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.
Our goal is to develop a novel tumor-selective DNA-damaging agent with diagnostic capabilities using specific biomarkers to predict which patients are likely to benefit from our innovative treatment strategy, which is directly relevant to public health. In addition, our novel small molecule may also be used as a biochemical tool to increase our understanding of DNA damage and repair mechanisms that could facilitate the identification of new treatment approaches and biomarkers to potentiate the tumor-selective effects of chemotherapeutic agents while preventing toxicity to normal cells.
