Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 7594757
• 负责人: JAMES B MITCHELL
• 金额: $ 63.51万
• 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/7594757
• 关键词: Adverse effects; Animals; Attention; Binding; Cell Cycle; Cell Hypoxia; Cells; Chemicals; Clinical Trials; DNA Damage; DNA Repair; Data; Dose; Electron Spin Resonance Spectroscopy; Evaluation; Fibroblasts; Fibrosis; Future; Genes; Goals; Halofuginone; Human; Hypoxia; Image; In Vitro; Invasive; Ionizing radiation; Knockout Mice; Late Effects; Loratadine; Mitosis; Modification; Molecular; Molecular Profiling; Molecular Target; Mus; Normal tissue morphology; Oxygen; Pathway interactions; Patients; Physiology; Positron-Emission Tomography; Process; Radiation; Radiation Induced DNA Damage; Radiation-Induced Gene Expression; Radiation-Protective Agents; Radioactive; Radiobiology; Research; Research Design; Resistance; Signal Transduction; Solid Neoplasm; TGF Beta Signaling Pathway; Therapeutic; Tracer; Transforming Growth Factor beta; Translating; Tumor-Associated Process; cancer therapy; chemotherapy; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); gene induction; improved; in vivo; inhibitor/antagonist; instrumentation; interest; kinase inhibitor; neoplastic cell; novel; pre-clinical research; preclinical study; pregna-4,17-diene-3,16-dione; radiation effect; receptor; response; soft tissue; trend; tumor; uptake

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. With respect to the tumor microenvironment, it has long been known that tumor cell hypoxia can cause resistance to radiation and chemotherapy treatment. Non-invasive imaging that could identify patients whose tumors are hypoxic would be useful clinically. A putative radioactive hypoxia marker, [64Cu]Cu-ATSM, was evaluated in tumor-bearing mice using dynamic positron emission tomography (PET). While this PET tracer avidly bound to tumor, it was unable to predictably detect changes in varying amounts of hypoxia when oxygenation levels of the tumor were modulated. In contrast, [18F]fluoromisonidazole demonstrated a positive trend with more tumor uptake as oxygen levels were lowered in the tumor. Future attempts of non-invasively assessing tumor hypoxia will be evaluated using electron paramagnetic resonance imaging (instrumentation developed in the Radiation Biology Branch) in conjunction with oxygen sensitive chemical probes. 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. 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. We have recently shown that fibroblasts isolated from these animals (compared to wild type fibroblasts) when exposed to radiation increase their DNA damage sensing mechanisms and decrease induction of pro-fibrotic genes. These basic studies suggest that targeting the TGF beta pathway with molecularly targeted agents may provide significant protection against radiation-induced fibrosis, an untoward side effect of radiation treatment. Recent mouse normal tissue studies using halofuginone, which targets the TGF beta pathways at several points or a TGF beta type 1 receptor kinase inhibitor have shown marked reduction in radiation-induced soft tissue fibrosis. Current studies are centered in confirming that both agents impact their molecular targets in vivo. The goal of these pre-clinical studies is to gain enough efficacy data to introduce these agents into human clinical trials.

为了改善癌症治疗，相当多的注意力已经放在辐射损伤的修饰上。正在研究各种化疗和/或分子靶向药物与放射的相互作用，以确定是否可以使肿瘤对放射治疗更敏感或使正常组织对放射治疗更耐受。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。该项目的一个目标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。已经完成的两项独立研究表明，辐射诱导的基因表达谱显着不同的细胞在体外暴露与相同的细胞生长为实体瘤在体内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，多部分辐射递送导致比单剂量辐射治疗更稳健的基因诱导。关于肿瘤微环境，长期以来已知肿瘤细胞缺氧可导致对放射和化学治疗的抗性。非侵入性成像可以识别肿瘤缺氧的患者，这在临床上是有用的。一个假定的放射性缺氧标志物，[64 Cu]Cu-ATSM，在荷瘤小鼠中使用动态正电子发射断层扫描（PET）进行了评价。虽然这种PET示踪剂与肿瘤紧密结合，但当肿瘤的氧合水平被调节时，它无法可预测地检测到不同缺氧量的变化。相比之下，[18F]氟咪唑表现出积极的趋势，随着肿瘤中氧水平的降低，肿瘤摄取更多。将使用电子顺磁共振成像（放射生物学分支开发的仪器）结合氧敏化学探针评价未来非侵入性评估肿瘤缺氧的尝试。增强肿瘤对辐射的响应而不增强给定治疗区域内的正常组织的能力是期望的。我们最近发现氯雷他定和guggulsterone在体外能增强肿瘤细胞的放射反应。初步的机制研究表明，氯雷他定可阻断细胞周期的G2/M期（细胞周期的G2/M期对辐射非常敏感），而guggulsterone似乎可干扰辐射诱导的DNA损伤修复。目前正在对这两种药物与放射联合治疗荷瘤小鼠进行评估。关于正常组织对辐射的反应，众所周知，TGF β信号传导途径是辐射诱导的迟发效应（纤维化）的主要参与者。我们以前的研究表明，TGF β信号传导缺陷的小鼠（Smad 3敲除小鼠-TGF β途径中的下游信号传导中间体）在接受高剂量辐射治疗时对纤维化具有抗性。我们最近已经表明，从这些动物中分离的成纤维细胞（与野生型成纤维细胞相比），当暴露于辐射时，会增加其DNA损伤传感机制，并减少促纤维化基因的诱导。这些基础研究表明，用分子靶向药物靶向TGF β通路可能对辐射诱导的纤维化（辐射治疗的不良副作用）提供显著的保护。最近的小鼠正常组织研究，使用卤夫酮，其靶向TGF β途径在几个点或TGF β 1型受体激酶抑制剂已显示辐射诱导的软组织纤维化显着减少。目前的研究集中在确认这两种药物在体内影响其分子靶点。这些临床前研究的目标是获得足够的疗效数据，以将这些药物引入人体临床试验。