Developing Therapeutics That Target RAD51 to Treat Leukemia and Lymphoma

开发针对 RAD51 的疗法来治疗白血病和淋巴瘤

• 批准号: 8645022
• 负责人: KEVIN D MILLS
• 金额: $ 21.35万
• 依托单位: CYTEIR THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645022
• 关键词: Acute Lymphocytic Leukemia; Adverse effects; Amides; Area; B-Cell Activation; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Biological; Biological Assay; Biological Products; Cancer Patient; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Chemicals; Chemistry; Chronic Lymphocytic Leukemia; Clinical; Clinical Oncology; DNA; DNA Double Strand Break; Development; Double Strand Break Repair; Drug Kinetics; Evolution; Family; Feasibility Studies; Genetic; Genome; Genomic Instability; Goals; Health; Human; In Vitro; Incidence; Laboratories; Laws; Lead; Leukemic Cell; Life; Light; Liver; Lymphoid; Malignant Neoplasms; Marketing; Measures; Mediating; Metabolic; Modeling; Modification; Multiple Myeloma; Mus; Mutase; Mutation; Neoplasms; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Oncogenic; Pharmaceutical Preparations; Phase; Policies; Property; Quality of life; Radio; Refractory; Relapse; Relative (related person); Resistance; Series; Specificity; Stilbenes; Structure; Structure of germinal center of lymph node; Sulfonic Acids; Taxes; The Jackson Laboratory; Therapeutic; Thiourea; Translations; United States; United States National Institutes of Health; Xenograft Model; activation-induced cytidine deaminase; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; conventional therapy; drug development; efficacy testing; homologous recombination; improved; in vivo; inhibitor/antagonist; leukemia; leukemia/lymphoma; meetings; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; patient population; pre-clinical; prevent; programs; public health relevance; recombinase; survivorship; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Genomic instability is a hallmark of cancer, yet is underdeveloped as a therapeutic target area The central goal of this program is to develop new cancer therapeutics that target genomic instability as a hallmark of cancer cells, bringing new, cancer-cell selective treatments to the clinical oncology market. Two key challenges in current cancer therapy are minimizing the side effects associated with chemotherapy; and preventing tumor cell "evolution" by acquired mutations that drive cancer progression and therapy resistance. Therapies that target genomic instability mechanisms have the potential to meet these critical clinical challenges. In recent years, the B-cell specific DNA mutase/recombinase Activation Induced Cytidine Deaminase (AID) has been implicated as a driver of oncogenic genomic instability. While its expression is normally restricted to activated, germinal center B-cells, AID is also overexpressed in a range of human neoplasms, especially B-cell lymphomas and leukemias. Cyteir Therapeutics, Inc. has partnered with The Jackson Laboratory to develop new cancer therapeutics that target AID-induced genomic instability to induce tumor-cell self-destruction with few off target side effects. This approach takes advantage of the discoveries that: (1) AID creates widespread DNA double strand breaks (DSBs) throughout the genome; and (2) the RAD51 family of DSB repair factors is critical for leukemic cells to survive this damage. In vitro, reduction in RAD51 function causes AID-mediated tumor cell death, but is tolerated by cells lacking AID expression, such as most normal tissues. The aims of this feasibility study are to assess the in vivo efficacy of targeting RAD51 using leukemia and lymphoma xenograft models; and to generate derivatives of our early RAD51 inhibitor lead that have drug-like pharmacokinetic properties, while retaining potency and specificity for AID-expressing tumors. We are focusing our current preclinical development efforts on B-cell neoplasms, such as non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL) that often requires intensive, long-term chemotherapy. There is still an unmet clinical need in these cancers, because conventional therapies can be physically taxing, cause severe and sometimes life-threatening side effects, and often fail to achieve cure. These Phase I feasibility studies will accelerate the preclinical development of new therapeutics that target genomic instability mechanisms, and will pave the path for their clinical and commercial development. !

描述（由申请人提供）：基因组不稳定性是癌症的标志，但作为治疗靶向领域尚未开发。该计划的中心目标是开发新的癌症治疗方法，将基因组不稳定性作为癌细胞的标志，为临床肿瘤学市场带来新的癌细胞选择性治疗。当前癌症治疗中的两个关键挑战是最大限度地减少与化疗相关的副作用;以及通过驱动癌症进展和治疗耐药性的获得性突变来防止肿瘤细胞“进化”。靶向基因组不稳定机制的疗法有可能应对这些关键的临床挑战。近年来，B细胞特异性DNA酶/重组酶激活诱导的胞苷脱氨酶（AID）已被认为是致癌基因组不稳定性的驱动因素。虽然其表达通常限于活化的生发中心B细胞，但AID也在一系列人类肿瘤中过表达，特别是B细胞淋巴瘤和白血病。Cyteir Therapeutics，Inc.与杰克逊实验室合作开发新的癌症疗法，靶向艾滋病诱导的基因组不稳定性，以诱导肿瘤细胞自我毁灭，几乎没有脱靶副作用。这种方法利用了以下发现：（1）AID在整个基因组中产生广泛的DNA双链断裂（DSB）;以及（2）DSB修复因子的RAD 51家族对于白血病细胞在这种损伤中存活至关重要。在体外，RAD 51功能的降低导致AID介导的肿瘤细胞死亡，但被缺乏AID表达的细胞耐受，如大多数正常组织。这项可行性研究的目的是评估使用白血病和淋巴瘤异种移植模型靶向RAD 51的体内功效;并产生我们早期RAD 51抑制剂先导物的衍生物，其具有药物样药代动力学特性，同时保留对表达AIDS的肿瘤的效力和特异性。我们目前的临床前开发工作主要集中在B细胞肿瘤上，如非霍奇金淋巴瘤（NHL）和急性淋巴细胞白血病（ALL），这些肿瘤通常需要密集的长期化疗。在这些癌症中仍然存在未满足的临床需求，因为常规疗法可能是体力劳动，导致严重的，有时危及生命的副作用，并且通常无法实现治愈。这些I期可行性研究将加速靶向基因组不稳定机制的新疗法的临床前开发，并为其临床和商业开发铺平道路。!