Mitigation of Radiation Induced Gastrointestinal Syndrome.

减轻辐射诱发的胃肠道综合症。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：目前，RAS被认为是癌症药物开发中的高价值目标超过30％的人类癌症 - 包括95％的胰腺癌和45％结直肠癌 - 由RAS基因家族的突变驱动。第一个临床来自Amgen的非小细胞肺的Lumakras™（Sotorasib）的G12C KRAS抑制剂的发射是 Carcinoma和Mirati Adagrasib™正在使用其G12C抑制剂进行批准。 Kras的G12D和V抑制剂的发展停滞在临床前领域，相似 G12C抑制剂使用的策略可能更困难或不可能应用于其他突变。此外，还存在过度活跃的野生型RAS突变的挑战蛋白质中的靶向突变因过度活跃的RAS途径而变得困难可能是由于其伴侣蛋白的RAS上调或失调而引起的。这不是通过目前试图抑制突变体形式的方法来解决，但实际上已经导致了RAS突变形式内具有复杂网络的抗性机制涉及RAS的同种型的途径。在这里，我们提出正在展现的另一个致癌性RA的可能目标。所有致癌Ras的标志是抑制磷酸酶和Tensin同源物是磷酸酶（PTEN）的表达。 Pten是一个多功能性肿瘤抑制剂在人类癌症中通常会丢失，但这是癌变的RAS信号传导以防止细胞能够死亡（导致永生化）。这是广泛认为是驾驶员突变。致癌Ras的另一个标志信号传导是一种称为GSK3的蛋白质过表达。我们最近报道了BCN057 恢复PTEN表达以消除致癌性KRAS中永生的表型。为什么这很重要，因为信号转导“接线”似乎在KRAS突变体与正常组织。这是通过增加对化学疗法的抵抗力和辐射时诱导KRAS突变肿瘤细胞中的细胞死亡，导致增加治疗指数。这是致癌Kras上皮癌和结直肠癌的突破癌症治疗，有时可能对各种癌症产生重大影响。仅美国就有超过15万例结肠直肠癌的新病例和研究基础医学（FM）估计KRAS突变频率约为50％。在摘要，拟议的工作将为与产品相关的随后研究提供清晰的途径在II期应用中的开发。