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Funded Research

Targeting genomic mechanisms of resistance to immunotherapy

Targeting genomic mechanisms of resistance to immunotherapy

Targeting genomic mechanisms of resistance to immunotherapy

Rizwan Haq, MD, PhD

Mentor F. Stephen Hodi, MD
Award Type Career Development Award
Institution Dana-Farber Cancer Institute
Donor Support With support from John and Amy McCarthy

Descriptions:

Immunotherapies, such as CTLA-4 or PD-1 inhibitors, have revolutionized the treatment of metastatic melanoma patients. However, a key challenge to optimize the opportunity provided by these therapies is the dramatically varied responses among different patients, or even among different tumors in the same patient. For example, only a minority of melanoma patients will benefit from PD-1 inhibitors, whereas the remainder of patients have either incomplete or no response. Understanding the mechanism of these varied responses has the potential to improve patient care by identifying patients who will respond, and identifying novel drug targets that overcome resistance. We have identified changes in hundreds of genes (mutations) associated with the emergence of resistance to PD-1 inhibitor immunotherapy. Unfortunately, the sheer number of genetic changes and their interdependence makes it difficult to ascertain how each one particular gene impacts immunotherapy response. To solve this problem, we have developed a unique tool that recreates any resistance mutation in mice within several weeks. The mice can be used to evaluate the impact of mutations associated with immunotherapy resistance, as well as creating a platform for testing therapies that overcome resistance. In this proposal, we will use this tool to (i) elucidate the role of hundreds of mutations we have associated with immunotherapy resistance; and (ii) test a novel strategy using drugs in clinical trials that may overcome resistance. Our approach shows promise to transform the way we understand and treat resistance to immunotherapy. 

Exploring neuritin-mediated immune suppression to improve melanoma therapy

Exploring neuritin-mediated immune suppression to improve melanoma therapy

Exploring neuritin-mediated immune suppression to improve melanoma therapy

Joseph Barbi, PhD

Mentor Sharon Evans, PhD
Award Type Career Development Award
Institution Roswell Park Cancer Institute
Donor Support Funded by the Draeger Family – Honoring Richard Arthur Draeger from his Family

Description:

Study Goals: Reveal how a molecule called neuritin supports a population of immune cells that actively interferes with the killing of melanomas; determine if therapies that block neuritin activity can slow or stop tumor growth in mice; and establish if such therapies are likely to improve the effectiveness of current anti-melanoma immunotherapies. Background: For the immune system to function properly, its destructive power must be controlled. Otherwise healthy tissues can be damaged by excessive or self-directed immune responses. Among the mechanisms keeping the immune system in check are so-called “regulatory” T cells (or Tregs). Through their ability to suppress the activity of other immune cells, Tregs restrain the immune system. Unfortunately, Tregs also accumulate in cancer patients and inhibit desirable anti-tumor immune responses. Unexpectedly, we found that Tregs highly express a molecule previously studied in nerves called neuritin. We also showed neuritin to be both important for Treg function and abundantly produced within mouse melanomas. Mice genetically lacking neuritin contained defective Tregs that allow for enhanced resistance to implanted melanomas. While the mechanism responsible for neuritin’s pro-Treg and pro-tumor effects remains unknown, our findings lead us to hypothesize that neuritin promotes the functions of Tregs and therefore can be targeted to improve ant-tumor immunity. Approach: We will examine the effects of neuritin on the function, fitness, and behavior of Tregs and other immune cells. Additionally we will implant melanomas into normal and mutant mice either lacking neuritin or engineered to express excessive amounts of it – revealing the effects of neuritin on tumor size and immune cell composition. Importantly, we will also test the anti-tumor effect of neuritin-blocking antibodies in melanoma-bearing mice. This experimental therapy will also be given in combination with proven immunotherapies to explore the potential for improved anti-tumor effects. Significance & Impact: The nature of neuritin’s suppressive function must be understood before it can be exploited as a therapeutic target. We propose to reveal the elusive mechanism behind neuritin’s function and take the first step in testing the therapeutic value of anti-neuritin antibodies. If successful, these studies will not only conceptually advance our grasp of Treg-mediated suppression in melanoma, they will also justify development and clinical testing of a new immunotherapy weapon. Innovation: We will reveal how neuritin, a completely unappreciated modifier of immune cell activity promotes melanoma growth in mice. We will also, for the first time to our knowledge, test neuritin-blocking therapy as a means to sabotage Tregs and enhance anti-tumor immunity in a preclinical melanoma model. In addition, targeting neuritin to enhance the efficacy of proven immunotherapy.

Targeting Elongation Factor-2 Kinase to Reinforce Melanoma Immunotherapy

Targeting Elongation Factor-2 Kinase to Reinforce Melanoma Immunotherapy

Targeting Elongation Factor-2 Kinase to Reinforce Melanoma Immunotherapy

Jin-Ming Yang, PhD

Award Type Established Investigator Award
Institution University of Kentucky

Description:

