Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 8158259
• 负责人: James Mitchell
• 金额: $ 64.92万
• 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/8158259
• 关键词: Therapeutic; response

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 loratadine, halofuginone, and guggulsterone enhance tumor cell radiation response in vitro. These agents enhance radiosensitivity by different mechanisms including cell cycle redistribution, inhibition of radiation-induced repair, and inhibition of TGF-beta signaling. A molecularly targeted Chk-1 inhibitor has demonstrated significant radiosensitive 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 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. In collaboration with the Radiation Oncology Branch a clinical trial is being submitted to evaluate this agent in colorectal cancer. We are also evaluating a CK2 inhibitor and preliminary data show this agent to be an effective in vitro radiation sensitizer of human tumor cell lines. Preliminary studies are underway evaluating an IGF-1R antibody, an anti-angiogenesis agent, and an epilone analogue as radiation modifiers. With respect to normal tissue response to radiation, it is widely known that the TGF-beta signaling pathway is a major player in radiation-induced late effects (fibrosis). Our previous studies have shown that mice deficient in TGF-beta signaling (Smad3 knock-out mice-downstream signaling intermediate in the TGF-beta pathway) are resistant to fibrosis when treated with high dose radiation. Recent mouse normal tissue studies using a TGF-beta type 1 receptor kinase inhibitor have shown marked reduction in radiation-induced soft tissue fibrosis. This agent blocks the TGF-beta signaling pathway. Lastly we have preliminary pre-clinical data suggesting that the nitroxide, Tempol (both systemic and topically applied) protects against radiation-induced oral mucositis. Oral mucositis is a common toxicity associated with the radiation treatment of head and neck cancers. We have also shown in preliminary studies that Tempol does not alter chemoradiation with respect to tumor regrowth delay, providing more data to introduce these experimental agents into human radiation oncology clinical trials.

为了改善癌症的治疗，人们对改变辐射损伤给予了相当大的关注。目前正在研究各种化疗和/或分子靶向药物与辐射的相互作用，以确定是否可以使肿瘤更敏感或正常组织对放射治疗更有抵抗力。中心目标是确定将导致净治疗增益的方法，从而改善癌症放射治疗。该项目的一个目标是定义和更好地理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。在给定的治疗范围内，增强肿瘤对辐射的反应而不增强正常组织的能力是可取的。我们最近的研究表明，氯雷他定，halofuginone和guguulsterone在体外增强肿瘤细胞的辐射反应。这些药物通过不同的机制增强辐射敏感性，包括细胞周期再分配、抑制辐射诱导的修复和抑制tgf - β信号传导。一种分子靶向Chk-1抑制剂在p53突变的人类肿瘤细胞系中显示出显著的放射敏感性。正常的人成纤维细胞（p53野生型）对该药物不具有放射致敏性，提示有不同的肿瘤致敏性。该制剂在体内也提供相当大的辐射增强，几乎没有正常组织毒性。虽然这种药物消除了正常的辐射诱导的细胞周期G2的延迟，但抑制辐射损伤的修复似乎是放射致敏的主要机制。与放射肿瘤学分会合作，正在提交一项临床试验，以评估该药物在结直肠癌中的作用。我们还在评估一种CK2抑制剂，初步数据显示这种药物是一种有效的体外辐射致敏剂，可用于人类肿瘤细胞系。初步研究正在评估IGF-1R抗体、抗血管生成剂和epilone类似物作为辐射调节剂的作用。关于正常组织对辐射的反应，众所周知，tgf - β信号通路是辐射诱导的晚期效应（纤维化）的主要参与者。我们之前的研究表明，tgf - β信号缺失的小鼠（Smad3敲除小鼠- tgf - β途径的下游信号中间体）在接受高剂量辐射治疗时对纤维化具有抗性。最近使用tgf - β 1型受体激酶抑制剂的小鼠正常组织研究显示，辐射诱导的软组织纤维化明显减少。这种药物阻断tgf - β信号通路。最后，我们有初步的临床前数据表明，氮氧化物Tempol（全身和局部应用）可以预防辐射引起的口腔黏膜炎。口腔黏膜炎是头颈部癌症放射治疗的常见毒性。我们还在初步研究中表明，Tempol在肿瘤再生延迟方面不会改变放化疗，这为将这些实验性药物引入人体放射肿瘤学临床试验提供了更多的数据。