Biology of the Hormonal Regulation of Cancer and Immuno Oncology Outcomes Research Proposal.

Oregon Health & Science University, Portland OR

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY / ABSTRACT This application is being submitted in response to “Administrative supplements to advance development of transdisciplinary and large-scale population science and cancer control research projects." Despite the significant progress made in cancer treatment across a broad range of indications by immune checkpoint blockade (ICB), a majority of patients still do not respond. The potential of these medications to improve cancer outcomes is additionally limited by the frequency and severity of immune-related adverse events (irAEs), class- specific toxicities of checkpoint inhibitors that can affect any organ system. Sex hormones, including both estrogen and androgens, have recently been identified as both a contributor to resistance to checkpoint inhibition and a risk factor for irAEs. The mechanisms by which this immunomodulation occurs, however, is not yet understood. This proposal will develop a framework for a set of studies to test the hypothesis that understanding hormone receptor expression and its impact on immune infiltration of the skin and gastrointestinal tract will provide insight into mechanisms of both irAE pathogenesis and resistance to ICB. Our team of transdisciplinary investigators comprises clinicians in multiple subspecialties as well as researchers with population science, computational biology, immunology, and cancer expertise, which provides the diversity of viewpoints necessary to build a framework supporting true bedside-to-bench-to-bedside translation. Using a whole person approach-from cancer diagnosis to symptom biology to treatment-associated toxicities and tissue specific hormone signaling, and finally the sex-specific immune landscape, we are integrating an array of methods to synergistically address sex differences in ICB and irAEs. Toward this end, this proposal will assemble a sex-balanced cohort of patients with cancers of the skin or gastrointestinal tract treated with standard-of-care ICB at the Knight Cancer Center (an NCI-designated Comprehensive Cancer Center) who have archived pre-treatment tissue blocks available. Treatment metadata on these patients will be integrated with data on their clinical features, symptom biology, hormone receptor expression, and publicly-available single-cell RNA sequencing data, creating a comprehensive treatment-, outcome-, symptom-, and tissue biology-informed repository for the study of the interface between hormone biology and cancer immunotherapy. This resource will then serve as the foundation upon we will build a comprehensive cancer control protocol for future prospective studies. This protocol will allow us to fully leverage our existing (dermatologic and gastrointestinal) toxicity care clinics within the Knight for recruitment of appropriate patients into both existing and novel research pipelines, allowing us to derive maximum experimental benefit from every patient willing to participate. Collectively, the efforts enabled by this proposal will drive a multi-armed research effort upon which we plan to build a future larger-scale program project application.