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 据估计，将有1，762，450例新的癌症病例被诊断出来，预计约有606，880人死亡 到2019年底，这种疾病。虽然癌症患者有许多治疗选择，但缺乏有效的治疗方法。 并且肿瘤选择性治疗策略仍然是当今对抗癌症的主要障碍。不期望 当以高剂量给药时，由于对单一药物产生耐药性而引起的毒性，特别是对 错误的病人可能会导致对正常细胞的意外损伤引发有害的副作用。最 在临床上仍然普遍用于癌症治疗的化学疗法是DNA靶向剂（例如， 交联药物），其抑制肿瘤中的异常复制和转录以诱导细胞死亡。 然而，这些药剂也影响正常组织。因此，我们开发了一类新的DNA交联 一种利用癌症细胞相对于正常细胞的独特性质进行肿瘤选择性激活的试剂。这里我们 我建议研究我们的前药的肿瘤选择性治疗作用， 由于特征性较高过氧化氢（H2 O2）水平，仅在肿瘤中诱导致死性DNA损伤 而正常细胞由于过氧化氢酶表达更高而受到保护， 猝灭H2 O2。我们还将确定肿瘤中可靠的预测生物标志物，以可能对以下患者进行分层： 与非肿瘤选择性交联相比， 临床中使用的试剂（例如，苯丁酸氮芥）。我们有前途的先导化合物将被合理地改进， 具有“治疗诊断”应用（具有治疗和诊断能力的分子）， 在治疗后立即测量治疗反应以优化剂量。我们的另一个目标是 检查是否涉及我们的新药物和遗传/药理学改变的组合策略 参与H2 O2产生和DNA修复的关键因素可能导致累加或协同致死。在这 本研究的目的是开发一种精确导向的治疗策略，以提高肿瘤选择性治疗效果 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H2 O2，以增强我们的H2 O2可激活的DNA交联的杀伤作用 剂我们的机制和治疗反应的研究将使用正常和恶性肿瘤 这是一个新的模式，特别是在肺癌，这仍然是所有癌症相关死亡的主要原因。如果我们的 最初假设是正确的，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地识别恶性癌症患者，这些患者最有可能对化疗产生反应。 治疗，减少由于对正常细胞的无意损伤而导致的危及生命的副作用， 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.