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

热休克转录因子（HSF）在血液恶性肿瘤中的作用

• 批准号: 10568307
• 负责人: NAHID F MIVECHI
• 金额: $ 46.26万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568307
• 关键词: Ablation; Accounting; Acute Myelocytic Leukemia; Acute leukemia; Adoptive Transfer; Adult; Antigens; Applications Grants; Attenuated; Automobile Driving; Bioenergetics; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Cellular Immunity; Cellular immunotherapy; Cessation of life; Chemoresistance; Childhood; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; Development; Diagnosis; Disease remission; Drug resistance; Effector Cell; Elderly; Epigenetic Process; Exhibits; Experimental Designs; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; Heat-Shock Response; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Human; Human Engineering; Immune; Immunity; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Mass Fragmentography; Mediating; Memory; Metabolic; Metabolism; Modernization; Molecular; Mus; Mutation; Myeloproliferative disease; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Physiology; Population; Prognosis; Proteins; Proteome; Recurrence; Refractory; Regulation; Relapse; Remission Induction; Research; Resistance; Role; Sampling; Signal Transduction; Stress; Study models; Survival Rate; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Tumor Immunity; Tumor Promotion; adaptive immunity; anti-tumor immune response; cancer cell; cancer regression; cancer therapy; cancer type; cell transformation; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; chromatin modification; clinical efficacy; clinically significant; epigenetic regulation; exhaustion; experimental study; fitness; genetic signature; genotoxicity; heat shock transcription factor; immunological intervention; improved; individual patient; leukemia; leukemia relapse; leukemia treatment; liquid chromatography mass spectrometry; long term memory; metabolic profile; metabolomics; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oncogene addiction; preclinical study; prevent; progenitor; programs; protein folding; stem; stemness; targeted treatment; therapeutic target; therapeutically effective; transcription factor; translational goal; treatment strategy; tumor; tumorigenesis

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.

摘要 在人类恶性血液病中，急性白血病类型包括急性髓细胞白血病 (AML)占全球所有癌症死亡的4%，占美国癌症人口的6%。AML是 在儿童和成人人群中第二常见的白血病类型，但最常见的是 发生在成人中，占所有白血病病例的约30%。诱导疗法通常包括 强化和遗传毒性化疗，可导致高缓解率（>80%），但长期 AML亚型的存活率仅为30- 50%。事实上，原发耐药和复发的预后 儿童和老年人白血病的发病率仍然很低。目前，有一个强大的理由， 免疫干预癌症，包括血液恶性肿瘤，但最近的临床试验， 表明免疫疗法的益处仅限于一小部分（约20%）癌症患者， 包括AML患者。这就需要更好地理解其背后的机制 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 对原发性耐药和复发性白血病的有效和选择性治愈率。 Hsf 1作为经典热休克反应的主要激活剂和蛋白质组的监护者， 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，Hsf 1依赖的蛋白质稳态和代谢程序，当失活时，可以导致 癌症消退，特别是有效的白血病抑制。令人鼓舞的是，我们最近的研究揭示了 Hsf 1抑制在代谢重编程和增强中具有高度新颖和临床意义的作用 抗肿瘤的T细胞免疫。这可能为改善白血病治疗提供一种新的方法， 靶向Hsf 1活性的抗肿瘤免疫能力。我们建议，通过禁止支持性非- 癌基因成瘾途径，干扰肿瘤促进代谢重编程，并改善 通过靶向Hsf 1活性预测抗肿瘤免疫的能力，我们可以开发有效的策略， 白血病的治疗干预。我们的实验策略需要以下两种主要方法： 1.确定Hsf 1缺失对AML诱导的影响，并探索其对晚期AML的治疗潜力。 化疗耐药AML，和2.研究Hsf 1缺失对改善MHC-1表达的治疗作用。 限制性TCR或嵌合抗原受体（CAR）-T细胞为基础的免疫疗法，用于原发性和药物 耐药/复发的人AML。总之，该项目的长期转换目标是测试 Hsf 1在人类AML中的靶向潜力。它还将为靶向Hsf 1介导的 用于化疗耐药的血液病的免疫学应用的代谢程序 恶性肿瘤