Development of Targeted Damaging Agents for the Treatment of Drug-Resistant Gliomas

开发治疗耐药神经胶质瘤的靶向损伤剂

• 批准号: 10812561
• 负责人: Gerald Francis Vovis
• 金额: $ 110.79万
• 依托单位: MODIFI BIOSCIENCES INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10812561
• 关键词: Achievement; Adenine; Alkylating Agents; Alkylation; Apoptosis; Base Pairing; Biological Markers; Cell Line; Cells; Central Nervous System; Chemistry; Clinical; Collection; Colon Carcinoma; DNA; DNA Repair; DNA biosynthesis; DNA lesion; DNA-Directed DNA Polymerase; Data; Defect; Development; Dose; Drug Kinetics; Drug resistance; Electronics; Excision; Exhibits; Futile Cycling; Genome; Glioblastoma; Glioma; Hydrogen; Hypermethylation; Isocitrate Dehydrogenase; Laboratories; Lead; Lesion; Lomustine; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Methyltransferase; Mismatch Repair; Modeling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncology; Pathway interactions; Patients; Penetrance; Penetration; Phase; Phase I Clinical Trials; Plasma; Positioning Attribute; Predisposition; Property; Recurrence; Refractory; Resected; Resistance; Rodent; Safety; Series; Small Business Innovation Research Grant; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Index; Thymine; Toxicology; Translational Research; Universities; Xenograft Model; analog; demethylation; epigenetic silencing; glioma cell line; improved; in vitro activity; in vivo; inhibitor; lead optimization; manufacture; mouse model; novel; pre-Investigational New Drug meeting; preclinical development; promoter; repaired; resistance mechanism; small cell lung carcinoma; small molecule; success; temozolomide; tumor; tumor xenograft

PROJECT SUMMARY Loss of O6-methylguanine methyltransferase (MGMT) expression is common in cancers and confers sensitivity to DNA alkylators, such as temozolomide (TMZ). Epigenetic silencing of MGMT via promoter hypermethylation is found in ~50% of glioblastomas (GBMs), and in most lower grade gliomas with isocitrate dehydrogenase-1/2 (IDH1/2) mutations. MGMT is also silenced in other cancers, including up to 40% of colon cancers, 35% of small cell lung cancers, and 25% of non-small cell lung cancers. In cells that lack MGMT expression (termed MGMT-cells), TMZ-derived O6-methylguanine (O6MeG) lesions mispair with thymine, during DNA replication, due to altered hydrogen base pairing, leading to activation of the mismatch repair pathway (MMR). MMR attempts to repair these lesions by resecting the newly synthesized strand, but thymine once again is inserted opposite of O6MeG. This reinsertion again triggers MMR, leading to iterative “futile cycles” of DNA repair and ultimately apoptosis. Clinically, MGMT promoter demethylation is rare, whereas MMR mutations occur frequently as a dominant mechanism of resistance to TMZ in many tumor types. Because MGMT silencing is found in many cancers, DNA lesions that overcome the MMR resistance (while still being resolvable by MGMT, so as to maintain a therapeutic index (TI)) will have a broad impact. Furthermore, as this biomarker persists even in the treatment-refractory setting (i.e., in the context of MMR defects), we argue that loss of MGMT expression has not been fully exploited for therapeutic gain. Based on the findings presented above, we seek to develop a new class of agents discovered in the laboratory of Drs. Ranjit Bindra and Seth Herzon that generate O6MeG lesions that are susceptible to MGMT removal (“MGMT dependent”) in healthy cells, but which can overcome MMR resistance (“MMR independent”). To this end, Drs. Bindra and Herzon have co-founded KL50 Therapeutics, LLC, and their studies lead to the identification of KL50, a novel alkylation agent that is more active against MMR- cell lines than MMR+ cell lines, while retaining MGMT resolvability. This molecule demonstrates exquisite sensitivity in MGMT-deficient cells independent of MMR status, with negligible activity in MGMT-proficient cells, and has a TI approximately 30 times greater than TMZ. Building on these achievements, in this fast-track SBIR project, we propose to conduct lead optimization to improve central nervous system (CNS) penetration, identify a collection of small molecules with in vivo efficacy in mouse models of high-grade gliomas (HGG), and further develop these compounds for use in a Phase 1 clinical trial. These MGMT dependent–MMR independent alkylating agents are anticipated to possess the positive attributes of TMZ, while circumventing the unavoidable MMR loss mediated resistance mechanism and, thereby, have a major impact on the way we treat GBMs and other tumors lacking MGMT. These molecules could represent a paradigm shift in oncology by dramatically improving their therapeutic index. If successful, our approach will significantly increase the safety and efficacy of DNA alkylators and will expand their use for a broader range of recurrent gliomas and many other cancers.

