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. 

Team Awards – Alejandro Villagra, PhD

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. 

Established Investigator – CURE OM – Andrew Aplin, PhD

Mutations in a small number of genes are found in a large fraction of human melanomas. For instance, so-called “driver” mutations in the “famous” melanoma genes BRAF, NRAS, and CDKN2A, are each found in ~20-50% of melanomas. Less frequent driver mutations have also been reported. We’ve been studying a multi-protein complex called the Anaphase Promoting Complex (APC), which contains fifteen distinct proteins. Although none of the APC subunits is mutated at a high frequency in melanomas, collectively, about 30% of melanomas contain a mutation in at least one APC subunit, making the APC as frequent a target for mutation as the well-known drivers. The APC is an enzyme responsible for the elimination of certain regulatory proteins. These are not defective proteins, but rather proteins that have completed their functions and need to be removed before subsequent functions can occur. Our hypothesis is that a mutation-caused reduction in APC activity favors melanoma development. There are two key predictions of this hypothesis that need to be tested. First is that melanoma cells have reduced APC function, which we will test in patient-derived cell lines that are maintained at Yale. The second prediction is that the APC mutations seen in patients are responsible for reduced APC activity, rather than just being random mutations of no consequence. (Melanomas have a high frequency of such background mutations.) We will test this prediction by putting the same mutations into normal cells and testing whether they result in reduced APC activity. These studies will add to our basic understanding of the development of melanoma, lead to the development of new prognostic markers, and possibly reveal a novel therapeutic target.

Established Investigator Award – Mark Solomon, PhD