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很好的治疗靶点。引人注目的临床例子包括非小细胞肺癌(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，以及慢性髓系白血病中的BCR-ABL易位。在所有情况下，有效和选择性的激酶抑制剂都显示出显著的临床活性，目前是治疗护理的标准。技术的进步，加上人类基因组测序，已经导致识别出具有临床意义的致癌改变的罕见癌症亚群。间变性淋巴瘤激酶(ALK)重排发生在约3%的非小细胞肺癌患者中。Crizotinib是一种ALK抑制剂，在临床上对ALK重排的NSCLC有效，在最初发现仅4年后就被专门批准用于治疗这种基因定义的癌症患者亚群。从发现到临床实施的这一快速进展，得益于癌症患者的系统基因分型，现在包括DFCI在内的许多机构都是常规做法。RET是一种跨膜受体酪氨酸激酶，通常在神经脊和泌尿生殖道来源的细胞中表达。在甲状腺髓样癌(MTC)中有50%发生突变，在乳头状癌中有35%发生重排。此外，RET突变是家族性癌症综合征2A型多发性内分泌瘤(MEN2A型)、2B型(男性2B型)和家族性甲状腺髓样癌的基础。Vanderinib是一种多靶点的激酶抑制剂，也能抑制RET，是一种基于III期临床试验的MTC批准疗法。我们最近在部分非小细胞肺癌患者中发现了RET(KIF5B-RET)的重排。这种融合基因在体外是致癌的，转化的细胞对多靶点的激酶抑制剂很敏感 抑制RET。因此，RET抑制剂在这类非小细胞肺癌患者中也可能在临床上有效。在这里，我们提出了一些关键的研究，这些研究将为RET抑制剂的临床部署提供信息，例如调查RET致癌形式的癌症生物学，研究肺癌中RET变化的发生率，以及开发用于临床研究的识别患者的策略。此外，目前批准的抑制RET的激酶抑制剂或临床开发中的任何一种都不是RET的特异性抑制剂。因此，更有效和更有选择性的RET抑制剂的开发可能对同时存在RET基因组改变的甲状腺和非小细胞肺癌患者的治疗具有治疗意义。我们计划通过以下具体目标实现这些目标。目的1：建立RET的致癌特性；目标2：开发新的RET抑制剂，使其具有效力、选择性和药理学特性，使其能够用于细胞和体内模型；目标3：开发和评估体内治疗RET中存在基因组改变的癌症的策略。这些研究的发现对存在RET基因组变化的癌症患者具有治疗意义，并催化了此类患者的临床试验的发展。

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.