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.

项目摘要 O6-甲基鸟嘌呤甲基转移酶（MGMT）表达的丧失在癌症中很常见，供词敏感性 到DNA烷基剂，例如替莫唑胺（TMZ）。 MGMT通过启动子高甲基化的表观遗传沉默 在约50％的胶质母细胞瘤（GBM）中发现，在大多数低级神经胶质瘤中，具有异质脱氢酶1/2 （IDH1/2）突变。其他癌症也会沉默MGMT，包括多达40％的结肠癌，35％的小癌症 细胞肺癌和25％的非小细胞肺癌。在缺乏MGMT表达（称为MGMT细胞）的细胞中，TMZ衍生的O6-甲基鸟嘌呤（O6meg）病变在DNA复制过程中与胸腺氨酸混乱 改变氢碱配对，导致不匹配修复途径（MMR）的激活。 MMR尝试 通过切除新合成的链来修复这些病变，但胸腺激素再次插入与 O6meg。这种再插入再次触发MMR，导致DNA修复的迭代“徒劳循环”，并最终导致 凋亡。在临床上，MGMT启动子脱甲基化很少见，而MMR突变经常以一种 许多肿瘤类型中对TMZ抗性的主要机制。因为在许多人中发现了MGMT沉默 克服MMR抗性的癌症，DNA病变（同时仍可以通过MGMT解析，以便 保持治疗指数（TI）将产生广泛的影响。此外，由于这个生物标志物甚至在 治疗难治性设置（即，在MMR缺陷的背景下），我们认为MGMT表达的损失具有 没有充分探索以获得治疗。根据上述发现，我们试图开发新的 在Drs实验室发现的代理商类别。 Ranjit Bindra和Seth Herzon产生O6meg病变 在健康细胞中容易删除MGMT（MGMT依赖性”），但可以克服MMR 电阻（“ MMR独立”）。为此，博士。 Bindra和Herzon共同创立了KL50 Therapeutics，LLC， 他们的研究导致KL50的鉴定，KL50是一种新型烷基化剂，对MMR细胞更活跃 线比MMR+细胞系，同时保留MGMT的分解性。该分子表现出独家灵敏度 在MGMT缺陷的细胞中，与MMR状态无关，在MGMT促成细胞中具有可忽略的活性，并且具有A Ti大约是TMZ的30倍。在这些成就的基础上，在这个快速的SBIR项目中，我们 提议进行铅优化以改善中枢神经系统（CNS）渗透，确定收集 在高级神经胶质瘤（HGG）的小鼠模型中具有体内效率的小分子，并进一步发展 用于在1期临床试验中使用的化合物。这些依赖MGMT独立烷基化剂是 预计具有TMZ的正属性，同时规避了不可避免的MMR损失介导的 抵抗机制，从而对我们治疗GBM和其他缺乏的肿瘤的方式产生重大影响 Mgmt。这些分子可以通过显着改善其肿瘤学的范式转移 治疗指数。如果成功，我们的方法将显着提高DNA烷基烷的安全性和效率 并将扩大其对更广泛的复发性神经胶质瘤和许多其他癌症的使用。