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：黑色素瘤是一种侵袭性疾病，直到最近才找到有效的治疗方法。由于传统化疗的影响有限以及免疫疗法调节一小部分患者临床病程的能力，晚期黑色素瘤的治疗历来落后于其他癌症。人们对导致黑色素瘤的体细胞遗传改变的了解不断加深，这引发了人们的希望：癌基因定向治疗可能在这种侵袭性疾病的治疗中发挥重要作用。 2002 年激活 BRAF 突变的发现'*'^' 为有效且选择性的药物抑制剂提供了第一个易于处理的靶标。然而，由于缺乏用于临床试验的此类药物，该领域多年来一直停滞不前，第一代 BRAF 抑制剂索拉非尼未能证明疗效。第一代高选择性 BRAF 抑制剂 PLX4032 和 GSK2118436 现已完成 1 期和 2 期测试，并在携带 BRAF 突变的转移性黑色素瘤患者中表现出前所未有的短期疗效'"^。60% 至 70% 的患者实现了在治疗过程的早期就有客观的反应，大约 90% 的患者实现了一定程度的肿瘤消退，然而，有证据表明单药治疗不会产生持久的临床益处。在晚期疾病的情况下，早期达到客观缓解的患者的中位缓解持续时间为 9 个月，而所有接受治疗的患者的总体中位无进展生存期为 6 至 7 个月。少于 10%）实现完全缓解或缓解持续 18 个月或更长时间，而与任何其他 BRAF 抑制剂相关的早期疗效结果与任何其他可用的晚期黑色素瘤疗法相比都非常有利，这些药物的监管批准正在等待批准。预计在不久的将来，显然需要研究耐药机制，以便在未来构建合理的联合治疗方案。总之，尽管选择性 BRAF 抑制剂在临床上取得了改变游戏规则的结果，但耐药性已成为该领域的中心问题：驱动新发耐药性和获得性耐药性的机制是什么？能否制定组合策略以尽量减少其出现？仅自主肿瘤细胞机制在起作用，还是 BRAF 突变黑色素瘤中的肿瘤微环境促进了“较小”抵抗逃避选择性 BRAF 抑制剂的抑制剂作用的路径