Targeting RET in Lung Cancer

描述（由申请人提供）：癌症的致癌基因组改变是极好的治疗靶点。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，强效和选择性激酶抑制剂已显示出显著的临床活性，是目前的治疗标准。技术的进步加上人类基因组的测序，已经导致鉴定出罕见的癌症亚群，这些亚群具有临床意义的致癌改变。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ALK重排的非小细胞肺癌中具有临床疗效，并且在最初发现后仅4年就被特别批准用于这种基因定义的癌症患者亚群的治疗。从发现到临床实施的这一快速进展，得益于对癌症患者进行系统的基因分型，这已成为包括DFCI在内的许多机构的常规工作。RET是一种跨膜受体酪氨酸激酶，通常在神经嵴和泌尿生殖道的细胞中表达。在约50%的甲状腺髓样癌（MTC）中发生突变，在约35%的甲状腺乳头状癌中发生重排。此外，RET突变是家族性癌症综合征多发性内分泌瘤2A型（MEN2A）、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，也可以抑制RET，是基于III期临床试验批准的MTC治疗药物。我们最近在一个非小细胞肺癌患者亚群中发现了RET （KIF5B-RET）的重排。这种融合基因在体外具有致癌性，转化后的细胞对多靶点激酶抑制剂敏感

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.