Role of heat shock transcription factors (HSFs) in hematological malignancies

摘要 在人类血液系统恶性肿瘤中，急性白血病类型包括急性髓系白血病 急性髓细胞白血病(AML)占全球所有癌症死亡的4%，占美国人口癌症死亡的6%。AML是 在儿童和成人人群中第二常见的确诊白血病类型，但最常见 发生在成人中，约占所有白血病病例的30%。诱导治疗一般包括 可导致高缓解率(80%)的高强度和基因毒性化疗，但长期的 AML亚型的存活率只有30-50%。的确，原发耐药和复发的预后 儿童和老年人群中的白血病仍然非常贫穷。目前，有一个强有力的理由来支持 免疫干预治疗癌症，包括血液系统恶性肿瘤，但最近的临床试验已经 证明免疫疗法的好处只属于一小部分(~20%)的癌症患者， 包括那些急性髓系白血病患者。这促使我们需要更好地理解潜在的机制。 白血病细胞的可塑性和适应性，以及开发新的治疗方法以实现更多 原发耐药和复发白血病的有效和选择性治愈率。 HSF1作为经典热休克反应的主要激活剂和蛋白质组的守护者，一直以来都是蛋白质组的守护者。 与癌症的发病机制有关。我们的临床前研究揭示了一种 协调的、依赖于HSF1的蛋白质稳态和代谢程序，当被灭活时，可以导致 癌症消退，尤其是对白血病的有效抑制。令人鼓舞的是，我们最近的研究揭开了面纱 HSF1抑制在代谢重编程和增强中的高度新颖和临床意义 抗肿瘤T细胞免疫。这可能为改善白血病的治疗提供一种新的方法 靶向HSF1活性的抗肿瘤免疫能力。我们建议通过抑制支持性的非 癌基因成瘾途径，干扰促进肿瘤的代谢重编程，并改善 通过靶向HSF1活性预测抗肿瘤免疫力，我们可以开发一种有效的策略 白血病的治疗干预。我们的试验性战略包括以下两个主要方法： 1.确定HSF1缺失对AML诱导的影响，并探讨其治疗晚期AML的潜力 化疗耐药的AML，以及2.研究HSF1缺失对MHC-1改善的治疗影响 限制性TCR或嵌合抗原受体(CAR)-T细胞为基础的初级和药物免疫治疗 耐药/复发的人类急性淋巴细胞白血病。总而言之，该项目的长期翻译目标是测试 HSF1靶向在人类急性髓系白血病中的潜在作用它还将提供针对HSF1介导的目标的概念验证 化疗耐药血液病免疫治疗应用的代谢方案 恶性肿瘤。

Abstract Among the human hematological malignancies, acute leukemia types including acute myeloid leukemia (AML) accounts for 4% of all cancer deaths worldwide and 6% of cancer in the US population. AML is the second most common type of diagnosed leukemia in pediatric and adult populations but most frequently occurs in adults accounting for about 30% of all leukemia cases. Inductive therapy generally involves intensive and genotoxic chemotherapy that can lead to high remission rates (>80%), but the long-term survival rates for AML subtypes are only 30-50%. Indeed, the prognosis of primary resistant and relapsed leukemia in pediatric and elderly populations remains very poor. Currently, there is a strong rationale for immune intervention in cancers, including hematological malignancies, but recent clinical trials have demonstrated that the benefits of immunotherapy are relegated to a small fraction (~20%) of cancer patients, including those with AML. This prompts the need for greater understanding of the mechanisms underlying leukemic cell plasticity and adaptation, as well as developing novel therapeutic approaches to achieve more effective and selective cure rates for primary drug-resistant and relapsed leukemia. Hsf1, as the master activator of the classical heat shock response and guardian of the proteome, has been implicated in the pathogenesis of cancer. Our preclinical studies have revealed the existence of a coordinated, Hsf1-dependent protein homeostatic and metabolic program that, when inactivated, can lead to cancer regression and, in particular, effective leukemia inhibition. Encouragingly, our recent studies unveiled a highly novel and clinically significant role for Hsf1 inhibition in metabolic reprogramming and enhancement of anti-tumor T cell immunity. This may provide a new approach to improve leukemia treatment by improving the anti-tumor immune capacity targeting Hsf1 activity. We propose that by inhibiting supportive non- oncogene addiction pathways, interfering with tumor-promoting metabolic reprogramming, and improving the predicted power of anti-tumor immunity through targeting of Hsf1 activity, we can develop a valid strategy for therapeutic interventions in leukemia. Our experimental strategy entails the following two major approaches: 1. Determine the impact of Hsf1 deletion on AML induction and explore its therapeutic potential for advanced chemotherapy-resistant AML, and 2. Investigate the therapeutic impact of Hsf1 deletion on improved MHC- restricted TCR or chimeric antigen receptor (CAR)-T cell-based immunotherapy for primary and drug resistant/relapsed human AMLs. In summary, the long-term translational goal of the project is to test the potential of Hsf1 targeting in human AML. It will also provide proof-of-concept for targeting Hsf1-mediated metabolic programs for immunotherapeutic application of chemotherapy-resistant hematological malignancies.