Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 8350044
• 负责人: James Mitchell
• 金额: $ 70.69万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8350044
• 关键词: Attention; Blood - brain barrier anatomy; Brain; Cancer cell line; Cell Cycle Inhibition; Cell Line; Cells; Cisplatin; Clinical Data; Clinical Trials; Fibroblasts; Goals; Head and Neck Cancer; Human; Ionizing radiation; Malignant neoplasm of lung; Modification; Molecular; Mucositis; Mus; Mutate; Normal tissue morphology; Physiology; Process; Radiation; Radiation Oncology; Radiation-Protective Agents; Radiation-Sensitizing Agents; Radiosensitization; Research; Research Design; Resistance; Therapeutic; Topical application; Toxic effect; Translating; Tumor Cell Line; Tumor-Associated Process; Xenograft procedure; cancer therapy; chemotherapy; improved; in vivo; inhibitor/antagonist; interest; novel; oral mucositis; pre-clinical; pre-clinical research; radiation effect; repaired; response; tempol; treatment response; tumor

In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We have recently shown that a molecularly targeted Chk-1 inhibitor provides significant radiosensitization in p53 mutated human tumor cell lines. Normal human fibroblasts (p53 wild type) are not radiosensitized by this agent suggesting differential tumor sensitization. This agent also provides considerable radiation enhancement in vivo (using xenografts) with very little to no normal tissue toxicity. While this agent abrogates the normal radiation-induced delay in G2 of the cell cycle, inhibition of repair of radiation damage appears to be the major mechanism of radiosensitization. We are also evaluating a CK2 inhibitor, which provides impressive radiosensitization when administered post-radiation exposure. Preliminary studies indicate that p53 WT cells are radiosensitized to a greater extent that p53 mutated cell lines. The major focus for the potential application of the CK2 inhibitor is head and neck cancer. Finally, we are evaluating a Jak2/Stat3 inhibitor in human lung cancer cell lines. Preliminary studies have demonstrated radiosensitization of the cell lines and mechanistic studies are ongoing. With respect to normal tissue response to radiation, we have identified a novel 5-membered ring nitroxide (23c) as a potent protector against radiation-induced lethality in mice and studies are planned to determine if protection can be observed in selected normal tissues in mice, particularly the brain since the nitroxide penetrates the blood brain barrier. Lastly, we have shown that the nitroxide, Tempol protects against radiation-induced oral mucositis (both systemic and topically applied). Oral mucositis is a common toxicity associated with the chemoradiation (cisplatin combined with fractionated radiation) treatment of head and neck cancers. Tempol also protects against chemoradiation-induced mucositis yet did not alter chemoradiation with respect to tumor regrowth delay, providing sufficient pre-clinical data to introduce Tempol into human radiation oncology clinical trials.

为了提高癌症的治疗水平，辐射损伤的修饰受到了极大的关注。各种化疗和/或分子靶向药物与辐射的相互作用正在研究中，以确定是否可以使肿瘤更敏感，或使正常组织对放射治疗更具抵抗力。中心目标是确定将导致净治疗收益的方法，从而改善癌症的放射治疗。该项目的目标之一是定义和更好地了解肿瘤生理学的这些方面，包括细胞和分子过程以及肿瘤微环境对治疗反应的影响。增强肿瘤对辐射的反应，而不增强给定治疗范围内的正常组织的能力是可取的。我们最近已经证明，一种分子靶向的Chk-1抑制剂在p53突变的人类肿瘤细胞系中提供了显著的放射增敏作用。正常人成纤维细胞(野生型P53)不受该药的辐射增敏，提示肿瘤增敏作用不同。该制剂还在体内(使用异种移植)提供了相当大的辐射增强，几乎没有正常的组织毒性。虽然这种药物消除了正常辐射诱导的G2期细胞周期的延迟，但抑制辐射损伤的修复似乎是辐射增敏的主要机制。我们还在评估一种CK2抑制剂，它在辐射暴露后使用时提供了令人印象深刻的放射增敏作用。初步研究表明，与P53突变细胞系相比，P53 WT细胞具有更大程度的放射增敏作用。CK2抑制剂潜在应用的主要焦点是头颈癌。最后，我们正在评估JAK2/STAT3抑制剂在人类肺癌细胞系中的作用。初步研究表明，细胞系具有放射增敏作用，机制研究正在进行中。关于正常组织对辐射的反应，我们已经确定了一种新的五元环氮氧化合物(23c)，它是一种有效的保护剂，可以抵御辐射诱导的小鼠死亡，并计划进行研究，以确定在选定的小鼠正常组织中是否可以观察到保护作用，特别是由于氮氧化物穿透血脑屏障。最后，我们已经证明，氮氧化物，坦普尔，预防辐射诱导的口腔粘膜炎(全身和局部应用)。口腔粘膜炎是头颈癌放化疗(顺铂联合分次放疗)治疗的常见毒性反应。坦波尔还可以预防化疗引起的粘膜炎，但不会改变放化疗对肿瘤再生延迟的影响，从而为将坦波尔引入人体放射肿瘤学临床试验提供了足够的临床前数据。