Overcoming hypoxic resistance to anti-cancer therapy

摘要 肿瘤缺氧降低了放疗、一些化疗和化疗的抗癌治疗效果 免疫检查点阻断疗法。对于放射治疗，生物物理测量表明，缺氧细胞需要 达到与完全充氧的细胞相同的杀伤力的剂量增加2.8倍。对于免疫治疗， 低氧已被证明有助于免疫逃避，甚至加速T细胞的耗尽。为了这些 由于种种原因，许多组织都试图将更多的氧气输送到肿瘤中，作为一种辅助手段来提高肿瘤的敏感性。 不幸的是，这种方法遇到了令人失望的临床结果。 我们对肿瘤的氧合有不同的看法，认为这是一种供需不匹配，供应是 不足以满足不断增长的肿瘤质量的需求。因此，如果我们能减少氧气需求 我们可以有效地减少缺氧并使肿瘤变得敏感，而不是增加供应。因为线粒体 是细胞内氧气的主要汇，我们认为新型线粒体抑制剂可以减少氧气。 需求与有限的供应相匹配。我们已经确认罂粟碱(PPV)是FDA批准的分子 在临床剂量下抑制线粒体功能的能力。我们小组发表的研究表明，在 罂粟碱可通过抑制线粒体功能而使小鼠肿瘤放射增敏，产生 “新陈代谢放射增敏”。罂粟碱最初是从罂粟中分离出来的，用作一种平滑的肌肉 血管松弛药可能是由于抑制了磷酸二酯酶10A。这项活动使其成为治疗 脑血管痉挛，但会导致全身血压下降和潜在的心血管不良影响。 因此，我们建议在这一应用中合成和评价新的罂粟碱小分子衍生物。 我们已经设计去除了它作为磷酸二酯酶抑制剂的活性，但保留了它作为一种 线粒体复合体1抑制剂。使用这些PPV衍生品和复杂的癌症小鼠模型，我们 旨在证明抑制线粒体功能是消除固体缺氧的有效策略 肿瘤不影响氧合良好的正常组织。初步数据支持总体理论，即 线粒体抑制剂增加肿瘤氧合能力和对放射治疗和免疫检查点的敏感性 封锁疗法。

ABSTRACT Tumor hypoxia reduces the effectiveness of anti-cancer treatment with radiotherapy, some chemotherapy and immune checkpoint blockade therapy. For radiotherapy, biophysical measures show that hypoxic cells require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For immunotherapy, hypoxia has been shown to contribute to immune evasion and even accelerate T cell exhaustion. For these reasons, many groups have tried to deliver more oxygen to tumors as an adjuvant to increase tumor sensitivity. Unfortunately, this approach has met with disappointing clinical results. We have looked at tumor oxygenation differently, as a supply and demand mismatch, with the supply being inadequate to meet the demand of the growing tumor mass. Therefore, if we could reduce oxygen demand rather than increase supply, we could effectively reduce hypoxia and sensitize tumors. Because mitochondria are the major sink for oxygen within a cell, we propose that novel mitochondria inhibitors would reduce oxygen demand to match the limited supply. We have identified papaverine (PPV) as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Published studies from our group showed that in mouse tumors that papaverine can radiosensitize through inhibition of mitochondrial function, producing “Metabolic Radiosensitization”. Papaverine was originally isolated from the poppy and used as a smooth muscle vasorelaxant presumably due to inhibition of phosphodiesterase 10A. This activity makes it an effective drug for cerebral vasospasm, but causes a systemic drop in blood pressure and potential adverse cardiovascular effects. We therefore propose in this application to synthesize and evaluate new small molecule derivatives of papverine that we have designed to remove its activity as a phosphodiesterase inhibitor, but retain its activity as a mitochondrial complex 1 inhibitor. Using these PPV derivatives, and sophisticated mouse models of cancer, we intend to prove that inhibition of mitochondrial function is an effective strategy for removing hypoxia in solid tumors without affecting well oxygenated normal tissue. Preliminary data supports the overall theory that mitochondrial inhibitors increase tumor oxygenation and sensitivity to radiotherapy and immune checkpoint blockade therapy.