Targeting Metastasis by Inhibiting Breast Cancer Metabolism and Immune-Suppression
Abstract
Our study will address the overarching challenges of (1) eliminating mortality associated with metastatic breast cancer by (2) revolutionizing treatment regimens to prevent or treat metastatic breast cancer. Rationale: Breast cancer arises in “epithelial cells” that line the skin and ducts of the body, and these cancers are termed “carcinomas.” Carcinomas are the most common types of cancer, likely because the epithelial cells are the most exposed to different insults and injuries from outside the body and they have a high rate of turnover and thus a high rate of mistakes in the genetic code when the cells multiply, and some of the mistakes can lead to cancer. Normal epithelial cells are attached to each other and at the bottom side of their cube-like shape to a “basement membrane,” and if they become detached, they are normally programmed to “self-destruct” and die because they should not move around in the body in adults (they only move during embryonic development when they are undergoing proper arrangement). However, carcinoma cells inappropriately survive and move around the body and cause problems with the normal functioning of various organs – that is what is called “metastasis” and is the major cause of death in breast cancer. Triple-negative breast cancer (TNBC) has a particularly high rate of metastasis and the risk of recurrence after surgical removal of the primary tumor is within the first few years of initial diagnosis. TNBC cells survive under conditions where we do not permit the cells to attach to a tissue culture dish (termed anchorage-independent) conditions much better than estrogen receptor (ER)-positive breast cancer cells. This “anchorage-independent survival” is one of the properties thought to be associated with the ability to survive in blood or lymph vessels to metastasize in the body. Indeed, ER+ breast cancer when it does metastasize in patients has a longer time to recurrence than TNBC. We find that TNBC cells can rapidly alter how they generate energy to survive and protect themselves from “self-destruction” signals in order to survive in the anchorage-independent condition and in low oxygen in a large tumor with poor blood supply or low nutrients. One of the things they change is protein that takes large amino acids such as tryptophan into the cell and allows tumor cells to steal the tryptophan away from the good antitumor immune cells that also need tryptophan to kill tumor cells. A product of tryptophan breakdown called kynurenine is well-recognized as a mediator of immune suppression. Recently, a Phase III clinical trial with a drug called Epacadostat, which inhibits a protein that can break down tryptophan called indoleamine-2,3-dioxygenase 1 (IDO1), was conducted in combination with the immunotherapy drug pembrolizumab (Keytruda) for people with a range of solid tumor types. The trial showed no difference between the epacadostat-treated versus pembrolizumab groups. However, right around the time that trial was ending, we published data generated through our original Breast Cancer Research Program Fiscal Year 2015 Breakthrough Award showing evidence that in TNBC the tryptophan catabolism pathway is induced by the enzyme tryptophan-2,3-dioxygenase (TDO2), not IDO1. Importantly, TDO2 is not targeted by epacadostat, but we now have new dual inhibitors of IDO and TDO2 not available at the time of the parent grant. TDO2 breaks down tryptophan to a product called kynurenine (Kyn), which protects tumor cells against cell death, but also when secreted from the tumor, is bad for the immune cells that should be killing tumor cells. Kyn was recently found to bind to receptors called aryl hydrocarbon receptors (AhR) in both tumor cells and immune cells. Kyn activation of AhR promotes the ability of tumor cells survive in the bloodstream. We also just published that tryptophan depletion and AhR activation by Kyn decreases the survival and function of anti-tumor immune cells call
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010617
Entities
People
- Jennifer K Richer
Organizations
- United States Army
- University of Colorado Denver