Role of Tumor in Therapeutic Response and Resistance

肿瘤在治疗反应和耐药中的作用

基本信息

批准号：
8744881
负责人：
LYNDA CHIN
金额：
$ 45.12万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-07-31
项目状态：
已结题

项目摘要

Rationale: Melanoma is an aggressive disease for which there has not been an effective curative treatment until recently. The treatment of advanced melanoma has historically lagged behind that of other cancers due to the limited impact of conventional chemotherapy and the aibllity of immunotherapy to modulate the clinical course of a small percentage of patients. An increasing understanding of the somatic genetic alterations that give rise to melanoma has spawned hope that oncogene, directed therapy might prove valuable in the management of this aggressive disease. The discovery of activating BRAF mutations in 2002'*'^' provided the first tractable target for a potent and selective pharmacologic inhibitor. However, the field was stalled for years by the lack of such agents for use in clinical trials, with the first generation BRAF inhibitor, sorafenib, failing to demonstrate efficacy'^. The first generation of highly selective BRAF inhibitors, PLX4032 and GSK2118436, have now completed phase 1 and phase 2 testing and have demonstrated unprecedented short-term efficacy among patients with metastatic melanoma harboring a BRAF mutation'"^. 60 to 70% of patients achieve objective responses early in the course of therapy, and approximately 90% of all patients realize some degree of tumor regression. However, evidence that single agent therapy will not produce long lasting clinical benefit in the setting of advanced disease has also manifested with the median duration of response being nine months for those who achieve an objective response early on. and the overall median progression free survival being 6 to 7 months for all patients treated. Only a small subpopulation (fewer than 10%) achieves complete responses or has responses that last for 18 months or longer. While the early efficacy results associated with either of the BRAF inhibitors compares very favorably to any other available therapy for advanced melanoma, and regulatory approval for these agents is anticipated in the near future, there is clearly a need for research into the mechanisms of resistance so that rational combination regimens can be constructed in the future. In summary, despite the game-changing results in the clinics by the selective BRAF inhibitor, resistance has become the central question in the field: what are the mechanisms driving de novo and acquired resistance? Can combination strategies be developed to minimize its emergence? Are only autonomous tumor-cell mechanisms at play or does the tumor microenvironment in BRAF mutant melanoma promote paths of "lesser" resistance to escaping the inhibitor^ effect of selective BRAF inhibitor

理由：黑色素瘤是一种侵略性疾病，直到最近才进行有效的治疗方法。由于传统化疗的影响有限，并且免疫疗法对调节一小部分患者的临床过程，因此历史上，晚期黑色素瘤的治疗历来落后于其他癌症。人们对引起黑色素瘤的躯体遗传改变的越来越多的了解产生了希望，即致癌基因的指示治疗可能在这种侵略性疾病的管理中被证明是有价值的。 2002年激活BRAF突变的发现为有效和选择性的药理抑制剂提供了第一个可拖动的靶标。但是，由于缺乏这种用于临床试验的药物，该领域被停滞了多年，第一代BRAF抑制剂索拉非尼（Sorafenib）未能证明疗效'^。第一代高度选择性的BRAF抑制剂PLX4032和GSK2118436现在已经完成了第1阶段和第2阶段的测试，并且已经证明了携带BRAF突变的转移性黑色素瘤患者的前所未有的短期疗效，该患者的患者中有60％至70％的患者在疗法的早期中实现了一定程度的90％，并在疗程中实现了几乎90％的范围，并在疗程中实现了90％的水平。单个药物的治疗在晚期疾病的情况下不会产生持久的临床益处，而较早的反应持续时间为九个月，而整个中位数的自由疾病的生存率为6至7个月。比较与任何其他可用的晚期黑色素瘤疗法相比，预计在不久的将来会对这些药物进行监管批准，显然需要研究抗药性机制，以便将来可以构建理性组合方案。总而言之，尽管选择性BRAF抑制剂在诊所发生了改变游戏的结果，但阻力已成为该领域的核心问题：哪些机制是从头开始并获得了阻力？可以制定组合策略以最大程度地减少其出现吗？仅是在玩耍时的自主肿瘤机制，或者BRAF突变体黑色素瘤中的肿瘤微环境会促进“较小”耐药性逃避抑制剂的抑制作用^选择性BRAF抑制剂的效果