Modulation of sensitivity & imaging therapeutic response of hypoxic cancer cells

描述（由申请人提供）：癌症治疗效果的主要障碍之一是肿瘤微环境经常超出其血液供应，并且含有对化疗和放疗具有抗性的缺氧区域。TRAIL是抑制癌症及其转移的宿主免疫系统的一部分，TRAIL和TRAIL受体激动剂抗体目前都处于早期临床试验测试阶段。在初步研究中，我们发现某些肿瘤细胞，包括p53缺失的人类HCT116结肠肿瘤细胞，在常氧条件下对TRAIL敏感，在严重缺氧条件下对TRAIL产生显著抗性。在缺氧条件下，通过TRAIL + 5-氟尿嘧啶、TRAIL +伊立替康或TRAIL +缺氧致敏剂替拉帕嗪的联合治疗，这些肿瘤细胞不能有效地对TRAIL致敏。这促使我们开发并开展了一种高通量化学文库筛选，该筛选已经确定了许多小分子，包括一系列结构相关的核苷类似物，我们称之为slm。slm在缺氧条件下是TRAIL的有效增敏剂，一些家族成员在缺氧条件下具有细胞毒作用。体内研究揭示了新型小分子联合TRAIL的抗肿瘤作用，新型无创全动物光学成像显示，这种组合与治疗肿瘤内缺氧水平降低以及血管性降低有关。这些令人兴奋的发现值得通过以下途径进一步研究：具体目标1：研究缺氧下TRAIL治疗的耐药机制，特别关注c-Myc、Mcl-1、HIF和NFkB信号通路。特定目标#2：通过高通量化学文库筛选分离的新型小分子SLMs，研究缺氧下TRAIL致敏机制。特异性目的#3：通过肿瘤缺氧和抗肿瘤作用的无创体内成像，研究肿瘤微环境对TRAIL + SLM敏感性的影响。这一建议与理解有效抗癌治疗的障碍高度相关，并且随着我们获得这一理解，它对其他系统和治疗具有广泛的适用性。该建议具有很高的翻译相关性，因为我们正在开发可能在临床测试的新型治疗组合。公共卫生相关性：肿瘤微环境中的缺氧是癌症治疗成功的主要障碍，需要对其进行研究以取得治疗开发的进展。本研究提出了在缺氧微环境中靶向致敏生物疗法TRAIL的方法。我们已经确定了具有抗肿瘤作用的新型有效增敏剂，而化疗或替拉帕嗪未能显着增敏。这项工作的进展可能会对具有很高临床转化潜力的新型治疗方法的发展产生影响。

DESCRIPTION (provided by applicant): One of the major obstacles to the efficacy of cancer therapy is the tumor microenvironment that often outgrows its blood supply and harbors hypoxic regions that are resistant to chemo- and radiotherapy. TRAIL is part of the host immune system that suppresses cancer and its metastases and both TRAIL as well as TRAIL receptor agonist antibodies are currently in early phase clinical trial testing. In preliminary studies we have uncovered evidence that certain tumor cells, including p53-null human HCT116 colon tumor cells that are sensitive to TRAIL under normoxic conditions, become significantly resistant to TRAIL under severely hypoxic conditions. Such tumor cells are not effectively sensitized to TRAIL under hypoxia by combination therapies that include TRAIL plus 5- Fluorouracil, TRAIL plus irinotecan, or TRAIL plus the hypoxia sensitizer Tirapazamine. This prompted us to develop and carry out a high throughput chemical library screen that has identified a number of small molecules, including a family of structurally-related nucleoside analogues we refer to as the SLMs. SLMs are potent sensitizers of TRAIL under hypoxia and some family members have cytotoxic effects as single agents under hypoxia. In vivo studies reveal anti-tumor effects of novel small molecules combined with TRAIL and novel non-invasive whole animal optical imaging reveals that such combinations are associated with reduced levels of hypoxia within treated tumors as well as reduced vascularity. These are exciting findings that merit further investigation through the following approaches: Specific Aim #1: Investigate mechanisms of resistance to TRAIL therapy under hypoxia with specific focus on c-Myc, Mcl-1, HIF and NFkB signaling pathways. Specific Aim #2: Investigate mechanisms of sensitization to TRAIL under hypoxia by novel small molecules, SLMs, isolated from high throughput chemical library screening. Specific Aim #3: Investigate the impact of the tumor microenvironment on TRAIL plus SLM sensitivity through non-invasive in vivo imaging of tumor hypoxia and anti-tumor effects. This proposal is highly relevant to the understanding of the barriers to effective anti-cancer therapy and has broad applicability to other systems and therapies as we gain this understanding. The proposal has high translational relevance as we are developing novel therapeutic combinations that may be tested in the clinic. PUBLIC HEALTH RELEVANCE: Hypoxia within the tumor microenvironment is a major obstacle to successful cancer therapy and needs to be investigated for progress to be made in therapeutic development. This proposal has developed methods for targeting sensitization to the biologic therapy TRAIL in the hypoxic microenvironment. We have identified novel effective sensitizers that have anti-tumor effects, whereas chemotherapy or Tirapazamine failed to sensitize significantly. The progress of this work is likely to have impact on the development of novel therapeutic approaches that have high potential for clinical translation.