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已被认为是抗癌药物开发的高价值靶点 超过30%的人类癌症--包括95%的胰腺癌和45%的 结直肠癌--是由RAS家族基因突变引起的。第一个临床 安进公司推出用于非小细胞肺的G12C KRAS抑制剂Lumakras™(Sotorasib) 癌症和Mirati Adagrasib™正在获得G12C抑制剂的批准，然而， KRAS的G12D和V抑制剂的开发在临床前领域停滞不前 用于G12C抑制剂的策略可能更难或不可能应用于其他 突变。此外，还有过度活跃的野生型RAS突变的挑战 蛋白中的靶向突变变得困难，因为过度活跃的RAS途径 可能是由于RAS上调或其伙伴蛋白调节失调所致。这不是 通过当前的方法解决，这些方法仅寻求抑制突变形式，但实际上 已经导致了RAS突变形式内的一种抗性机制，该机制具有复杂的 参与RAS同种类型的途径。在这里，我们展示了正在展开的另一个 可能是致癌RAS的靶点。所有致癌RAS的一个特征是抑制 磷酸酶和张力蛋白同源物是一种磷酸酶(PTEN)的表达。PTEN是一种多层次的 一种功能性肿瘤抑制因子，在人类癌症中非常常见地缺失，但在 癌变的RAS信号可防止细胞死亡(导致永生)。 因此，这被广泛认为是一种驱动因素突变。致癌RAS的另一个标志 信号转导是一种被称为Gsk3的蛋白质，过度表达。我们最近报道了BCN057 恢复PTEN的表达，以消除致癌KRAS中永生化的表型。为什么 这一点很重要，因为KRAS突变体和KRAS突变体的信号转导“连接”似乎不同 正常组织。因此，正常组织通过增加其对化疗和 辐射诱导KRAS突变型肿瘤细胞死亡 治疗指数。这是致癌的KRAS上皮癌和结直肠癌的突破 癌症的治疗，并可能最终对多种癌症产生重大影响。在……里面 仅在美国就有超过15万例新的结直肠癌病例和研究 基础医学(FM)估计KRAS突变频率约为50%。在……里面 综上所述，拟议的工作将为后续与产品有关的研究提供明确的途径 在第二阶段应用程序中进行开发。