Modulation of Therapeutic Response

为了改善癌症的治疗，对辐射损伤的调节已经引起了相当大的关注。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。已经完成的两项独立研究表明，辐射诱导的基因表达谱在体外暴露的细胞与体内作为实体瘤生长的相同细胞之间存在显著差异，进一步强调了肿瘤微环境对辐射反应的影响。此外，我们已经表明，与单剂量放射治疗相比，多剂量放射治疗对基因的诱导作用更强，尤其是包括STAT-1在内的干扰素相关基因。我们将尝试调节这些基因，以确定它们对多组分放射治疗的影响。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。我们最近表明，氯雷他定和谷固酮增强肿瘤细胞的放射反应在体外。初步的机制研究表明，氯雷他定在细胞周期中施加G2/M阻滞（细胞周期的G2/M期对辐射非常敏感）和谷固酮，这似乎干扰辐射诱导的DNA损伤修复。目前正在对这两种药物联合辐射对荷瘤小鼠的影响进行评估。我们还评估了另一种分子靶向药物，这是一种Chk-1抑制剂。该制剂在体外和体内对肿瘤细胞提供相当大的辐射增强作用，几乎没有正常组织毒性。工作假设是，由于辐射损伤的不完全修复，该制剂消除了正常辐射诱导的细胞周期G2延迟，从而增强了辐射应答。我们还通过H2AX实验证明了该试剂直接抑制辐射诱导的损伤修复。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通路的下游信号中间体）在高剂量辐射治疗时具有纤维化抗性。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。该药物阻断TGF β信号通路，目前的研究主要集中在证实该药物在体内对TGF β信号通路的影响。最后，我们有初步的临床前数据表明，氮氧化物Tempol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。这些临床前研究的目标是获得足够的疗效数据，以便将这些实验性药物引入人体放射肿瘤学临床试验。

Modulation of Therapeutic Response Summary 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. Two independent studies have been completed showing that radiation-induced gene expression profiles differ significantly for cells exposed in vitro versus the same cells growing as a solid tumor in vivo further underscoring the influence of the tumor microenvironment on the radiation response. Further we have shown that multi-fraction radiation delivery results in a more robust induction of genes than single dose radiation treatment, in particular the interferon-related genes including STAT-1. We will attempt to modulate these genes to determine their influence on multi-fraction radiation treatment. 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 and guggulsterone enhance tumor cell radiation response in vitro. Preliminary mechanistic studies indicate that loratadine imposes a G2/M block in cell cycle (G2/M phases of the cell cycle are very radiosensitive) and guggulsterone, which appears to interfere with radiation-induced DNA damage repair. Evaluation of both agents in combination with radiation in tumor bearing mice is currently underway. We have also evaluated another molecularly targeted agent, which is a Chk-1 inhibitor. This agent provides considerable radiation enhancement of tumor cells in vitro and in vivo with very little to no normal tissue toxicity. The working hypothesis is that the agent abrogates the normal radiation-induced delay in G2 of the cell cycle, thus enhancing the radiation response because of incomplete repair of radiation damage. We have also shown that this agent directly inhibits radiation-induced damage repair using the H2AX assay. 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 and current studies are centered in confirming that this agent impacts TGF beta signaling in vivo. Lastly we have preliminary pre-clinical data suggesting that the nitroxide, Tempol protects against radiation-induced oral mucositis. Oral mucositis is a common toxicity associated with the radiation treatment of head and neck cancers. The goal of these pre-clinical studies is to gain enough efficacy data to introduce these experimental agents into human radiation oncology clinical trials.