DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted May 22, 2020

The rates of melanoma have been increasing over the past few decades; the American Cancer Society estimates that 100,350 new melanoma cases will be diagnosed in the United States in 2020. The average age of diagnosis is 65, but melanoma is also one of the most common cancers in young adults. This is of particular interest to the US military, as the majority of Service members are younger than 40. Additionally, over three million Service members were deployed to Afghanistan and Iraq between 2001-2014, and prolonged exposure to sunlight increases the risk of melanoma development. Although the use of immunotherapy has increased the survival rates of patients with metastatic melanoma, not all patients will respond to this type of treatment. Thus, it is imperative that additional treatment options be developed. For Fiscal Year 2019, the Melanoma Research Program funded four Concept Awards. This award mechanism supports the exploration of highly innovative and untested ideas that address important problems relevant to melanoma. Three of these projects are focused on identifying novel candidates for targeted therapy; the fourth project plans to analyze immune cells present in the sentinel lymph node biopsy to predict patients at risk for recurrence of the disease.

Epigenetic Regulation of Immunogenic Endogenous Retrovirus (ERV) by Histone Demethylase KDM5B in Melanoma

MRP
Dr. Shang-Min Zhang
Shang-Min Zhang, Ph.D., Yale University

Immune checkpoint blockade, such as anti-PD1 immunotherapy, has revolutionized the way melanoma patients are treated. However, there is a subset of patients who will not respond to anti-PD1 therapy. There is an urgent need to identify combination therapies to increase the number of patients responding to immunotherapy. Epigenetic changes, such as DNA methylation and histone modification, affect gene activity and expression and are a potential target for cancer treatment. Dr. Zhang will focus on the H3K4 demethylase KDM5B, which has been shown to be critical for melanoma’s continuous growth. Inhibiting KDM5B has been shown to up-regulate immunomodulatory pathways, suggesting that this could be a promising target to combine with immunotherapy. This project will determine whether and how KDM5B loss in melanoma cells could sensitize melanoma cells to immune checkpoint blockade.

Link:
Public and Technical Abstracts: Epigenetic Regulation of Immunogenic Endogenous Retrovirus (ERV) by Histone Demethylase KDM5B in Melanoma

Targeting the Oncoprotein RLIP as Novel Therapy for Melanoma

MRP
Dr. Sharad Singhal
Sharad Singhal, Ph.D., City of Hope Beckman Research Institute

Melanocytes are rich in oxidative stress enzymes, and these enzymes are increased further during melanomagenesis. This project will focus on RLIP, a cell membrane protein important for oxidative stress signaling, and whether it can be targeted to inhibit UV-induced melanomagenesis. Mice lacking the RLIP gene are highly resistant to cancer and exhibit no deleterious metabolic side effects. Using compounds that deplete, inhibit, or down-regulate RLIP will be used to ask two questions. First, does blocking RLIP result in anti-cancer effects? Secondly, does targeting RLIP inhibit UV-induced melanomagenesis? Growth inhibition of anti-RLIP compounds will be assessed using tumor xenografts in vivo, and the transcriptional pathways involved in RLIP inhibition will be analyzed. 

Link:
Public and Technical Abstracts: Targeting the Oncoprotein RLIP as Novel Therapy for Melanoma

Calcineurin-NFAT Axis Is a Potential Therapeutic Target for Uveal Melanoma Metastasis

MRP
Dr. Jae Hyuk Yoo
Jae Hyuk Yoo, Ph.D., University of Utah

Uveal melanoma is a rare form of cancer that develops from melanocytes in the eye. Approximately 50% of uveal melanoma patients will develop metastatic disease, most commonly to the liver. Once metastasis occurs, the prognosis is poor; however, there are currently no approved therapies for metastatic uveal melanoma. GNAQ and GNA11 are mutated in over 90% of uveal melanomas but remain difficult therapeutic targets. This project will investigate downstream effectors of GNAQ and GNA11 to identify potential targets for treating uveal melanoma. Dr. Yoo hypothesizes that the growth factors hepatocyte growth factor and insulin-like growth factor 1 (IGF1) hyperactivate ARF6 and downstream targets calceneurin and NFAT to promote tumor invasion and metastasis, and that inhibition of this pathway will significantly reduce liver metastasis.

Link:
Public and Technical Abstracts: Calcineurin-NFAT Axis Is a Potential Therapeutic Target for Uveal Melanoma Metastasis

Tumor-Draining Lymph Node B Cells as Regulators of Melanoma Progression

MRP
Dr. Eduarta K. Holl
Eduarta K. Holl, Ph.D., Duke University

Approximately 90% of patients with Stage I or Stage II cutaneous melanoma can be cured with surgical removal of the tumor. However, patients with recurrent metastatic disease have a poor prognosis. Many patients at the time of surgery undergo a sentinel lymph node (SLN) biopsy, a procedure to assess if the primary tumor has spread to the lymphatic system. The goal of this project is to extract information from the SLN biopsy to identify patients at high risk for tumor recurrence. Dr. Holl hypothesizes that B cell status in the SLN may predict prognosis. This study will potentially innovate how we identify and define biomarkers predictive of recurrence. 

Link:
Public and Technical Abstracts: Tumor-Draining Lymph Node B Cells as Regulators of Melanoma Progression

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Last updated Wednesday, October 7, 2020