Interstrand Crosslink Repair as a Squamous Cell Carcinoma Vulnerability

Chemical elimination of cancer cells (chemotherapy) remains among the oldest and most successful treatment strategies in cancer care but carries significant side effects. While different chemotherapies work in a variety of ways, many kill cancer cells by generating catastrophic damage to DNA. Unfortunately, this strategy is also highly toxic because such chemotherapies also generate catastrophic DNA damage in normal cells. As a result, patients undergoing chemotherapy suffer side effects that dramatically reduce their quality of life, limit treatment efficacy or prove to be fatal. Additionally, some tumors adapt to these types of chemotherapies, rendering the patient resistant to treatment. In these cases, the patient experiences the steep negative side effects of treatment without any of the benefits. Understanding how and why this resistance occurs would prevent such cases and greatly improve the cancer care and quality of life for those with chemotherapy-resistant disease. In this proposal, we seek to design a smarter, less toxic therapeutic strategy that selectively kills cancer cells, leaving normal cells unharmed. We also seek to apply these lessons to predict which patients respond to existing chemotherapies. We discovered that the type of DNA damage caused by commonly used chemotherapies naturally occurs in certain cancer cells but not normal cells. We conclude that cancer cells have adapted to survive this otherwise lethal DNA damage. We predict that identifying and inhibiting the adaptive mechanisms enabling cancer cells to survive this DNA damage will kill cancer cells while sparing normal cells that do not have this form of DNA damage. Such an approach is theoretically as effective as chemotherapies in killing cancer cells but without their negative side effects. We will test this approach herein. We also attempt to predict how patients will respond to the chemotherapy cisplatin based on whether signatures of these adaptive mechanisms are present in the patient's tumor. We will test this possibility in the proposed studies, with the goal of developing a biomarker that ensures that only patients who can benefit from toxic chemotherapies receive them. To arrive at our conclusions, we used a model of head and neck squamous cell carcinoma (HNSCC), which accounts for 570,000 newly diagnosed cases and 344,000 deaths annually. We leveraged HNSCC organoids, which are derived from patient tumors but can be grown in the lab and used for experimentation. Our lab has extensively published demonstrating that these organoid models are functional avatars of patient tumors useful for biological and drug sensitivity studies. We will employ this model in our studies. We aim to 1) define the mechanisms enabling tumor cells to tolerate increased DNA damage, 2) inhibit these mechanisms as therapeutic strategy that builds on chemotherapy's success while limiting its toxic side effects and 3) establish a biomarker that ensures that only patients who can benefit from toxic chemotherapies receive them.