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Funded Research

Mechanism of metastasis in a less common molecular subset of uveal melanoma

Mechanism of metastasis in a less common molecular subset of uveal melanoma

Mechanism of metastasis in a less common molecular subset of uveal melanoma

Jae Hyuk Yoo, PhD

Mentor Dean Li, MD, PhD; Martin McMahon, PhD
Award Type Career Development Award – CURE OM
Institution University of Utah
Donor Support CURE OM Junior fellowship award made possible by a grant from AstraZeneca

Description:

The major cause of death in uveal melanoma patients is the spread or metastasis of the cancer to other vital organs such as the liver. Although most patients do not show signs of metastasis at the time of diagnosis, eventually about 50% of patients will develop metastatic disease, which is almost invariably fatal. Recently, it has been shown that about 80% of uveal melanomas possess a mutation in one of two similar Gaq genes, known as GNAQ and GNA11. These mutations are known to drive the formation and growth of the tumors. We have recently shown that the activation of a particular protein known as ARF6 by these mutations controls all of the known signaling pathways that are involved in cancer formation and growth. However, the genes that control the spread of the cancer to other parts of the body are not known for either the cancers with these more common Gaq mutations or for the remaining 20% of uveal melanomas that do not have mutations in the Gaq genes. Given that metastasis of the cancer is the primary cause of death, it is very important to identify the molecular basis for this process. In an earlier study, we showed that activation of ARF6 also controlled the metastasis of cutaneous melanoma. Our preliminary data for the present study suggest that activation of ARF6 by the binding of WNT5A to the cell surface receptor ROR2 enhances the molecular signaling pathways downstream of ROR2 and that ARF6 accomplishes this role by helping to move ROR2 from the cell surface to the inside of the cell. We have preliminary data suggesting that ARF6 not only promotes the internalization of ROR2 but also its localization to the nucleus of the cell where it functions in unknown ways possibly to promote uveal melanoma metastasis. Although we have preliminary data for all of these ARF6 functions, we need to confirm these results and try to better understand the mechanisms that govern these functions. Our experiments are designed to establish the role of ARF6 in uveal melanoma metastasis and begin to tease apart the mechanism underlying them. During the course of these experiments, we will be testing the function of ARF6 by reducing its expression levels and by inhibiting its activation using a small molecule compound that directly targets ARF6. If our experiments are successful and we show that ARF6 plays a critical role in uveal melanoma metastasis, we will have not only identified a novel molecule that could be targeted to reduce metastasis, but we will have generated a proof of concept for future drug development by showing the efficacy of inhibiting ARF6 activation using a small molecule compound. Such a compound could be used as a template for development of even more potent and specific compounds that could become drugs for the treatment or prevention of uveal melanoma metastatic disease. 

Epigenetic effectors of tumor response to immune checkpoint inhibitors

Epigenetic effectors of tumor response to immune checkpoint inhibitors

Epigenetic effectors of tumor response to immune checkpoint inhibitors

Kunal Rai, PhD

Mentor Andrew Futreal, PhD
Award Type Career Development Award
Institution MD Anderson Cancer Center

Description:

Treatment of advanced melanoma with immunotherapy agents shows striking responses in some patients, however overall responses are low. In addition, a significant proportion of patients do not achieve a response at all. Hence, there is critical need to 1) identify biomarkers that may predict response and resistance to immune checkpoint blockade therapies and 2) Identify potential targets for combination treatment with immune check point blockade agents. We hypothesize that epigenetic processes in the tumors and immune cells play critical roles in governing the response to immune check point blockade. With our expertise in epigenomic technologies, we aim to 1) perform a systematic study of epigenomic content of tumors from responsive and non-responsive patients treated with anti-PD1 and 2) identify those epigenetic factors whose inhibition in combination with anti-PD1 treatment could enhance anti-tumor response of T-cells. Our study will provide insights into mechanisms of response and resistance to immune checkpoint blockade therapy. 

The role of the Anaphase-Promoting Complex in human melanoma

The role of the Anaphase-Promoting Complex in human melanoma

The role of the Anaphase-Promoting Complex in human melanoma

Mark Solomon, PhD

Award Type Established Investigator Award
Institution Yale University
Donor Support Funded by Ross and Jeanne Bierkan

Description:

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.