Developing Therapeutics That Target RAD51 To Treat Leukemia and Lymphoma

 描述(由申请人提供)：基因组不稳定是癌症的一个标志，代表了一种可靶向的脆弱性，但作为治疗领域还不发达。这一第二阶段计划的中心目标是完成针对RAD51的新型癌症疗法的早期临床前开发，在生物标记物定义的白血病和淋巴瘤的亚类中提供有效的癌细胞选择性治疗。当前癌症治疗的两个关键挑战是克服推动癌症进展和治疗耐药性的肿瘤细胞“进化”，以及将靶外毒性引起的副作用降至最低。针对基因组不稳定机制的治疗有可能应对这些关键的临床挑战。近年来，B细胞特异性DNA变位酶/重组酶激活诱导的胞苷脱氨酶(AID)被认为是致癌基因组不稳定的驱动因素。虽然AID的表达通常局限于激活的生发中心B细胞，但它在一系列人类肿瘤中也过表达，特别是B细胞性非霍奇金淋巴瘤(NHL)和慢性淋巴细胞白血病(CLL)。Cyteir治疗公司与杰克逊实验室合作，已经证明了在这些癌症中靶向RAD51的可行性，并开发了新的候选先导化合物。我们的新治疗方法利用了以下发现：(1)AID既是一个生物标记物，也是DNA损伤的驱动因素，在整个基因组中造成广泛的DNA双链断裂(DSB)；(2)RAD51在修复这些由AID诱导的恶性双链断裂方面具有独特的作用，因此对转化的AID+细胞的生存至关重要。Cyteir的主要RAD51抑制剂是有效的，高度选择性的 对于AID+的细胞，在体外和体内对NHL和CLL细胞有效，并且非常 在临床前动物模型中耐受性良好。这项第二阶段研究的目的是完成在提交研究性新药(IND)申请和开始第一阶段临床试验之前所需的早期临床前测试和开发。我们将为我们的先导化合物开发一种临床剂型，开展单剂量和多剂量耐受性和射程发现研究，建立临床剂量形式的药代动力学和毒代动力学，并使用非霍奇金淋巴瘤和慢性淋巴细胞性白血病的人-鼠异种移植模型产生全面的比较疗效数据。我们组建了一支由学术和行业领袖组成的令人印象深刻的团队，并辅之以一个由顶级思想领袖组成的顾问小组，以推进这一计划并建立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，为我们的研发工作提供了学术基础，并提供了一个独特的体内测试技术平台，使其能够快速过渡到临床阶段。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，并在第一阶段或第二阶段试验后建立合作伙伴关系或退出许可，以创造公司和投资者的价值，并创造收入，以继续建设可持续的药物开发管道。

 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.