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Funded Research

Regulation of the response to targeted inhibitors in uveal melanoma

Regulation of the response to targeted inhibitors in uveal melanoma

Regulation of the response to targeted inhibitors in uveal melanoma

Andrew Aplin, PhD

Award Type Established Investigator – CURE OM
Institution Thomas Jefferson University
Donor Support #CUREOM Unite! Grant and matching funds by Mark and Alison Weinzierl

Description:

Melanoma of the uveal tract (a region of the eye) is the most common ocular malignancy in adults and accounts for 5% of all melanomas. According to National Cancer Institute data, there are 4.3 new cases of uveal melanoma per 1,000,000 individuals in the U.S. per year. Very little is known about the initial causes and factors that contribute to progression in this disease. Approximately, 2,000 adults are diagnosed every year. Uveal melanomas are very aggressive cancers. Half of patients will develop metastasis within 15 years of diagnosis. Uveal melanomas typically metastasize to the liver and are invariably fatal. Despite recent breakthrough in cutaneous melanoma, there are no U.S. Food and Drug-approved (FDA) targeted therapies for uveal melanoma. A glimmer of promise has been provided by targeted therapeutic agents known as MEK inhibitors, but additional therapeutic agents must be added to a MEK inhibitor regimen to enhance the response rates and provide more durable effects in patients. This application will analyze ways in which the anti-tumor action of MEK inhibitors may be enhanced in uveal melanoma. At Thomas Jefferson University, we have access to unique uveal melanoma resources and a large patient population. Additionally, we are collaborating with others in the field to promote multi-institutional efforts. At the completion of our experiments, we expect to have identified resistance-promoting mechanisms to targeted inhibitors and provide the basis for the design of new therapeutic strategies for metastatic uveal melanoma. 

Use of selective HDACi to improve antibody blockade immunotherapy

Use of selective HDACi to improve antibody blockade immunotherapy

Use of selective HDACi to improve antibody blockade immunotherapy

Alejandro Villagra, PhD

Co-PI Eduardo Sotomayor, MD; Jeffrey Weber, MD
Award Type Team Awards
Institution George Washington University

Description:

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.