Targeting RET in Lung Cancer

靶向 RET 治疗肺癌

基本信息

批准号：
8725098
负责人：
Pasi A Janne
金额：
$ 52.55万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725098
关键词：
BRAF gene Biological Assay Biology Cancer Biology Cancer Patient Cells Chemicals Chronic Myeloid Leukemia Clinical Clinical Research Clinical Trials Coupled DNA Sequence Rearrangement Development Epidermal Growth Factor Receptor Genetically Engineered Mouse Genitourinary system Genomics Genotype Goals Hereditary Malignant Neoplasm Human Genome In Vitro Incidence Study Institution Lead Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thyroid Modeling Multiple Endocrine Neoplasia Type 2a Mutate Mutation Neural Crest Non-Small-Cell Lung Carcinoma Oncogenic Papillary thyroid carcinoma Patients Pharmaceutical Chemistry Phase III Clinical Trials Phosphotransferases Population Property Receptor Protein-Tyrosine Kinases Resistance Signal Transduction Somatic Mutation Specimen Syndrome Technology Therapeutic Thyroid Gland Translating anaplastic lymphoma kinase base bcr-abl Fusion Proteins cell transformation clinically significant comparative efficacy fusion gene in vivo in vivo Model inhibitor/antagonist kinase inhibitor medullary thyroid carcinoma melanoma mouse model novel public health relevance scaffold standard of care therapeutic target tumor

项目摘要

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.

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。令人信服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 突变以及慢性粒细胞白血病中的 BCR-ABL 易位。在所有情况下，有效且选择性的激酶抑制剂已表现出显着的临床活性，并且是目前的治疗标准。技术的进步加上人类基因组测序，已导致鉴定出具有临床显着致癌改变的罕见癌症亚型。约 3% 的 NSCLC 患者会发生间变性淋巴瘤激酶 (ALK) 重排。 Crizotinib 是一种 ALK 抑制剂，在临床上对 ALK 重排 NSCLC 有效，并且在最初发现后仅 4 年内就被专门批准用于治疗这一基因定义的癌症患者亚群。从发现到临床实施的快速进展得益于对癌症患者的系统基因分型，该分型现在在包括 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衍生的细胞中表达。它在大约 50% 的甲状腺髓样癌 (MTC) 中发生突变，在大约 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、2A 型多发性内分泌肿瘤 (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，也能抑制 RET，是基于 III 期临床试验批准的 MTC 疗法。我们最近在一部分 NSCLC 患者中发现了 RET (KIF5B-RET) 重排。该融合基因在体外具有致癌性，转化细胞对多靶点激酶抑制剂敏感，抑制RET。因此，RET 抑制剂在临床上也可能对这一 NSCLC 患者群体有效。在这里，我们提出了关键研究，这些研究将为 RET 抑制剂的临床部署提供信息，例如研究 RET 致癌形式的癌症生物学、研究肺癌中 RET 改变的发生率以及制定识别临床研究患者的策略。此外，目前批准抑制 RET 或处于临床开发阶段的激酶抑制剂都不是 RET 的特异性抑制剂。因此，开发更有效和更具选择性的 RET 抑制剂可能会对治疗患有 RET 基因组改变的甲状腺和 NSCLC 患者产生治疗意义。我们计划通过以下具体目标来实现这些目标。目标 1：确定 RET 的致癌特性；目标 2：开发具有效力、选择性和药理学特性的新型 RET 抑制剂，使其能够在细胞和体内模型中使用；目标 3：开发和评估治疗携带 RET 基因组改变的癌症的体内策略。这些研究的结果对于携带 RET 基因组改变的癌症患者具有治疗意义，并促进针对此类患者的临床试验的开展。