Development of a dual small-molecule BCl-XL/BCL-2 inhibitor for non-small cell lu

描述（由申请人提供）：BCL 2L 1（BCL-XL）和MCL 1在实体瘤（包括NSCLC）中经常扩增。NSCLC对BCL-XL或MCL-1的成瘾性已通过靶向这些分子的遗传和分子方法得到证实。尽管ABT-263是目前最好的小分子BCL-2/BCL-XL抑制剂，已在BCL-2驱动的肿瘤如慢性淋巴细胞白血病中显示出临床疗效，但其在实体瘤中的活性非常有限，部分原因是其在细胞环境中拮抗BCL-XL的有效性较低。因此，迫切需要能够有效拮抗细胞BCL-XL和/或MCL-1的新型小分子，以开发高效的癌症治疗剂。本申请的目的是确定BM-1197（一种最近发现的高效小分子BCL-XL/BCL-2抑制剂）治疗NSCLC的治疗潜力。中心假设是BM-1197作为单一药物对BCL-XL成瘾的NSCLC亚组具有强抗肿瘤活性，并且当与可以中和MCL-1的药物组合时，在NSCLC中表现出更广泛的抗肿瘤活性。该假设基于令人兴奋的初步研究，其显示BM-1197：（1）通过在多种细胞系模型中靶向BCL-XL和BCL- 2有效地诱导细胞凋亡;（2）即使每周给药，也在肿瘤异种移植物模型中实现完全和持久的肿瘤消退;（3）引起小鼠中的短暂血小板减少，但在其他方面耐受良好;（4）在具有扩增的BCL 2L 1的NSCLC细胞系中表现出有效的抑制活性;（5）在显著比例的NSCLC细胞系中实现与多西他赛和最近FDA批准的MEK抑制剂曲美替尼的强协同作用;和（6）在直接比较中，比ABT-263在体外更有效和在体内更有效。为实现BM-1197作为一种新型、有效、个体化的NSCLC治疗药物的最终目标，本研究将实现三个具体目标：1）确定BM-1197作为一种单一药物在NSCLC中的体外和体内抗肿瘤活性，并确定其敏感性的分子决定因素; 2）在体外和体内确定BM-1197-多西他赛组合在NSCLC中的作用机制、抗肿瘤活性和潜在毒性;和3）在体外和体内确定BM-1197-曲美替尼组合在NSCLC中的作用机制、抗肿瘤活性和潜在毒性。 将采用多个互补的临床前模型，包括大量充分表征的NSCLC细胞系、细胞系来源的异种移植物和小鼠中患者来源的NSCLC异种移植物。该项目预计将在NSCLC的补充临床前模型中确定BM-1197的强抗肿瘤活性，并确定BM- 1197在单药和联合用药环境中敏感性的关键分子决定因素。BM-1197正在进行IND研究，并将很快进入临床试验。因此，该项目的成功将对BM-1197转化为NSCLC的新疗法产生重大影响。确定BM-1197敏感性的分子决定因素将极大地促进BM-1197作为NSCLC的新型个性化治疗的发展。

DESCRIPTION (provided by applicant): BCL2L1 (BCL-XL) and MCL1 are frequently amplified in solid tumors, including NSCLC. The addiction of NSCLC to BCL-XL or MCL-1 has been demonstrated by genetic and molecular approaches targeting these molecules. Although ABT-263, the current best small-molecule BCL-2/BCL-XL inhibitor, has demonstrated clinical efficacy in BCL-2-driven tumors, such as chronic lymphocytic leukemia, it has very limited activity in solid tumors, partially due to its less effectiveness in antagonizing BCL-XL in cellula context. Therefore, there is a critical need for novel small-molecules that can effectively antagonize cellular BCL-XL and/or MCL-1 for the development of highly effective cancer therapeutics. The objective of this application is to determine the therapeutic potential of BM-1197, a recently discovered highly potent small-molecule BCL-XL/BCL-2 inhibitor, for the treatment of NSCLC. The central hypothesis is that BM-1197 possesses strong antitumor activity as a single-agent against a subset of NSCLC addicted to BCL-XL, and exhibits a much broader antitumor activity in NSCLC when combined with drugs that can neutralize MCL-1. This hypothesis is based on the exciting preliminary studies, which show that BM-1197: (1) effectively induces apoptosis by targeting BCL-XL and BCL- 2 in a variety of cell line models; (2) achieves complete and persistent tumor regression in tumor xenograft models even with weekly dosing; (3) causes transient platelet reduction in mice, but otherwise is well-tolerated; (4) exhibits potent inhibitory activity in NSCLC cell lines with amplified BCL2L1; (5) achieves strong synergy with docetaxel and the recently FDA-approved MEK inhibitor trametinib in a significant proportion of NSCLC cell lines; and (6) in direct comparison, is more potent in vitro and more efficacious in vivo than ABT-263. To achieve the ultimate goal of developing BM-1197 as a new, effective, and personalized medicine for NSCLC, three specific aims will be pursued: 1) determine the antitumor activity of BM-1197 as a single agent in NSCLC in vitro and in vivo and identify the molecular determinants for its sensitivity; 2) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-docetaxel combination in NSCLC in vitro and in vivo; and 3) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-trametinib combination in NSCLC in vitro and in vivo. Multiple complementary preclinical models, including a large panel of well-characterized NSCLC cell lines, cell lined-derived xenografts, and patient-derived xenografts of NSCLC in mice will be employed. This project is expected to establish the strong antitumor activity of BM-1197 in complementary preclinical models of NSCLC and identify key molecular determinants for the sensitivity of BM- 1197 in the settings of single agent and combinations. BM-1197 is undergoing IND-enabling studies and will enter clinical trials shortly. Therefore, the success of this project will have a significant impact for translation of BM-1197 into a new therapy for NSCLC. Identifying the molecular determinants for the sensitivity of BM-1197 will greatly facilitate the development of BM-1197 as a novel personalized therapy for NSCLC.