Overcoming hypoxic resistance to anti-cancer therapy

摘要 肿瘤缺氧降低了放疗、一些化疗和化疗等抗癌治疗的有效性。 免疫检查点阻断疗法。对于放射治疗，生物物理测量显示缺氧细胞需要 2.8-以达到与完全氧合的那些相同的细胞杀伤。对于免疫疗法， 缺氧已显示有助于免疫逃避，甚至加速T细胞耗竭。为这些 由于这些原因，许多研究小组试图将更多的氧气输送到肿瘤中，作为一种辅助手段来增加肿瘤的敏感性。 不幸的是，这种方法遇到了令人失望的临床结果。 我们以不同的方式看待肿瘤氧合，认为这是一种供需不匹配， 不足以满足日益增长的肿瘤块的需求。因此，如果我们能减少氧气需求 而不是增加供应，我们可以有效地减少缺氧和致敏肿瘤。因为线粒体 是细胞内氧的主要汇，我们提出新的线粒体抑制剂将减少氧 需求与有限的供应相匹配。我们已经将罂粟碱（PPV）鉴定为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， 罂粟碱可以通过抑制线粒体功能，产生放射增敏作用的小鼠肿瘤， 代谢性放射增敏罂粟碱最初是从罂粟中分离出来的，用作平滑肌 血管舒张剂，可能是由于抑制磷酸二酯酶10A。这种活性使其成为有效的药物， 脑血管痉挛，但会导致全身血压下降和潜在的心血管不良反应。 因此，我们在本申请中提出合成和评价新的罂粟碱小分子衍生物 我们已经设计了去除其作为磷酸二酯酶抑制剂的活性，但保留其作为 线粒体复合物1抑制剂。使用这些PPV衍生物和复杂的小鼠癌症模型，我们 旨在证明抑制线粒体功能是消除固体中缺氧有效策略 肿瘤不会影响氧合良好的正常组织。初步数据支持了总体理论， 线粒体抑制剂增加肿瘤氧合和对放疗和免疫检查点的敏感性 阻断疗法

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.