Targeting RET in Lung Cancer

描述（由申请人提供）：癌症中的致癌基因组改变是极好的治疗靶点。引人注目的临床实例包括非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）的体细胞突变、黑色素瘤中的BRAF突变和慢性髓性白血病中的BCR-ABL易位。在所有情况下，强效和选择性激酶抑制剂已显示出显著的临床活性，并且是目前的治疗标准。技术的改进加上人类基因组的测序，已经导致鉴定出具有临床显著致癌改变的罕见癌症亚群。约3%的NSCLC患者发生间变性淋巴瘤激酶（ALK）重排。克唑替尼是一种ALK抑制剂，在ALK重排的NSCLC中具有临床有效性，并且在其最初发现后仅4年就被专门批准作为这种遗传定义的癌症患者子集的治疗。这种从发现到临床实施的快速进展，得到了癌症患者系统基因分型的帮助，现在在包括DFCI在内的许多机构都是常规的。RET是跨膜受体酪氨酸激酶，通常在神经嵴和泌尿生殖道来源的细胞中表达。它在约50%的甲状腺髓样癌（MTC）中突变，在约35%的甲状腺乳头状癌中重排。此外，RET突变是家族性癌症综合征多发性内分泌瘤2A型（MEN 2A）、2B型（MEN 2B）和家族性甲状腺髓样癌的基础。Vandetinib是一种多靶点激酶抑制剂，也可抑制RET，是一种基于III期临床试验的MTC批准疗法。我们最近在NSCLC患者的一个子集中发现了RET（KIF 5 B-RET）的重排。该融合基因在体外是致癌的，并且转化的细胞对多靶向激酶抑制剂敏感， 抑制RET。因此，RET抑制剂在NSCLC患者人群中也可能具有临床有效性。在这里，我们提出了关键的研究，将通知RET抑制剂的临床部署，如调查致癌形式的RET的癌症生物学，研究肺癌中RET改变的发生率，并制定策略，以确定临床研究的患者。此外，目前批准的抑制RET的激酶抑制剂或临床开发中的激酶抑制剂都不是RET的特异性抑制剂。因此，开发更有效和选择性的RET抑制剂可能对治疗甲状腺和携带RET基因组改变的NSCLC患者具有治疗意义。我们计划通过以下具体目标实现这些目标。目标1：建立RET的致癌特性;目的2：开发具有效力、选择性和药理学特性的RET抑制剂，使其能够用于细胞和体内模型;目的3：开发和评价体内治疗RET基因组改变的癌症的策略。这些研究的发现对RET基因组变异的癌症患者具有治疗意义，并促进了此类患者临床试验的发展。

DESCRIPTION (provided by applicant): Oncogenic genomic alterations in cancer are excellent therapeutic targets. Compelling clinical examples include somatic mutations in the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC), BRAF mutations in melanoma, and BCR-ABL translocations in chronic myeloid leukemia. In all instances, potent and selective kinase inhibitors have demonstrated significant clinical activity and are currently the therapeutic standard of care. Improvements in technology coupled with sequencing of the human genome, has led to identification of rare cancer subsets that harbor clinically significant oncogenic alterations. Rearrangements of the anaplastic lymphoma kinase (ALK) occur in ~ 3% of NSCLC patients. Crizotinib, an ALK inhibitor, is clinically efficacious in ALK rearranged NSCLC and was specifically approved as a therapy for this genetically defined subset of cancer patients in just 4 years after its initial discovery. This rapid progress, from discovery to clinical implementation, has been aided by systematic genotyping of cancer patients, now routine at many institutions including at the DFCI. RET is transmembrane receptor tyrosine kinase that is normally expressed in cells derived from neural crest and the urogenital tract. It is mutated in ~ 50% of medullary thyroid cancer (MTC) and rearranged in ~35% of papillary thyroid cancer. In addition, RET mutations underlie the familial cancer syndromes multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN 2B) and familial medullary thyroid cancers. Vandetinib, a multitargeted kinase inhibitor that also inhibits RET, is an approved therapy for MTC based on a phase III clinical trial. We recently identified a rearrangement in RET (KIF5B-RET) in a subset of NSCLC patients. This fusion gene is oncogenic in vitro and the transformed cells are sensitive to multi-targeted kinase inhibitors that inhibit RET. Thus RET inhibitors may also be clinically effective in this population of NSCLC patients. Here we propose critical studies that will inform the clinical deployment of RET inhibitors such as investigating the cancer biology of oncogenic forms of RET, studying the incidence of RET alterations in lung cancers and developing strategies to identify patients for clinical studies. Furthermore, none of the kinase inhibitors currently approved that inhibit RET, or in clinical development, are specific inhibitors of RET. Thus the development of more potent and selective RET inhibitors will likely have therapeutic implications for the treatment of patient with both thyroid and NSCLC harboring genomic alterations in RET. We plan to achieve these goals through the following specific aims. Aim 1: To establish the oncogenic properties of RET; Aim 2: To develop novel inhibitors of RET that possess the potency, selectivity, and pharmacological properties that will enable their use in cellular and in vivo models; Aim 3: To develop and evaluate in vivo strategies to treat cancers harboring genomic alterations in RET. Findings from these studies have therapeutic implications for patients with cancers harboring genomic alterations in RET and catalyze the development of clinical trials for such patients.