Role of Tumor in Therapeutic Response and Resistance

肿瘤在治疗反应和耐药中的作用

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8744881
• 关键词: Automobile Driving; BAY 54-9085; BRAF gene; Clinic; Clinical; Clinical Trials; Disease; Future; Generations; Immunotherapy; In complete remission; Malignant Neoplasms; Metastatic Melanoma; Mutation; Oncogenes; Patients; Phase; Play; Progression-Free Survivals; Regimen; Research; Resistance; Role; Testing; Therapeutic; advanced disease; chemotherapy; inhibitor/antagonist; melanoma; mutant; neoplastic cell; resistance mechanism; response; tumor; tumor microenvironment

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，直到最近才有有效的治疗方法。晚期黑色素瘤的治疗在历史上落后于其他癌症，这是由于常规化疗的影响有限以及免疫疗法调节小部分患者的临床过程的能力。随着对引起黑色素瘤的体细胞遗传改变的了解的增加，癌基因定向治疗可能在这种侵袭性疾病的治疗中被证明是有价值的。2002年发现的激活BRAF突变为有效和选择性药理学抑制剂提供了第一个易处理的靶标。然而，由于缺乏用于临床试验的此类药物，该领域停滞了多年，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PLX 4032和GSK 2118436现已完成1期和2期试验，并在携带BRAF突变的转移性黑色素瘤患者中显示出前所未有的短期疗效。60%至70%的患者在治疗过程的早期实现了客观缓解，约90%的患者实现了一定程度的肿瘤消退。然而，也有证据表明，单药治疗在晚期疾病背景下不会产生持久的临床获益，早期达到客观缓解的患者的中位缓解持续时间为9个月，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。只有一小部分亚群（少于10%）达到完全缓解或缓解持续18个月或更长时间。虽然与任何一种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治疗方法相比非常有利，并且预计这些药物在不久的将来会获得监管批准，但显然需要研究耐药机制，以便将来可以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核心问题：驱动新发和获得性耐药性的机制是什么？是否可以制定组合战略，以尽量减少其出现？是只有自主肿瘤细胞机制在起作用，还是BRAF突变型黑色素瘤中的肿瘤微环境促进了“较小”抗性的路径，以逃避选择性BRAF抑制剂的抑制剂效应？