Precision Targeting of Multicellular Vulnerabilities in Aggressive Renal Cancers
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and its rates are on the rise worldwide. Metastatic ccRCC, which accounts for about 30%-40% of all cases, is refractory to current treatment options and is therefore incurable. Indeed, only a modest proportion of patients benefit from durable response to treatments with anti-angiogenesis (e.g., anti-VEGF) or immune-checkpoint inhibitors (ICIs). There is thus an urgent need to identify, characterize, and target novel drivers of ccRCC progression and resistance to therapies to improve disease outcomes and patient survival. This goal has been hindered by the underlying complexity of ccRCC, a solid tumor that contains cancerous cells along with non-cancerous cell-types of the body that support tumor growth, including blood vessels and the matrix onto which the tumor is anchored, and regulatory cells of the immune system that suppress the antitumor function of tumor-infiltrating immune cells. Recently, we penetrated this complexity by applying high-resolution single-cell genomic technologies to advanced ccRCC tumors that we had transplanted into mice to model live aggressive tumors outside of the human body. This allowed us to distinguish tumor-specific gene signatures from those originating from normal cells. Our subsequent computational analyses of tumor-specific signatures revealed that a gene called lysyl oxidase (LOX) is over-produced in some ccRCC tumor cells, which concomitantly produce molecular signals that are associated with poor outcome. Our preliminary work has demonstrated a dependence on LOX for renal tumor growth; when we reduce the amount of LOX in cancer cells they are no longer able to proliferate or to form solid tumors in immune-deficient mice. We also have evidence that LOX plays a pivotal role in signaling to the surrounding matrix of tumor cells to reprogram the tumor microenvironment in a way that stabilizes tumor growth. These are very exciting observations as they indicate that targeting LOX (through pharmacological inhibition) has tremendous potential to improve disease outcome and response to current therapies. We foresee that LOX inhibition will (1) eliminate cancerous cells that produce LOX and other tumor-promoting signals, (2) block LOX function in promoting a favourable microenvironment for tumor growth through remodeling the surrounding matrix, and (3) potentiate response to current anti-angiogenesis and immune-checkpoint therapies by removing immune-suppressive cells and increasing drug penetrance into the tumor bulk. Indeed, our recent published study in breast cancer showed that inhibiting LOX sensitizes treatment-resistant breast cancers to systemic therapies by increasing the penetration of drugs into the tumor bulk. The objective of this project is to understand the ways by which LOX drives renal cancer growth and metastasis and to investigate the development of a novel targeted therapy based on LOX inhibition. To achieve this goal, we have established a collaborative network between scientists and labs with different and complementary expertise across the United States and Canada. This network enables us to leverage expertise in genomics, bioinformatics and computational sciences, cancer biology, urological oncology, ccRCC modeling, and preclinical studies to ensure the successful realization of our objectives. Notably, to target and inhibit LOX, we will use a novel small molecule, which has been found by one of the lead investigators of our project at the Department of Drug Discovery and Biomedical Sciences, University of South Carolina (Dr. O. Sahin). Currently, this molecule is being optimized for preclinical and clinical applications, and the optimized version will be available for testing in the context of our project using various mouse models of ccRCC. This Idea Development Award application will address the following FY20 KCRP Areas of Emphasis: Treatments/Survivorship (Therapeut
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110945
Entities
People
- Yasser Riazalhosseini
Organizations
- McGill University
- United States Army