Development of a novel biochemical tool with tumor-selective theranostic anti-cancer potential

开发具有肿瘤选择性治疗诊断抗癌潜力的新型生化工具

• 批准号: 10246511
• 负责人: Edward Ayson Motea
• 金额: $ 18.52万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246511
• 关键词: A549; Affect; Antineoplastic Agents; Ascorbic Acid; Biological Markers; Bystander Effect; CRISPR/Cas technology; Cancer Model; Cancer Patient; Cell Death; Cell Line; Cells; Cessation of life; Characteristics; Chlorambucil; Clinic; Clinical Trials; Crosslinker; DNA; DNA Crosslinking Agent; DNA Damage; DNA Repair; DNA Repair Gene; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Enzymes; FDA approved; Family; Flow Cytometry; Generations; Genetic; Genetic Transcription; Goals; Hydrogen Peroxide; In Vitro; Lead; Life; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Melphalan; Metabolism; Methods; Microscopy; Mind; Modeling; NQO1 gene; Normal Cell; Normal tissue morphology; Patients; Pharmaceutical Preparations; Pharmacology; Prodrugs; Production; Property; Proteomics; Public Health; Quality of life; Reactive Oxygen Species; Resistance; Resistance development; TFRC gene; Therapeutic; Therapeutic Effect; Toxic effect; United States; analog; anti-cancer; base; biochemical tools; cancer biomarkers; cancer therapy; catalase; chemotherapeutic agent; chemotherapy; combinatorial; crosslink; design; effective therapy; fight against; improved; innovation; lung cancer cell; mortality; neoplastic cell; novel; novel lead compound; novel marker; overexpression; patient stratification; precision medicine; predictive marker; prevent; receptor expression; repaired; response; side effect; small hairpin RNA; small molecule; specific biomarkers; synergism; targeted agent; theranostics; treatment response; treatment strategy; tumor; tumor DNA

Project Summary Cancer remains one of the deadliest diseases in the world. In the United States alone, it is projected that an estimated 1,762,450 new cases of cancer will be diagnosed and about 606,880 people are projected to die from this disease by the end of 2019. While cancer patients have many treatment options, the lack of effective and tumor-selective treatment strategy remains a major obstacle in the fight against cancer today. Undesirable toxicities due to the development of resistance to a single drug when given at high doses, especially to the wrong patients can cause harmful side effects triggered by unintended damage to normal cells. Most chemotherapies that are still commonly used in the clinic for cancer treatment are DNA-targeting agents (e.g., crosslinking drugs), which inhibit aberrant replication and transcription in tumors to induce cell death. However, these agents also affect normal tissues. Therefore, we developed a new class of DNA crosslinking agent that utilizes the unique properties of cancer versus normal cells for tumor-selective activation. Here, we propose to investigate the tumor-selective therapeutic effects of our prodrug that is preferentially activated to induce lethal DNA damage only in tumors due to characteristically higher hydrogen peroxide (H2O2) levels needed for drug activation; whereas normal cells are protected due to higher Catalase expression that quenches H2O2. We will also identify reliable predictive biomarkers in tumors to possibly stratify patients who will significantly benefit from our innovative treatment approach compared to non-tumor-selective crosslinking agents used in the clinic (e.g., chlorambucil). Our promising lead compound will then be rationally improved to have a “theranostic” application (a molecule with both therapeutic and diagnostic capabilities) to potentially measure therapeutic response immediately following treatment for dose optimization. Our other objective is to examine whether combinatorial strategies involving our novel agents and genetic/pharmacological alterations of critical factors involved in H2O2 production and DNA repair may cause additive or synergistic lethality. In this aim, we will develop a precision-guided treatment strategy to sensitize the tumor-selective therapeutic effects of our new anti-cancer drugs as a monotherapy or combined with existing agents (at low doses) that are known to generate H2O2 preferentially in tumors to enhance the killing effect of our H2O2-activatable DNA crosslinking agent. Our mechanistic and therapeutic response studies will be done using normal and malignant cancer models, particularly in lung cancer, which still remains the leading cause of all cancer-related deaths. If our initial hypothesis is correct, our new anti-cancer drug and treatment strategy based on predictive cancer biomarkers could accurately identify patients with malignant cancers that will most likely respond to the treatment, reduce life-threatening side-effects due to unintentional damage to normal cells, and significantly improve the overall quality of life for the patients and their families.

项目概要 据预测，癌症仍然是世界上最致命的疾病之一。 估计将诊断出 1,762,450 例新癌症病例，预计将有约 606,880 人死亡 到 2019 年底，癌症患者将摆脱这种疾病。虽然癌症患者有很多治疗选择，但缺乏有效性 肿瘤选择性治疗策略仍然是当今抗击癌症的主要障碍。 高剂量给药时，由于对单一药物产生耐药性而产生毒性，特别是对 错误的治疗可能会对正常细胞造成意外损伤，从而引发有害的副作用。 临床上仍常用的癌症治疗化疗是 DNA 靶向药物（例如， 交联药物），抑制肿瘤中的异常复制和转录以诱导细胞死亡。 然而，这些试剂也会影响正常组织，因此，我们开发了一种新型 DNA 交联剂。 利用癌症与正常细胞的独特特性来选择性激活肿瘤的药物。 提议研究我们的前药的肿瘤选择性治疗作用，该前药优先被激活 由于过氧化氢 (H2O2) 水平较高，因此仅在肿瘤中引起致命的 DNA 损伤 药物激活所需的；而正常细胞由于较高的过氧化氢酶表达而受到保护 我们还将鉴定肿瘤中可靠的预测生物标志物，以可能对患者进行分层。 与非肿瘤选择性交联相比，我们的创新治疗方法将显着受益 然后，我们将合理改进临床中使用的药物（例如苯丁酸氮芥）。 具有“治疗诊断”应用（具有治疗和诊断能力的分子） 我们的另一个目标是在治疗后立即测量治疗反应以优化剂量。 检查是否涉及我们的新药和遗传/药理学改变的组合策略 参与 H2O2 产生和 DNA 修复的关键因素可能会导致叠加或协同致死。 目标，我们将制定精准引导的治疗策略，以提高肿瘤选择性治疗效果 我们的新型抗癌药物作为单一疗法或与已知的现有药物（低剂量）联合使用 在肿瘤中优先产生 H2O2，以增强我们的 H2O2 可激活 DNA 交联的杀伤作用 我们的机制和治疗反应研究将使用正常和恶性癌症进行。 模型，特别是肺癌，它仍然是所有癌症相关死亡的主要原因。 最初的假设是正确的，我们的新抗癌药物和治疗策略基于预测癌症 生物标志物可以准确识别患有恶性癌症的患者，这些患者最有可能对治疗产生反应 治疗，减少因正常细胞无意损伤而产生的危及生命的副作用，并显着 提高患者及其家人的整体生活质量。