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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在人类血液系统恶性肿瘤中，急性白血病类型包括急性粒细胞白血病 (AML) 占全球癌症死亡人数的 4%，占美国人口癌症死亡人数的 6%。反洗钱是在儿童和成人中第二常见的诊断白血病类型，但最常见发生于成人，约占所有白血病病例的 30%。诱导疗法通常涉及强化和基因毒性化疗可以带来高缓解率（>80%），但长期 AML 亚型的生存率仅为 30-50%。事实上，原发耐药和复发的预后儿童和老年人的白血病发病率仍然非常低。目前，有充分的理由对癌症（包括血液恶性肿瘤）进行免疫干预，但最近的临床试验表明证明免疫疗法的益处只限于一小部分（~20%）癌症患者，包括患有 AML 的患者。这提示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目标原发性耐药和复发性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，已被参与癌症的发病机制。我们的临床前研究揭示了存在协调的、Hsf1 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，特别是有效抑制白血病。令人鼓舞的是，我们最近的研究揭示了 Hsf1 抑制在代谢重编程和增强中具有高度新颖且具有临床意义的作用抗肿瘤T细胞免疫。这可能为改善白血病治疗提供一种新方法针对 Hsf1 活性的抗肿瘤免疫能力。我们建议通过抑制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 Hsf1 活性来预测抗肿瘤免疫的能力，我们可以制定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Hsf1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性 AML，以及 2. 研究 Hsf1 缺失对改善 MHC- 的治疗影响用于初级和药物的限制性 TCR 或嵌合抗原受体 (CAR)-T 细胞免疫疗法耐药/复发的人类 AML。总之，该项目的长期翻译目标是测试 Hsf1 靶向治疗人类 AML 的潜力。它还将为靶向 Hsf1 介导的化疗耐药血液细胞免疫治疗应用的代谢方案恶性肿瘤。