Anti-tumor potential of temperature-sensitive p53 mutants

p53肿瘤抑制因子经常因癌症突变而失活。大多数p53点 突变位于DNA结合结构域中，阻止折叠或破坏DNA结合表面。 拯救肿瘤细胞中突变型p53的结构缺陷和转录活性， 死亡或细胞周期停滞，带来显著的治疗益处。然而，这一假设仍然存在。 因为目前还没有能够有效地再激活突变型p53的特异性药物。到 绕过这一限制，并严格测试突变型p53功能拯救的临床潜力，我们 建立了一个程序，通过药理学阻断脑- 调节产热。这个小鼠模型使我们能够使用低温来重新激活温度- 敏感的（TS）p53突变体，以评估治疗效果。初步实验 证实了tsp 53激活与化疗联合诱导肿瘤消退的能力。 淋巴瘤异种移植物重要的是，在一个肿瘤亚组中观察到持久缓解。这 一项有希望的发现为突变型p53作为潜在癌症的功能性拯救提供了概念验证 治疗此外，由于癌症中约14%的p53点突变体是温度敏感的，我们的研究表明， 结果提高了使用治疗性低温治疗表达TS突变型p53的肿瘤的可能性。 为了探索这种新方法的翻译潜力和分子机制，我们提出了 以下具体目的：（1）研究肿瘤对ts p53激活的反应，并优化治疗方案。 功效(2)研究ts突变型p53在实体瘤和PDX模型中的潜力。（三） 使用基因工程小鼠研究内源性ts p53激活的作用 模型(4)通过饱和筛选鉴定所有具有肿瘤抑制活性的p53 ts突变体。 这些实验将为特异性靶向表达ts突变体的肿瘤提供概念验证 p53，有可能影响大量癌症患者。

The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 point mutations are located in the DNA binding domain that prevent folding or disrupt the DNA binding surface. Rescuing the structural defect and transcriptional activity of mutant p53 in tumor cells should induce cell death or cell cycle arrest that bring significant therapeutic benefits. However, this hypothesis remains unproven because currently there are no specific drugs capable of efficiently reactivating mutant p53. To bypass this limitation and rigorously test the clinical potential of mutant p53 functional rescue, we established a procedure to induce sustained hypothermia in mice by pharmacological blockade of brain- regulated thermogenesis. This mouse model enabled us to use hypothermia to reactivate temperature- sensitive (ts) p53 mutants in tumors to evaluate therapeutic efficacy. Preliminary experiments demonstrated the ability of ts p53 activation in combination with chemotherapy to induce regression of lymphoma xenografts. Importantly, durable remission was observed in a subset of tumors. This promising finding provides proof-of-concept for mutant p53 functional rescue as a potential cancer treatment. Furthermore, since ~14% of p53 point mutants in cancer are temperature-sensitive, our results raised the possibility of using therapeutic hypothermia to treat tumors expressing ts mutant p53. To explore the translational potential and molecular mechanism of this novel approach, we propose the following specific aims: (1) Investigate tumor response to ts p53 activation and optimize therapeutic efficacy. (2) Investigate the potential of ts mutant p53 in solid tumors and PDX models. (3) Investigate the effect of endogenous ts p53 activation using a genetically engineered mouse model. (4) Identify all p53 ts mutants with tumor suppressor activity in vivo by saturation screen. These experiments will provide proof-of-concept for specific targeting of tumors expressing ts mutant p53, with the potential to impact a large number of cancer patients.