Novel therapeutics for the targeted eradication of DDR-defective tumors

靶向根除 DDR 缺陷肿瘤的新疗法

• 批准号: 10734414
• 负责人: Ranjit Bindra
• 金额: $ 65.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734414
• 关键词: Address; Alkylating Agents; Alkylation; Apoptosis; Biological Availability; Cells; Central Nervous System Agents; Chemicals; Clinic; Colon Carcinoma; Cyclization; Cytosine; DNA; DNA Alkylation; DNA Damage; DNA Interstrand Crosslinking; DNA Repair; DNA Repair Disorder; DNA Repair Gene; Data; Dealkylation; Development; Drug resistance; Excision; Futile Cycling; Genes; Genetic; Genome; Genomics; Glioblastoma; Glioma; Goals; Grant; Guanosine; Human; Hypermethylation; Ions; Kinetics; Lesion; MGMT gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methyltransferase; Mismatch Repair; Modeling; Modification; Mutagens; Non-Small-Cell Lung Carcinoma; Oligonucleotides; Oral; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Polymerase; Prodrugs; Proliferating; Radiation therapy; Reaction; Research; Resected; Resistance; Structure; Testing; Therapeutic; Therapeutic Index; Thymine; Time; Tissues; Toxic effect; Transferase; Translating; Translations; Work; adduct; bench to bedside; chemotherapy; clinically significant; crosslink; cytotoxicity; design; efficacy evaluation; experience; functional loss; improved; in vivo; ineffective therapies; inhibitor; mouse model; new therapeutic target; novel; novel strategies; promoter; repaired; response; small cell lung carcinoma; standard of care; synergism; systemic toxicity; targeted agent; temozolomide; tissue culture; treatment strategy; trial design; tumor; tumor specificity

PROJECT SUMMARY/ABSTRACT. O6-Methylguanine methyltransferase (MGMT) reverts O6-alkylguanosine residues to guanosine via dealkylation by SN2 displacement. MGMT is ubiquitously expressed in healthy tissue but is silenced (referred to as “MGMT– “) in ~50% of glioblastomas (GBMs), most gliomas, and in up to 40% of colon cancers, 35% of small cell lung cancers, and 25% of non-small cell lung cancers. MGMT– tumors are sensitized to DNA alkylation agents, such as temozolomide (TMZ). This sensitization creates a therapeutic index (TI). TMZ prolongs survival of patients with MGMT– GBM by ~8 mo. The cytotoxicity of TMZ relies on an intact DNA mismatch repair (MMR) pathway. MMR silencing (referred to as “MMR–”) is the primary mechanism of acquired TMZ resistance, and second-line therapies are ineffective. Despite >20 y of research, efforts to overcome MMR silencing-based resistance have not been successful. Herein, we present 2-fluoroethylating agents (FEtAs) as novel, orally bioavailable com- pounds that selectively eradicate MGMT–/MMR– GBM in vivo, without systemic toxicity. Our data indicate FEtAs induce DNA interstrand cross-links (ICLs) only in MGMT– tumors by formation of O6-(2-fluoroethyl)guanosine (O6FEtG), slow cyclization to an N1,O6-ethanoguanine (EG) intermediate, and ring-opening by the adjacent cytosine. The slow rates of EG formation provide time for MGMT to reverse the initial alkylation in healthy (e.g., MGMT+) cells, leading to a high TI. In contrast, chloroethylation agents, such as mitozolomide, generate O6-(2- chloroethyl)guanosine (O6ClEtG), which cyclizes to EG competitively with MGMT reversal. This leads to the formation of ICLs or toxic DNA–MGMT cross-links, via opening of EG by MGMT, in healthy cells. Additionally, the chloroethylsulfide formed on MGMT reversal of O6ClEtG converts to a reactive episulfonium ion, which also cross-links MGMT to DNA, while MGMT reversal of O6FEtG creates a stable fluoroethylsulfide. Together, these differences lend a higher MGMT TI to FEtAs suggesting they are likely to display improved tolerability in humans. Since ICL toxicity is MMR-independent, FEtAs retain activity in TMZ-resistant, MMR– tumors. Here we will study the amount of O6FEtG formed from FEtAs and the rate of its reversal by MGMT. We will characterize the structure and reaction kinetics of the ICLs using oligonucleotides containing a single O6FEtG. We will conduct studies to improve FEtA CNS penetration. We will probe for synergy between FEtAs and DDR inhibitors, other DNA repair deficiencies, and radiotherapy. Completion of this research will lead to the identification of novel chemotherapies with high CNS penetration that operate by a novel, MMR-independent mechanism, thereby addressing acquired TMZ resistance. As FEtAs are structurally-related to TMZ, we expect rapid translation to the clinic. MGMT is silenced in a range of tumor types; this work will set the stage to evaluate FEtAs as treatments for other MGMT– tumors, alone or in combination regimes. Finally, to the best of our knowledge, the relative rates of DNA chemical modification and repair have not previously been exploited to obtain tumor specificity; we believe this “kinetic lethal” strategy may constitute the first iteration of a new approach to targeted chemotherapeutic design.

项目总结/抽象。