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: 9138224
• 负责人: KEVIN D MILLS
• 金额: $ 103.9万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138224
• 关键词: Adverse effects; Animal Model; Area; B-Cell Activation; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological Availability; Biological Markers; Biotechnology; Cancer Model; Cancer Patient; Cells; Cessation of life; Characteristics; Chronic; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Collaborations; Complement; Country; Cyclophosphamide; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Development; Dosage Forms; Dose; Drug Kinetics; Evolution; Formulation; Foundations; Genome; Genomic Instability; Goals; Health; Human; In Vitro; Incidence; Industry; Investigational Drugs; Investigational New Drug Application; Lead; Licensing; Life; Lymphoblastic Leukemia; Lymphoid; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Marketing; Measures; Metabolic; Multiple Myeloma; Mus; Mutase; Neoplasms; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Oncogenic; Oral; Oral Administration; Patients; Phase; Phase I Clinical Trials; Preclinical Testing; Prednisone; Preparation; Property; Quality of life; Rattus; Regimen; Resistance; Role; Route; Safety; Structure of germinal center of lymph node; Technology; Testing; The Jackson Laboratory; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Translations; United States; Vincristine; Xenograft Model; activation-induced cytidine deaminase; asparaginase; cancer cell; cancer therapy; chemotherapy; commercialization; comparative efficacy; drug development; drug discovery; drug market; fludarabine; humanized mouse; improved; in vivo; inhibitor/antagonist; leukemia/lymphoma; meetings; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; oncology; overexpression; patient population; phase 2 study; phase II trial; pre-clinical; preclinical study; programs; public health relevance; recombinase; repaired; research and development; research clinical testing; response; rituximab; success; survivorship; targeted treatment; therapeutic target; treatment response; tumor; tumor progression

 DESCRIPTION (provided by applicant): Genomic instability is a hallmark of cancer, and represents a targetable vulnerability, yet is underdeveloped as a therapeutic area. The central goal of this Phase 2 program is to complete the early preclinical development of a new class of new cancer therapeutics that uniquely target RAD51, delivering effective cancer-cell selective therapy in subsets of biomarker-defined leukemia and lymphoma. Two key challenges in current cancer therapy are overcoming tumor cell "evolution" that drives cancer progression and therapy resistance; and minimizing the side effects due to off-target toxicity. 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 non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). Cyteir Therapeutics, Inc., in partnership with The Jackson Laboratory, has demonstrated the feasibility of targeting RAD51 in these cancers and has developed new lead candidate compound. Our novel therapeutic approach takes advantage of the discoveries that: (1) AID is both a biomarker and a DNA damage driver, creating widespread DNA double strand breaks (DSBs) throughout the genome; and (2) RAD51 has a unique role in the repair of these malignant, AID-induced DSBs and is, therefore, critical for viability in transformed, AID+ cells. Cyteir's lead RAD51 inhibitor is potent, highly selective for cells that are AID+, effective against NHL and CLL cells in vitro and in vivo, and is extremely well tolerated in preclinical animal models. The aims of this Phase 2 study are to complete early preclinical testing and development required prior to the filing of investigational new drug (IND) application and commencement of phase I clinical trials. We will develop a clinical dosage form for our lead compound, carry out single- and multiple-dose tolerability and range finding studies, establish pharmacokinetics and toxicokinetics for the clinical dose form, and generate comprehensive comparative efficacy data using human- to-mouse xenograft models of NHL and CLL. We have assembled an impressive team of academic and industry leaders, complemented by an advisory panel of top thought leaders, to advance this program and build the Cyteir drug discovery engine. One of our strengths is the continuing partnership with The Jackson Laboratory, providing both an academic foundation for our R&D efforts and a platform of unique in vivo testing technologies to enable rapid translation to the clinical phase. Our commercialization plan for this program calls for completion of the proposed preclinical studies, commencement of clinical trials and partnership or out licensing after either phase I or phase II trials, to create company and investor value and generate revenue to continue building a sustainable drug development pipeline.

 描述（由申请人提供）：基因组不稳定性是癌症的一个标志，代表了一种可靶向的脆弱性，但作为一个治疗领域尚未开发。该2期项目的中心目标是完成一类新的癌症治疗药物的早期临床前开发，这些药物独特地靶向RAD 51，在生物标志物定义的白血病和淋巴瘤的子集中提供有效的癌细胞选择性治疗。当前癌症治疗中的两个关键挑战是克服肿瘤细胞“进化”，其驱动癌症进展和治疗抗性;以及最小化由于脱靶毒性引起的副作用。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细胞非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）。Cyteir Therapeutics，Inc.，与杰克逊实验室合作，已经证明了在这些癌症中靶向RAD 51的可行性，并开发了新的先导候选化合物。我们的新治疗方法利用了以下发现：（1）AID既是生物标志物又是DNA损伤驱动器，在整个基因组中产生广泛的DNA双链断裂（DSB）;和（2）RAD 51在修复这些恶性的、AID诱导的DSB中具有独特的作用，因此对于转化的AID+细胞的活力至关重要。Cyteir的领先的RAD 51抑制剂是有效的，高选择性的 对于AID+的细胞，在体外和体内有效对抗NHL和CLL细胞， 在临床前动物模型中耐受良好。本II期研究的目的是在提交研究性新药（IND）申请和开始I期临床试验之前完成所需的早期临床前试验和开发。我们将为我们的先导化合物开发临床剂型，进行单次和多次给药耐受性和范围探索研究，建立临床剂型的药代动力学和毒代动力学，并使用NHL和CLL的人-小鼠异种移植模型生成全面的比较疗效数据。我们已经组建了一个令人印象深刻的学术和行业领导者团队，并辅之以由顶级思想领袖组成的咨询小组，以推进该计划并构建Cyteir药物发现引擎。我们的优势之一是与杰克逊实验室的持续合作伙伴关系，为我们的研发工作提供学术基础，并提供独特的体内测试技术平台，以便快速转化为临床阶段。我们对该计划的商业化计划要求完成拟议的临床前研究，开始临床试验和合作伙伴关系，或在I期或II期试验后获得许可，以创造公司和投资者价值，并产生收入，继续建立可持续的药物开发管道。