Role of Tumor in Therapeutic Response and Resistance

理论基础：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一直落后于其他癌症，这是因为传统化疗的影响有限，而且免疫疗法可以调节一小部分患者的临床病程。对导致黑色素瘤的体细胞基因改变的了解日益加深，这让人们产生了希望，即癌基因、定向治疗可能被证明在这种侵袭性疾病的管理中有价值。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易处理的靶点。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其疗效。第一代高选择性BRAF抑制剂PLX4032和GSK2118436现在已经完成了第一阶段和第二阶段的测试，并在携带BRAF突变的转移性黑色素瘤患者中展示了前所未有的短期疗效。60%到70%的患者在治疗过程早期达到客观反应，大约90%的患者实现了某种程度的肿瘤消退。然而，有证据表明，单一药物疗法在晚期疾病的背景下不会产生长期的临床益处，对于那些较早达到客观有效的人来说，有效时间的中位数为9个月。所有接受治疗的患者的中位无进展生存期为6-7个月。只有一小部分人(不到10%)达到完全应答或应答持续18个月或更长时间。虽然与BRAF抑制剂中的任何一种相关的早期疗效结果与任何其他可用的治疗晚期黑色素瘤的方法相比都非常有利，预计这些药物将在不久的将来获得监管部门的批准，但显然需要对耐药机制进行研究，以便在未来构建合理的联合方案。 综上所述，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，但耐药性已经成为该领域的中心问题：驱动从头产生和获得性耐药的机制是什么？能否开发组合策略，将其出现的可能性降至最低？BRAF突变型黑色素瘤的肿瘤微环境是否促进了逃避选择性BRAF抑制剂作用的“较小”抵抗途径？

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