Developing Therapeutics That Target RAD51 to Treat Leukemia and Lymphoma

描述（由申请人提供）：基因组不稳定性是癌症的一个标志，但作为治疗靶点领域还不发达。本项目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一个标志，为临床肿瘤市场带来新的癌细胞选择性治疗。目前癌症治疗的两个关键挑战是最小化与化疗相关的副作用；并通过获得性突变来阻止肿瘤细胞的“进化”，这些突变会推动癌症的进展和治疗耐药性。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突变酶/重组酶激活诱导胞苷脱氨酶（AID）被认为是致癌基因组不稳定的驱动因素。虽然AID的表达通常局限于活化的生发中心b细胞，但它也在一系列人类肿瘤中过度表达，尤其是b细胞淋巴瘤和白血病。Cyteir Therapeutics公司与杰克逊实验室合作开发了一种新的癌症疗法，该疗法针对艾滋病引起的基因组不稳定性，诱导肿瘤细胞自我毁灭，并且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（DSBs）；(2) DSB修复因子RAD51家族对白血病细胞存活至关重要。在体外，RAD51功能的降低会导致AID介导的肿瘤细胞死亡，但对缺乏AID表达的细胞（如大多数正常组织）是耐受的。本可行性研究的目的是利用白血病和淋巴瘤异种移植模型评估靶向RAD51的体内疗效；并生成我们早期RAD51抑制剂先导物的衍生物，这些衍生物具有类似药物的药代动力学特性，同时保留对表达艾滋病的肿瘤的效力和特异性。我们目前的临床前研究重点是b细胞肿瘤，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。这些癌症的临床需求仍未得到满足，因为传统疗法可能会对身体造成负担，导致严重的、有时危及生命的副作用，而且往往无法治愈。这些I期可行性研究将加速针对基因组不稳定机制的新疗法的临床前开发，并将为其临床和商业开发铺平道路。！

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. !