Mitigation of Radiation Induced Gastrointestinal Syndrome.

减轻辐射诱发的胃肠道综合症。

• 批准号: 10706240
• 负责人: Andrew John Norris
• 金额: $ 103.49万
• 依托单位: BCN BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706240
• 关键词: Acute; Affect; American Cancer Society; Ames Assay; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Applications Grants; Biological Models; Biological Sciences; Body mass index; Bone Marrow; Bone Marrow Cells; Bone Marrow Involvement; CCL2 gene; Cancerous; Carcinoma; Cell Death Induction; Cells; Chemotherapy and/or radiation; Chromosome abnormality; Clinical; Colon Carcinoma; Colorectal Cancer; Complex; Data; Data Reporting; Development; Disease; Dose; Epithelium; Equation; Exclusion; Exposure to; Foundations; Frequencies; Gene Mutation; Grant; Hematopoietic; Hematopoietic System; Human; Inflammation; Inflammatory; Injury; Intestines; Investigation; Ionizing radiation; KRAS oncogenesis; KRAS2 gene; Knowledge; LGR5 gene; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Medicine; Modeling; Mucous Membrane; Mutation; Myeloid Cells; Natural regeneration; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nuclear Accidents; Oncogenic; Organoids; Oryctolagus cuniculus; PTEN gene; Paper; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Phosphoric Monoester Hydrolases; Plasma; Play; Population; Proteins; Publishing; RAS Family Gene; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Toxicity; Radiation exposure; Rectal Cancer; Reporting; Research; Research Personnel; Resistance; Rodent; Role; Route; STEM field; Safety; Schedule; Sepsis; Signal Transduction; Skin Cancer; Small Business Innovation Research Grant; Syndrome; System; Technology; Testing; Therapeutic Index; Tissues; Toxic effect; Toxicology; Tumor Suppressor Proteins; United States; Up-Regulation; Validation; Whole-Body Irradiation; Work; animal rule; cancer diagnosis; chemokine; colorectal cancer treatment; design; driver mutation; drug development; gastrointestinal; gastrointestinal epithelium; immunoregulation; inhibitor; intestinal epithelium; irradiation; lead candidate; mouse model; mutant; neoplastic cell; nonhuman primate; overexpression; pharmacologic; pre-Investigational New Drug meeting; pre-clinical; prevent; product development; public health relevance; radiation mitigation; radiation-induced injury; recruit; regeneration following injury; regenerative; regenerative therapy; repaired; resistance mechanism; safety study; stem cells; subcutaneous; success; systemic inflammatory response; timeline; tumor

Abstract: Currently RAS has been considered a high value target in cancer drug development considering that over 30 percent of all human cancers – including 95% of pancreatic cancers and 45% of colorectal cancers — are driven by mutations of the RAS family of genes. The first clinical launch of a G12C KRAS inhibitor is Lumakras™ (sotorasib) from Amgen for non-small cell lung carcinoma and Mirati Adagrasib™ is on the way to approval with its G12C inhibitor however, the development of G12D and V inhibitors of KRAS are stalled in the preclinical realm with similar strategies used for G12C inhibitors which is likely more difficult or impossible to apply to other mutations. In addition, then there is also the challenge of overactive wildtype RAS mutations where targeting mutations in the protein become difficult with an overactive RAS pathway which can result from RAS upregulation or dysregulation of its partnering proteins. This is not addressed by the current approaches which seeks to inhibit the mutant forms only but in fact has led to a mechanism of resistance within the mutant forms of RAS with a complex network of pathways where isotypes of RAS are involved. Here we present what is unfolding as another possible target for oncogenic RAS. A hallmark of all oncogenic RAS is suppression of Phosphatase and tensin homolog is a phosphatase (PTEN) expression. PTEN is a multi- functional tumor suppressor that is very commonly lost in human cancer but is a requirement in cancerous RAS signaling to prevent the cells from being able to die (causing immortalization). Thus, this is widely regarded as a driver mutation. The other hallmark of oncogenic RAS signaling is a protein known as GSK3 is overexpressed. We have recently reported BCN057 restores PTEN expression to abrogate the immortalized phenotype in oncogenic KRAS. Why this is important is because the signal transduction “wiring” appears to differ in KRAS mutant vs normal tissue. Thus, normal tissue responds by increasing its resistance to chemotherapy and radiation while inducing cell death in the KRAS mutant tumor cells resulting in an increase in the therapeutic index. This is a breakthrough for oncogenic KRAS epithelial cancers and colorectal cancer treatment and may eventually have significant implications for a variety of cancers. In the US alone there are over 150,000 new cases of colorectal cancers and studies like Foundation Medicine (FM) estimate a KRAS mutation frequency of approximately 50%. In summary, the proposed work will provide a clear path to subsequent studies related to product development in a phase II application.

摘要： 目前，RAS被认为是癌症药物开发中的高价值靶标， 超过30%的人类癌症，包括95%的胰腺癌和45%的 结直肠癌-由RAS基因家族的突变驱动。第一临床 Amgen公司推出一种用于非小细胞肺癌G12 C KRAS抑制剂Lumakras™（sotorasib） Mirati Adagrasib™正在批准其G12 C抑制剂，然而， KRAS的G12 D和V抑制剂的开发在临床前领域停滞， 用于G12 C抑制剂的策略可能更难或不可能应用于其他药物。 突变。此外，还有过度活跃的野生型RAS突变的挑战。 其中蛋白质中的靶向突变变得困难，过度活跃的RAS途径， 可能是由于RAS上调或其伙伴蛋白的失调。这不是 目前的方法只寻求抑制突变形式，但事实上， 导致了具有复杂网络的RAS突变形式中的耐药机制 参与RAS同种型的途径。在这里，我们提出了什么是展开作为另一个 可能是致癌RAS的靶点。所有致癌RAS的标志是抑制 磷酸酶和张力蛋白同源物是磷酸酶（PTEN）表达。PTEN是一种多- 功能性肿瘤抑制因子在人类癌症中非常常见，但在癌症中是必需的。 癌性RAS信号传导以防止细胞能够死亡（导致永生化）。 因此，这被广泛认为是一种驱动突变。致癌RAS的另一个标志是 信号传导是一种被称为GSK 3的蛋白质过度表达。我们最近报道了BCN 057 恢复PTEN表达以消除致癌KRAS中的永生化表型。为什么 这一点很重要，因为KRAS突变体与 正常组织因此，正常组织通过增加其对化疗的抗性来响应， 辐射同时诱导KRAS突变肿瘤细胞中的细胞死亡，导致KRAS突变肿瘤细胞中的细胞凋亡增加。 治疗指数这是致癌KRAS上皮癌和结直肠癌的突破。 癌症治疗，并可能最终对各种癌症产生重大影响。在 仅美国就有超过15万例新的结直肠癌病例， 基础医学（FM）估计KRAS突变频率约为50%。在 总而言之，所提出的工作将为后续与产品相关的研究提供一条清晰的道路。 在第二阶段的应用中。