Selectively Targeting Oncogenic NRAS in Cancer

选择性靶向癌症中的致癌 NRAS

基本信息

批准号：
9040123
负责人：
KEVIN M. SHANNON
金额：
$ 55.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040123
关键词：
Address Alleles Amino Acids Biochemical Biochemistry Biology Cancer Burden Cancer cell line Cells Characteristics Chemicals Collaborations Cysteine Data Development Dominant-Negative Mutation Enzymatic Biochemistry Enzymes Frequencies Generations Genes Genetic Goals Growth HRAS gene Health Hematologic Neoplasms Hematopoietic Human Knock-in Knock-in Mouse Malignant - descriptor Malignant Neoplasms Methods Molecular Molecular Biology Techniques Mouse Strains Mus Mutant Strains Mice Mutate Mutation NRAS gene Oncogenes Oncogenic Output Pathogenesis Pathway interactions Play Post-Translational Protein Processing Protein Isoforms Proteins Proto-Oncogenes Reagent Reporting Research Personnel Serine Serine Hydrolase Signal Transduction Staging Synthesis Chemistry TAP2 gene Tertiary Protein Structure Testing Therapeutic activity-based protein profiling base cancer cell cancer type cell growth conditional mutant design drug discovery gain of function improved in vivo inhibitor/antagonist leukemia mutant novel novel strategies novel therapeutic intervention palmitoylation pre-clinical progenitor protein function ras GTPase-Activating Proteins ras Proteins research study small molecule libraries therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): RAS proto-oncogenes are mutated in ~30% of human cancers, but no mechanism-based treatments exist for reversing the biochemical output of oncogenic Ras proteins, which are exceedingly difficult targets for rational drug discovery. Our long-term goal is to implement mechanistic strategies to selectively inhibit the growth of cancers with somatic RAS mutations. In this project, we will investigate the Ras palmitoylation/depalmitoylation cycle, which regulates the subcellular trafficking of the N-Ras, H-Ras, and K-Ras4a isoforms, as a therapeutic target for selectively inhibiting the growth of malignancies with oncogenic NRAS mutations. Acyl protein thioesterase 1 and 2 (APT1 and APT2) catalyze N-Ras depalmitoylation and we found that "first generation" chemical inhibitors designed to inhibit these enzymes (Palmostatin B and Palmostatin M) selectively reduced the growth of primary hematopoietic progenitors and leukemia cells expressing oncogenic N-RasG12D. However, our recent studies also infer the existence of additional biochemical targets of these compounds that are essential for the growth of NRAS mutant cancer cells. This project involves a cross-disciplinary collaboration that brings together investigators with extensive expertise in synthetic chemistry (Dr. Howell), enzymology and chemical biology (Dr. Cravatt), and hematologic cancer, Ras signaling, and preclinical therapeutics (Dr. Shannon). We have collaborated to generate extensive preliminary data and novel reagents, which we will use to pursue the goals of: (1) identifying additional biochemical targets of the palmostatins; (2) developing new chemical inhibitors with improved potency and selectivity for palmostatin targets; (3) using these inhibitors combined with genetic methods to discern the relevant enzyme(s) that regulate N-Ras depalmitoylation in cancer cells; and, (4) utilizing human cancer cell lines and a new strain of mice to interrogate the palmitoylation/depalmitoylation cycle as a therapeutic target in early stage and advanced NRAS-mutant cancers. We will address these questions through two highly integrated specific aims. In Aim 1, we will identify additional biochemical targets of palmostatin M, design and characterize new chemical inhibitors, and evaluate the efficacy of these compounds in cancer cells with NRAS mutations. In Aim 2, we will utilize a novel strain of NrasG12D,C181S "knock in" mice to ask if the palmitoylation/depalmitoylation cycle is required for the growth of oncogenic Nras-driven cancers in vivo. These studies will rigorously assess the importance of the palmitoylation/depalmitoylation cycle and inform the development of new therapeutic strategies for cancers with oncogenic RAS mutations.

描述（由应用提供）：RAS原始癌基因在约30％的人类癌症中突变，但是没有基于机制的治疗方法可以逆转致癌性RAS蛋白的生化输出，这是对理性药物发现的极其困难的靶标。我们的长期目标是实施机械策略，以有选择地抑制具有体细胞RAS突变的癌症的生长。在该项目中，我们将研究RAS棕榈酰化/去氨酰二酰化周期，该周期调节N-RAS，H-RAS和K-RAS4A同工型的亚细胞运输，作为选择性抑制肿瘤NRAS突变恶性肿瘤生长的治疗靶点。酰基蛋白硫酯酶1和2（APT1和APT2）催化N-RAS二甲酰二酰化，我们发现旨在抑制这些酶的“第一代”化学抑制剂选择性地降低了原发性造血祖细胞和白血病细胞表达oncecencencogenic n-rasg12的生长。但是，我们最近的研究还推断了这些化合物的其他生化靶标对于NRAS突变癌细胞的生长至关重要。该项目涉及跨学科的合作，将研究人员汇集在一起，具有广泛的合成化学专业知识（Howell博士），酶学和化学生物学（Cravatt博士），血液学癌症，RAS信号传导和临床前疗法（Shannon博士）。我们已经合作生成广泛的初步数据和新颖的试剂，我们将用来追求以下目标：（1）确定最小的最大的生化目标；（2）开发新的化学抑制剂，具有提高的效力和对紫色靶标的选择性的提高；（3）使用这些抑制剂与遗传学方法结合使用，以辨别调节癌细胞中N-RAS depalmitoylation的相关酶；（4）利用人类癌细胞系和新的小鼠菌株将棕榈酰化/去氨酰二酰化循环作为早期和晚期NRAS突变癌的治疗靶标。我们将通过两个高度集成的特定目标解决这些问题。在AIM 1中，我们将确定最苍白的Movstatin M的其他生化靶标，设计和表征新的化学抑制剂，并评估这些化合物在具有NRAS突变的癌细胞中的有效性。在AIM 2中，我们将利用一种新型的NRASG12D，C181S“敲击”小鼠的菌株，询问棕榈酰化/去氨酰二酰化周期是否需要在体生中生长致癌NRAS驱动的癌症。这些研究将严格评估棕榈酰化/depalmitoylation循环的重要性，并为患有致癌RAS突变的癌症的新治疗策略开发。