type of macrophage, called alternatively-activated macrophages, that decreases the ability of the immune system to fight and can promote ICB resistance. Therefore, we think that increased IGFBP-2 in melanomas with decreased p16 promotes the observed ICB resistance. In this proposal, we aim to investigate whether limiting IGFBP-2 in melanomas with decreased p16 will avoid alternatively-activated macrophages accumulation and hence resensitize these tumors to ICB therapies.

Successful completion of these studies will improve the treatment for melanoma patients with decreased p16 (~40%) who are likely resistant to current standard-of-care ICB therapies.

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Rana Falahat, PhD

Mentor James Mule, PhD
Award Type Career Development Award
Institution Moffitt Cancer Center

 

Adoptive cell therapy (ACT) using naturally occurring tumor-infiltrating lymphocytes (TIL) can mediate durable tumor regressions and, in some cases, cure in patients with metastatic melanoma. However, its efficacy remains highly variable and patient-specific. Two most likely reasons why some patients do not respond favorably to this therapy include: 1) lack or loss of signals in tumor cells that make them visible to immune T cells and 2) lack or insufficient infiltration and presence of tumor-fighting T cells within tumors. An important signaling pathway that contributes to interactions between tumor cells and immune T cells is the type I interferon signaling pathway. The type I interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune T cells. One of the key molecules in the type I interferon signaling pathway is stimulator of interferon genes (STING). When activated, STING induces expression of molecules called T cell-homing chemokines that are critical for the recruitment and localization of immune T cells within tumors. We have recently discovered an important loss and defect in STING gene expression in melanoma cells which helps them to evade from immune T cell detection and destruction. We have also shown that this loss of STING expression in melanoma cells can be reversed with a clinically available demethylating drug. In this proposal, we will test a series of STING-activating and -restoring strategies to generate and empower autologous TIL expansion and function in mouse models of melanoma. We predict the findings from these studies will provide opportunities for future development of more effective T cell–based immunotherapies in patients with metastatic melanoma who do not currently benefit from these interventions.

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Stanley (Ching-Cheng) Huang, PhD

Mentor Alex Huang, MD, PhD
Award Type Career Development Award
Institution Case Western Reserve University

 

While significant progress has been made in developing new therapeutics to control melanoma, the promising clinical outcomes of immune checkpoint inhibitors have drastically shifted the paradigm of cancer treatment. However, a high rate of primary resistance impedes the efficacy of checkpoint inhibitor treatments. Therefore, there is an urgent need for a more detailed understanding of how immune cells govern melanoma progression, as it provides a critical foundation for developing novel interventions and targets to enhance current melanoma immunotherapies. Macrophages are the frontline soldiers of the immune system. Their role is to reduce pathogenic insults and alert other immune cells to an external attack. Macrophages need to adopt different types of defense modes (or armors) in order to carry out their diverse functions, from combating the different types of invading pathogens to fighting cancer. These modes are referred to as pro-inflammatory M1 and anti-inflammatory M2. It was recently found that changes in cell-intrinsic and extrinsic metabolism can alter the immunity mode adapted by macrophages to respond to the pathogenesis of cancer but the mechanism underlying decision-making is still elusive. We propose that an important metabolic network called “serine one-carbon metabolism” plays a crucial role in M2 macrophages, and can be controlled to win the fight against melanoma. By investigating this and the different ‘forces’ that shape macrophage immunity, we hope to understand how macrophages decide to choose their armor to eliminate cancer. The ultimate aim is the ability to harness macrophage immunity to develop new and effective immunotherapies for melanoma.