Mechanisms of uveal melanoma dormancy and targeted therapy tolerance

转移性黑色素瘤的临床图景自2009年以来取得了突破性进展。 靶向治疗和免疫治疗。这些治疗剂现在正在进入佐剂 布景。目前一个尚未得到满足的需求是了解黑色素瘤的生物学，这些黑色素瘤对这两种药物都不起作用 靶向或免疫疗法，以制定新的治疗策略。一种针对这些非 反应亚群为葡萄膜/眼黑色素瘤。进一步的并发症是近50%的葡萄膜 黑色素瘤患者最终会发展为晚期肝转移疾病，如果没有 在主要部位复发；然而，通常有几年到几十年的滞后期 原发肿瘤治疗与肝脏大转移的关系。这一观察结果 强调早期肿瘤细胞扩散(DTC)和远处休眠的临床重要性。 我们正在研究葡萄膜肿瘤休眠和对靶向抑制剂耐受性的细胞机制。 黑色素瘤。我们的目标是确定播散性葡萄膜黑色素瘤休眠的控制机制。 肿瘤细胞。机械性的洞察将导致新的目标方法；因此，我们的目标是提供预 葡萄膜黑色素瘤患者的新治疗组合的临床数据。异常的细胞周期调节 是癌症的一个显著特征。在葡萄膜黑色素瘤中，通过突变促进细胞周期进展 在鸟嘌呤核苷酸结合蛋白中，GNAQ和GNA11。选择性CDK4/6抑制剂是FDA- 已批准用于ER阳性/HER2阴性的乳腺癌，但用于葡萄膜黑色素瘤需要 优化药物组合和时间表。我们的目标是了解如何利用CDK4/6抑制剂 治疗葡萄膜黑色素瘤，并将其与针对休眠细胞和/或耐药的药物联合使用 坚持者。我们的目标是确定这些治疗诱导的药物耐受持久性的分子特征。 转移性葡萄膜黑色素瘤的细胞。在这个多PI R01中，协同是由我们建立的 已发表和正在进行的关于改变信号通路、细胞休眠、转移的合作 生物学和靶向治疗的反应。我们在休眠和黑色素瘤生物学方面的研究专长 相互补充，并与我们机构的临床优势相联系。我们的研究将决定如何 休眠和致癌信号通路决定葡萄膜黑色素瘤DCs的存活和静止 以及如何针对它们来防止转移性再生长。我们预计我们对机械的洞察力 葡萄膜黑色素瘤DTC和转移生物学将形成新的治疗选择的基础，在 不久的将来，可能会产生更有效和更持久的治疗反应。

The clinical landscape of metastatic melanoma has advanced rapidly since 2009 with the breakthroughs of targeted therapies and immunotherapy. These therapeutic agents are now moving into the adjuvant setting. A current unmet need is to understand the biology of melanoma that fail to respond to either targeted or immunotherapy in order to devise new treatment strategies. A paradigm for these non- responsive subsets is uveal/ocular melanoma. A further complication is that nearly 50% of uveal melanoma patients will ultimately develop advanced disease involving liver metastasis without recurrence at the primary site; however, there is often a lag period ranging from years to decades between primary tumor treatment and development of liver macro-metastasis. This observation highlights the clinical importance of early tumor cell dissemination (DTC) and dormancy at distant sites. We are studying the cellular mechanisms of tumor dormancy and tolerance to targeted inhibitors in uveal melanoma. We aim to identify mechanisms controlling dormancy in uveal melanoma disseminated tumor cells. Mechanistic insights will lead to novel targeting approaches; thus, we aim to provide pre- clinical data for new treatment combinations for uveal melanoma patients. Aberrant cell cycle regulation is a hallmark feature of cancer. In uveal melanoma, cell cycle progression is promoted through mutations in the guanine-nucleotide binding proteins, GNAQ and GNA11. Selective CDK4/6 inhibitors are FDA- approved in ER-positive/HER2-negative breast cancer but their use in uveal melanoma will require optimization of drug combinations and schedules. We aim to understand how to utilize CDK4/6 inhibitors in uveal melanoma and combine them with agents that target dormant cells and/or drug tolerant persisters. We aim to define the molecular signatures of these therapy-induced drug tolerant persisterp cells in metastatic uveal melanoma. In this multi-PI R01, synergy is provided by our established published and ongoing collaborations on altered signaling pathways, cellular dormancy, metastasis biology and response to targeted therapies. Our research expertise in dormancy and melanoma biology complement each other and link to clinical strengths at our institutions. Our studies will determine how dormancy and oncogenic signaling pathways dictate survival and quiescence of uveal melanoma DTCs and how to target them to prevent metastatic re-growth. We anticipate that our mechanistic insights into uveal melanoma DTCs and metastasis biology will form the basis for new treatment options that in the near future could result in more potent and durable therapy responses.