Project Summary/Abstract: Cancer is the second leading cause of death in the United States. In some patients, cancer can be cured with surgery and/or radiation. Many patients will develop advanced disease that must be managed with various systemic medications and treatments. Unfortunately, the majority of patients in this group will eventually develop treatment resistant cancer, which is often lethal. Despite its importance, our understanding of how this resistance develops and evolves is limited. The primary challenge is that the study of treatment resistance requires obtaining tumor samples before, during, and after it develops. However, obtaining these samples involves surgical or other invasive procedures that carry some risk of causing a complication which could harm the patient. Repeatedly obtaining tissue samples for research is not feasible for the majority of patients. We propose to use a new “liquid” biopsy technique in which molecular information about the tumor is collected from serial blood samples, which patients with cancer are frequently providing for a variety of laboratory tests already. This information can then be used to understand how treatment resistance develops and how it evolves over time. This will allow us to identify potential strategies to overcome this resistance, as well as create tests to pick it up early so that treatment can be adjusted before the cancer grows and the patient gets sicker. This strategy could be used across cancers and treatments and change the paradigm in how we understand cancer progression as well as change how we monitor and treat patients.

Project Narrative: Almost all advanced cancers will eventually progress on treatment, but the emergence of resistance in cancer is poorly understood despite its clinical importance. The primary challenge is that serial tissue samples (pre- and post-resistance as well as in-between) must be obtained to understand the molecular mechanisms of resistance, but this is not feasible at scale given the logistical challenges as well as potential for procedure- related complications of invasive tissue sampling. We propose to utilize a novel integrated clinical-grade liquid biopsy platform to comprehensively profile DNA, RNA, and methylation alterations from blood samples in order to more fully understand the dynamic evolution of treatment resistance in cancer, and to develop potential biomarkers for early detection.