Targeting a Novel Pocket on ITGAV

瞄准 ITGAV 上的新颖口袋

• 批准号: 10911393
• 负责人: NICOLE MATTSON
• 金额: $ 8.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-29 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10911393
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Advanced Malignant Neoplasm; Apoptosis; Award; Binding; Biological; Biological Assay; Biology; Breast; CRISPR screen; Cancer Model; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Death Induction; Cell surface; Cells; Cessation of life; Cities; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; Colon; Colon Carcinoma; Combined Modality Therapy; Complex; Computer Models; Cutaneous T-cell lymphoma; Data; Docking; Drug Targeting; Energy Transfer; Essential Genes; FDA approved; Fellowship; Genes; Goals; Impairment; In Vitro; Integrin alphaV; Integrin beta Chains; Integrins; Invaded; Knock-out; Laboratories; Liquid substance; MAPK10 gene; Machine Learning; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurable; Methods; Mitogen-Activated Protein Kinases; Modeling; Monitor; Mutate; Mutation; Oncogenic; Pancreas; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Postdoctoral Fellow; Proteomics; Research; Research Project Grants; Role; Scanning; Scientist; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; Structure; System; Techniques; Technology; Therapeutic; Time; Training; Translational Research; United States; Validation; Western Blotting; Work; beta catenin; biomarker discovery; cancer cell; cancer survival; cell killing; comparison control; density; design; effective therapy; high throughput screening; improved; in silico; inhibitor; lead candidate; malignant breast neoplasm; mathematical model; migration; nemo-like kinase; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pre-doctoral; predictive modeling; prevent; skills; small molecule; statistics; triple-negative invasive breast carcinoma; tumor

Project Summary. Cancer deaths remain at an all-time high in the United States leaving an urgent clinical need to develop novel therapeutic strategies to help patients. The lack of effective treatments is in part due to underlying complexities in cancer that current scientific approaches are just beginning to uncover. Technological advances are rapidly changing the landscape of scientific discovery; for example, the combination of mathematical modeling in tandem with laboratory based validation leading to better combinational therapies to treat cancer. For this reason, I propose training in both with the F99/K00 Predoctoral to Postdoctoral Fellow Transition Award. For the F99 phase, the dissertation research, I will focus on laboratory based research skills to identify and propose a novel therapeutic to treat cancers. In a high level CRISPR screen targeting about 580 genes on the cell surface we found that Integrin Alpha V (ITGAV) is essential for the survival of solid tumors (colon, pancreatic, and breast cancer). To validate ITGAV as the most essential integrin we designed a second layer screen targeting all 26 integrins and found that ITGAV and Integrin Beta 5 (ITGB5) are the only essential integrins in solid tumors. Interestingly, integrins must for an obligate heterodimer between an alpha and a beta subunit of which ITGAV and ITGB5 are one of the known 24. As the more essential pair, ITGAV was probed with a high-density CRISPR tiling scan and we found a small pocket to be essential for ITGAV function and it was amendable to small molecule binding. A structure based analysis found a loop structure of the beta pair of ITGAV interacts with the discovered pocket, leading to our hypothesis that the pocket is essential for the heterodimer stability between ITGAV and its beta pair. Indeed, from a high-throughput screen of 500 small molecules we found one compound that appears to bind in our pocket and disrupt the heterodimer between ITGAV and ITGB5. Further validation of this potential will be the remaining work to be done for the dissertation research and upon completion, will fill an unmet clinical need since no there no FDA approved drugs targeting integrins approved for cancer indications. To further advance the potential to treat cancer I plan to use mathematical modeling approaches to identify novel therapeutic strategies by understanding the complexities of cancer signaling during the K00 phase, the proposed postdoctoral work. To study complex cancer signaling, in collaboration with Dr. Pirrotte, we generated kinase activity scores in cells where ITGAV was knocked out. With this data we can model the effects of signaling as it relates to measurable changes in the cancer cells. Specifically, we will study cell cycle control, which is inhibited with ITGAV loss. Additionally, we can model known inhibitors to common signaling cascades as novel combinational therapeutic strategies. To confirm our model, I will use laboratory based skill developed during the F99 phase. Overall with the training with the F99/K00 award I will gain skills to be able to build mathematical models to study cancer and validate those models with laboratory based skills. This will allow me to become and independent research and leading scientist in translational research.

项目摘要。在美国，癌症死亡仍处于历史最高水平 制定新的治疗策略来帮助患者。缺乏有效治疗的部分原因是 当前科学方法刚刚开始揭露的癌症的基本复杂性。技术 进步正在迅速改变科学发现的景观；例如，结合 与基于实验室的验证同时进行数学建模，从而使得更好的组合疗法 治疗癌症。因此，我在F99/k00的博士后培训培训 过渡奖。对于F99阶段，论文研究，我将重点关注基于实验室的研究技能 识别并提出一种新型治疗癌症的治疗方法。在高水平的CRISPR屏幕中，目标约为580 细胞表面上的基因我们发现整联蛋白alpha V（ITGAV）对于实体瘤的存活至关重要 （结肠，胰腺和乳腺癌）。为了验证itgav为最重要的整合素蛋白，我们设计了第二个 靶向所有26个整合素的层屏幕，发现Itgav和Integin Beta 5（ITGB5）是唯一必需的 实体瘤中的整合素。有趣的是，整联蛋白必须在alpha和beta之间具有强制性异二聚体 ITGAV和ITGB5的亚基是已知的24个。作为更重要的对，ITGAV被探测 高密度的CRISPR平铺扫描，我们发现一个小口袋对于Itgav功能至关重要，它是 可以对小分子结合进行修正。基于结构的分析发现beta对的循环结构 与发现的口袋相互作用，导致我们的假设是袋对异二聚体至关重要 ITGAV与其Beta对之间的稳定性。实际上，从500个小分子的高通量屏幕中我们 找到了一种似乎在我们的口袋里绑定并破坏ITGAV和ITGB5之间的异二聚体的化合物。 进一步验证这一潜力将是为论文研究以及在 完成，将满足未满足的临床需求 对于癌症的适应症。为了进一步促进治疗癌症的潜力，我计划使用数学建模 通过了解在 K00阶段，拟议的博士后工作。研究复杂的癌症信号传导，与博士合作 Pirrotte，我们在将ITGAV被淘汰的细胞中产生了激酶活性评分。有了这些数据，我们可以建模 信号传导的影响与癌细胞的可测量变化有关。具体来说，我们将研究细胞 循环控制，它被ITGAV损失抑制。此外，我们可以将已知抑制剂建模为常见 信号级联作为新型组合治疗策略。为了确认我们的模型，我将使用实验室 在F99阶段开发的基于技能。总体而言，通过获得F99/K00奖的培训，我将获得技能 能够建立数学模型来研究癌症并以基于实验室的技能验证这些模型。 这将使我成为转化研究的独立研究和领先的科学家。