A Novel TNBC Therapeutic Opportunity: Cystine Addiction
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Overview. Fifteen to 20% of breast tumors do not express the estrogen receptor, progesterone receptor, or the Her2 receptor tyrosine kinase. They are termed Triple Negative (TNBC). Patients with TNBC are generally younger, disproportionately of African-American and Hispanic heritage, with more rapid disease progression, and poorest clinical outcomes. No therapeutic that specifically targets TNBC exists. Patients are treated with chemotherapies that affect all cells of the body, with doses limited by toxic effects on normal tissues.
 
 
 
 
 
 
 
 Work from our laboratory is establishing a new therapeutic paradigm: that targeting abnormal, tumor specific metabolic behaviors and proteins will successfully produce novel, potent drugs. This idea grows out of experiments in which we identified a new cystine transporter on the surface of about 1/3 of TNBC. This transporter, named xCT, must be functional for these TNBC to thrive, because they have lost the ability to produce their own cystine. Nor can they acquire cystine from the environment by using other transporters. Few normal cells in the body express xCT. In animal experiments, normal cells that do express xCT do not appear to be harmed if it is blocked or if the DNA encoding it is removed from the genome. This makes xCT an ideal, tumor-specific drug target. We are translating these findings into an urgently-needed new drug which may be the first specific therapeutic for TNBC.
 
 
 
 
 
 
 
 
 
 We first visualized using this drug alone to treat susceptible TNBC, but by understanding the biology of cystine use in tumor cells, we have come to an exciting hypothesis (below) with potentially huge clinical impact. TNBC need increased amounts of cystine from their environment in order to make a molecule called glutathione. Tumors use glutathione for two important activities related to therapeutic resistance: 1. Control of reactive oxygen species (ROS), which are potent mutagens created by radiation therapy and some chemotherapeutics, and 2. Direct chemotherapeutic inactivation. Historically, drugs that directly inhibit the cellular enzymes that synthesize glutathione have been developed by other investigators. But those studies had to be abandoned since normal cells in the body also make and use those enzymes and the drugs had unacceptably toxic side effects. In contrast, we are targeting a transporter with a highly restricted expression pattern that provides a nutrient (cystine) required for these enzymes to make glutathione.
 
 
 
 
 
 
 
 
 
 Central Hypothesis. We hypothesize that an xCT inhibitor, used in combination therapies will specifically sensitize tumors to treatment with a variety of commonly-used chemotherapeutics and/or radiation therapy, while having little or no effect on normal cells of the body. This would reduce the dose of therapeutics that physicians need to give to patients, and lower the treatment side effects, while maintaining or increasing the effects on tumor cells. We will also produce critical reagents to clearly identify patient populations that will benefit from an xCT inhibitor, including specific ethnic minorities and/or age groups, who may disproportionately over-express xCT and be the patients most likely to benefit from anti-xCT therapy. This research is directly in line with the CBCRP Priority Issue IV: Detection, Prognosis and Treatment: Delivering Clinical Solutions.
 
 
 
 
 
 
 
 
 
 Methods. We will use cells from a panel of 50 breast cancer cells in experiments in vitro and in xenografts, to identify which of four common TNBC therapeutics synergize with xCT inhibition. We will generate reagents to specifically identify xCT and therefore patients that are good subjects for our drug. We will analyze expression datasets from patient tumors to compare expression patterns of xCT before and after treatment, to identify biomarkers of xCT susceptibility, and association with common breast cancer disparity groups. We will test several new improved versions of our xCT inhibitor. 
 
 
 
 
 
 
 
 
 
 Innovative Elements. This project would be the first CBCRP funded effort that attacks this completely new class of breast tumor cell features: their abnormal metabolic requirements for viability. Our studies may ultimately produce a novel therapeutic with a novel mechanism of action, and may potentiate many different standard chemotherapeutics and/or radiation therapy. Our evidence suggests that xCT may be also be overexpressed by cancer stem cells and some estrogen receptor positive tumors. Thus an xCT inhibitor may ultimately have a large clinical impact, and importantly, be the first specific therapeutic for TNBC, the most underserved population of breast cancer patients. They deserve our best efforts.