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

项目摘要 癌症仍然是世界上最致命的疾病之一。仅在美国，预计一个 估计将诊断出1,762,450例新的癌症病例，预计约有606,880人死亡 在2019年底之前从这种疾病中解脱出来。虽然癌症患者有很多治疗选择，但缺乏有效的 而肿瘤选择性治疗策略仍然是当今抗击癌症的主要障碍。不受欢迎 高剂量给药时因对单一药物产生抗药性而产生的毒性，尤其是对 错误的患者可能会引起有害的副作用，这些副作用是由对正常细胞的意外损害引发的。多数 仍然在临床上用于癌症治疗的化疗药物是DNA靶向剂(例如， 交联剂)，抑制肿瘤中的异常复制和转录，从而诱导细胞死亡。 然而，这些制剂也会影响正常组织。因此，我们开发了一类新的DNA交联 一种利用癌症与正常细胞的独特性质进行肿瘤选择性激活的试剂。在这里，我们 建议研究我们的优先激活的前药的肿瘤选择性治疗作用 仅在肿瘤中由于过氧化氢(H_2O_2)水平较高而导致致命的DNA损伤 而正常细胞由于更高的过氧化氢酶表达而受到保护 熄灭双氧水。我们还将在肿瘤中识别可靠的预测生物标记物，以可能对 与非肿瘤选择性交联剂相比，我们的创新治疗方法将显著受益 临床上使用的药剂(例如，氯氨丁苯)。我们有希望的先导化合物将被合理地改进为 具有治疗作用(一种同时具有治疗和诊断能力的分子)潜在地 在治疗后立即测量治疗反应，以实现剂量优化。我们的另一个目标是 检查组合策略是否涉及我们的新药和遗传/药物改变 参与过氧化氢产生和DNA修复的关键因素可能会导致相加或协同致死。在这 目的：我们将开发一种精确引导的治疗策略，以敏化肿瘤的选择性治疗效果。 我们的新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 在肿瘤中优先产生过氧化氢以增强我们的过氧化氢激活的DNA交联物的杀伤效果 探员。我们的机制和治疗反应研究将使用正常癌症和恶性肿瘤进行。 特别是肺癌，它仍然是所有与癌症相关的死亡的主要原因。如果我们的 最初的假设是正确的，我们的新抗癌药物和治疗策略是基于预测癌症 生物标记物可以准确地识别最有可能对 治疗，减少因意外损害正常细胞而危及生命的副作用，并显著 提高患者及其家属的整体生活质量。

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.