Melanoma, one of the most aggressive and fatal neoplasms, is responsible for over 80% of skin cancer-related deaths. As melanoma mostly expresses tumor-specific neo-antigens, immunotherapy such as adoptive cell transfer-based therapy (ACT) is considered a promising and effective treatment for this malignancy. Nevertheless, due to a variety of factors that weaken antitumor immunity, the clinical outcome of this therapy remains less satisfactory. Accumulating evidence suggests that metabolic status of both immune cells and tumor cells have great impact on effectiveness of ACT, and metabolic reprogramming may represent a new viable target for reinforcing the efficacy of immunotherapy. The objective of this project is to understand the role and importance of eukaryotic elongation factor-2 kinase (eEF-2K), a unique enzyme that regulates protein synthesis and is highly expressed in several types of neoplasm including melanoma, in regulation of anti-tumor immunity, and to determine the impact and implication of this kinase in immunotherapy for melanoma. We have revealed a critical role for eEF-2K in promoting aerobic glycolysis (Warburg effect) in cancer, and the underlying mechanism. Intriguingly, our recent preliminary studies showed that eEF-2K is critical for the survival of certain suppressive immune cells. As metabolic reprogramming such as aerobic glycolysis plays crucial roles in regulating immune response and tumor sensitivity to therapeutic intervention, we propose to investigate the roles and implication of eEF-2K in melanoma ACT. We hypothesize that the activity of eEF-2K promotes survival of suppressive immune cells and melanoma cells; targeting this kinase can reduce resilience of tumor and suppressive immune cells, hasten tumor cell death via enhancing the cytotoxicity mediated by CD8+ T cells. To test this hypothesis, we propose to investigate the precise role of eEF-2K in modulating tumor cell response to ACT, with the intent to devise novel approaches to improving the outcome of immunotherapy for patients with advanced melanoma. In Aim #1, we will investigate whether and how tumoral expression of eEF-2K affect tumor cell response to ACT; in Aim #2, we wish to assess and optimize the strategy of targeting eEF-2K for improving ACT against melanoma. The small molecule inhibitors of eEF-2K that we discovered (NH125) and obtained from Janssen (JNJ-978) may provide an exciting opportunity to test their effectiveness as novel modulating agents in immunotherapy. We anticipate that the proposed studies will not only reveal eEF-2K as a unique molecular determinant of anti-tumor immunity, but also lead to identification of novel and effective immune modulators (i.e., inhibitors of eEF-2K) for treatment of this intractable tumor through improving immunotherapy. 

GPER Signaling in Melanoma

GPER Signaling in Melanoma

GPER Signaling in Melanoma

Todd Ridky, MD, PhD

Award Type Established Investigator Award
Institution University of Pennsylvania

Description:

Melanoma immunotherapy works by stimulating immune cells to kill tumor. In many cases, immune cells are drawn to tumor by immunogenic proteins on the surface of tumor cells that are also present on normal skin melanocytes, but absent on other cell types. For this reason, many patients who respond to immune therapy also develop vitiligo in skin that is otherwise normal. We hypothesize that drugs that increase the amount of these immunogenic melanocyte proteins will make tumor cells more visible, and therefore more vulnerable, to killing by immune cells. In preliminary experiments we determined that G-1, a small molecule related to estrogen (but that doesn’t have regular estrogen effects) acts on melanoma cells to slow proliferation and increase expression of the immunogenic proteins. When given to mice with melanoma, G-1 cooperated with the immunotherapy drug aPD-1 to dramatically extend survival beyond that seen with either agent alone. The G-1 effects on melanoma cells are mediated through a specific cell surface receptor on the tumor cells called GPER that has not been targeted with FDA approved drugs for any condition. Thus G-1 may be the first example of an entirely new class of medicines that are useful against melanoma. When administered to animals, G-1 was extremely well-tolerated and no adverse side-effects or toxicity was observed. If successful, the studies described in this work will provide much of the data needed to start a melanoma trial to determine whether G-1 cooperates with currently used immunotherapy approaches to further extend survival.

MC1R-selective small melanocortin analogs for melanoma prevention

MC1R-selective small melanocortin analogs for melanoma prevention

MC1R-selective small melanocortin analogs for melanoma prevention

Zalfa Abdel-Malek, PhD

Award Type Established Investigator Award
Institution University of Cincinnati
Donor Support In Memory of John N. Decker

Description:

Melanoma is the deadliest form of skin cancer, and despite the exciting advancements in treatment, there is still no cure for late stage disease. The incidence of melanoma continues to rise, particularly in young adults. Therefore, there is an urgent need to develop effective melanoma prevention strategies that will reduce the morbidity and mortality associated with this aggressive tumor. Sun exposure is a main causal factor for melanoma, and skin pigmentation and DNA repair capacity are important determinants for melanoma risk. We propose to develop a melanoma chemoprevention strategy based on targeting the melanocortin 1 receptor (MC1R), a major regulator of pigmentation and DNA repair in melanocytes, the precursors of melanoma. Expression of loss-of-function variants of the MC1R gene is strongly associated with red hair, fair skin, poor tanning, and increased risk for melanoma. More than 24% of all melanoma patients are carriers of a loss-of-function MC1R variant. Additionally, almost 50% of the White population of the U.S.A. are carriers of one of many MC1R variants, which predisposes them to melanoma. These statistics underscore the significance of this gene as a melanoma susceptibility gene. We have developed small peptide analogs of a-melanocyte stimulating hormone (a-MSH), the physiological agonist of the MC1R. These peptides mimic a-MSH in enhancing repair of ultraviolet radiation (UV)-induced DNA damage, and stimulating pigmentation in human melanocytes in the absence of any UV exposure. Our peptides are unique in their high selectivity for MC1R, which should reduce any off target effects. We propose to develop these peptides in a topical formulation, and to test their efficacy in stimulating pigmentation and reducing UV-induced DNA damage in cultured human skin substitutes in vitro and in vivo. The translational outcome of this project, which is based on compelling and extensive data that we have generated, will have a huge impact on melanoma prevention in millions worldwide with high risk for melanoma, particularly those who are carriers of MC1R variants and/or mutations in other melanoma predisposition genes, such as CDKN2A (p16).