Modulation of sensitivity & imaging therapeutic response of hypoxic cancer cells

描述（由申请人提供）：癌症治疗有效性的主要障碍之一是肿瘤微环境，该微环境通常超出其血液供应，并含有耐化疗和放疗的缺氧区域。TRAIL是抑制癌症及其转移的宿主免疫系统的一部分，并且TRAIL以及TRAIL受体激动剂抗体目前都处于早期临床试验测试中。在初步研究中，我们发现了某些肿瘤细胞，包括p53-null人HCT 116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具有显著抗性的证据。通过包括TRAIL加5-氟尿嘧啶、TRAIL加伊立替康或TRAIL加缺氧致敏剂替拉扎明的组合疗法，在缺氧条件下这些肿瘤细胞不能有效地对TRAIL致敏。这促使我们开发并进行高通量化学文库筛选，该筛选已经鉴定了许多小分子，包括我们称为SLM的结构相关核苷类似物家族。SLM是TRAIL在缺氧下的有效增敏剂，并且一些家族成员在缺氧下作为单一药剂具有细胞毒性作用。体内研究揭示了与TRAIL组合的新型小分子的抗肿瘤作用，并且新型非侵入性全动物光学成像揭示了这种组合与治疗的肿瘤内低氧水平降低以及血管分布减少相关。这些是令人兴奋的发现，值得通过以下方法进行进一步研究：具体目标#1：研究缺氧条件下对TRAIL治疗的抗性机制，特别关注c-Myc，Mcl-1，HIF和NFkB信号通路。具体目标#2：通过从高通量化学文库筛选中分离的新型小分子SLM，研究在缺氧条件下对TRAIL的敏化机制。具体目标#3：通过肿瘤缺氧和抗肿瘤作用的非侵入性体内成像，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种理解，对其他系统和治疗具有广泛的适用性。该提案具有高度的翻译相关性，因为我们正在开发可在临床上进行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成功的癌症治疗的主要障碍，并且需要进行研究以在治疗开发中取得进展。该提案开发了在缺氧微环境中靶向致敏生物治疗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，而化疗或替拉扎明未能显著增敏。这项工作的进展可能会对开发具有高度临床转化潜力的新型治疗方法产生影响。

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.