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Therapeutic Strategies to Induce Dormancy in Disseminated Melanoma Cells

Maria Sosa, PhD

Mentor Marisol Soengas, PhD
Award Type Career Development Award
Institution Icahn School of Medicine at Mount Sinai
Donor Support Funded by the William H. Canon Foundation
Description:

Metastasis is the main cause of melanoma death. Current treatments mostly fail to cure metastasis. It is of common knowledge that disseminated cancer cells (DCCs) are the seeds of future metastasis. Once these DCCs arrive to secondary organs they undergo a dormancy program that involves cell cycle arrest or quiescence. DCCs could remain in this state for months to almost decades and they are able to survive current treatments. The reason is because most current therapies target anti-proliferative cells, thus dormant DCCs remain unaffected. Eventually these DCCs reactivate and they start forming metastases. After the detection of a melanoma lesion and treatment, patients enter a phase of remission in where no symptoms of disease are detectable and one can say that patients are “cured.” However, the majority of these patients will develop metastasis that will arise from DCCs. Clinical analyses suggest that dissemination of DCCs happens very early during melanoma progression. Therefore, understanding how DCCs enter dormancy and what makes them reactivate to form metastasis is of extreme significance to design novel treatments. We designed a protocol to reprogram tumor cells into long-term dormancy by combining an inhibitor of methylation plus retinoic acid. These reprogrammed dormant cells upregulated a transcription factor named NR2F1, which was responsible for the dormancy phase. We validated that NR2F1 could be used as a biomarker to determine dormancy status of DCCs in breast and prostate cancer patients. Moreover, the above-mentioned protocol is now part of a clinical trial to treat advanced cancer patients. In addition, previous results showed that patients with melanoma positive for a secreted factor named Midkine relapsed earlier than those patients that were negative for Midkine. Interestingly, when we blocked Midkine the levels of NR2F1 factor were upregulated reinforcing dormancy of DCCs and reducing metastasis formation. Thus, we propose a therapeutic strategy to keep those DCCs in a dormancy phase by blocking the reactivation signal (midkine) and inducing dormancy signals (NR2F1). We believe this treatment could stop DCCs from forming life-threatening metastases.