项目概要 O6-甲基鸟嘌呤甲基转移酶 (MGMT) 表达缺失在癌症中很常见，并赋予敏感性 DNA 烷基化剂，例如替莫唑胺 (TMZ)。通过启动子高甲基化导致 MGMT 的表观遗传沉默 存在于约 50% 的胶质母细胞瘤 (GBM) 中，并且存在于大多数具有异柠檬酸脱氢酶的低级别胶质瘤中-1/2 (IDH1/2) 突变。 MGMT 在其他癌症中也被沉默，包括高达 40% 的结肠癌、35% 的小肠癌 细胞肺癌和 25% 的非小细胞肺癌。在缺乏 MGMT 表达的细胞（称为 MGMT 细胞）中，TMZ 衍生的 O6-甲基鸟嘌呤 (O6MeG) 损伤在 DNA 复制过程中与胸腺嘧啶错配，原因是 改变氢碱基配对，导致错配修复途径（MMR）的激活。 MMR 试图 通过切除新合成的链来修复这些损伤，但胸腺嘧啶再次插入到与 O6MeG。这种重新插入再次触发 MMR，导致 DNA 修复的迭代“无效循环”，最终 细胞凋亡。临床上，MGMT 启动子去甲基化很少见，而 MMR 突变经常作为 许多肿瘤类型对 TMZ 耐药的主要机制。因为 MGMT 沉默存在于许多 癌症、克服 MMR 耐药性的 DNA 损伤（同时仍可通过 MGMT 解决，以便 维持治疗指数（TI））将产生广泛的影响。此外，由于这种生物标志物即使在 治疗难治性环境（即，在 MMR 缺陷的情况下），我们认为 MGMT 表达的丧失 没有被充分利用来获得治疗效果。基于上述发现，我们寻求开发一种新的 博士实验室发现的一类药剂。 Ranjit Bindra 和 Seth Herzon 产生 O6MeG 损伤 在健康细胞中容易被 MGMT 去除（“MGMT 依赖性”），但可以克服 MMR 电阻（“独立于 MMR”）。为此，博士。 Bindra 和 Herzon 共同创立了 KL50 Therapeutics, LLC， 他们的研究导致了 KL50 的鉴定，这是一种新型烷基化剂，对 MMR 细胞更具活性 细胞系优于 MMR+ 细胞系，同时保留 MGMT 可分辨性。该分子表现出极高的敏感性 在 MGMT 缺陷细胞中，与 MMR 状态无关，在 MGMT 熟练细胞中活性可忽略不计，并且具有 TI大约是TMZ的30倍。在这些成就的基础上，在这个快速 SBIR 项目中，我们 提议进行先导化合物优化以提高中枢神经系统（CNS）渗透率，确定集合 在高级神经胶质瘤（HGG）小鼠模型中具有体内功效的小分子，并进一步开发这些 用于一期临床试验的化合物。这些依赖于 MGMT 且独立于 MMR 的烷化剂是 预计具有 TMZ 的积极属性，同时避免不可避免的 MMR 损失介导 耐药机制，从而对我们治疗 GBM 和其他缺乏耐药性的肿瘤的方式产生重大影响。 管理MT。这些分子可以通过显着提高其活性来代表肿瘤学的范式转变。 治疗指数。如果成功，我们的方法将显着提高 DNA 烷化剂的安全性和有效性 并将扩大其用于更广泛的复发性神经胶质瘤和许多其他癌症的用途。