Targeting metastatic TNBC by scavenging blood glutamate
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: Non-technical overview of the research topic and relevance to breast cancer: 
 Here we propose to evaluate the therapeutic efficacy of a novel strategy for Blood Glutamate Scavenging (BGS) to block metastatic growth in triple negative breast cancer (TNBC). About 25-46% of patients with breast cancer are at higher risk of brain metastasis. TNBC is an aggressive BC subtype that accounts for around 25% of breast cancer deaths. Brain metastasis poses a life-threatening challenge for women with advanced metastatic TNBC. Unfortunately, once metastatic lesions are established in the central nervous system, only 1 in 5 women survive a year. These are also hard to treat with various emerging targeted antibody-based therapeutics due to their difficulty in penetrating through the blood-brain barrier. Thus, there is an urgent need to explore new therapies that will prevent disseminated cells from exiting a dormant state and start proliferation and invasion. An ever increasing body of evidence has suggested that glutamate (Glu), the major excitatory neurotransmitter in the brain, plays a crucial role in the growth of glioma, melanoma and breast cancer (BC) cells, by facilitating their proliferation, invasiveness and their ability to destroy the neighboring tissue. Specifically, inhibition of extracellular Glu release or Glu receptor activation decreases proliferation, migration and invasion of cancer cells. Here we propose an entirely novel approach to treat metastatic TNBC by inhibition of the glutamatergic system and prevention of exit-from-dormancy into proliferation and tissue invasion. Since a treatment of such a multifactorial disease like metastatic TNBC ought to be subjected to combination therapeutic regimens, our new treatment that aims to target mechanisms controlling brain metastasis but also those in other organs like bone could increase the effectiveness of the standard of care for this disease or of other emerging treatments as cancer immunotherapy. Importantly, the technology is currently in an advance stage of preparation for clinical trials for the treatment of stroke and brain cancer and protected by a patent. 
 
 
 
 The question(s) or central hypotheses of the research: Aiming at targeting metastatic cells in TNBC, here we propose to utilize our recently developed technology by decreasing excess glutamate (Glu) to limit their proliferation and invasion. Following the testing of this technology for the treatment of stroke and brain cancer, our study presents a real opportunity for this treatment to be of high clinical significance for the treatment of TNBC patients in the very near future. Specifically we would like to: 
 
 
 
 -Elucidate the specific sets of conditions under which Blood Glutamate Scavenging with our technology affects the proliferation and invasion of TNBC cells in mice.- 
 Determine the efficacy of Blood Glutamate Scavenging on inhibiting metastatic growth of TNBC cells in mice. -
 Examine the mechanism by which treatment with Blood Glutamate Scavenging delays or prevents the development of brain and bone metastasis from TNBC cells, with the purpose of suggesting this treatment in a combination setting with standard of care and/or in a neo-adjuvant or adjuvant settings. 
 
 
 
 The general methodology: We utilize TNBC cell lines, which were purified from metastatic brain cells of the TNBC human cell line. The cells are injected into immunocompromised mice, followed by daily treatment with our new therapy in various concentrations, starting immediately or two weeks post-injection. At the end of the treatment, mice will be sacrificed and all organs will be analyzed for the presence of metastatic foci or single metastatic cells. The cells will also be characterized for various markers of invasion and proliferation and the levels of Glu will be monitored and correlated with metastatic burden. The results will be compared to the control group of mice. 
 
 
 
 Innovative elements of the project and potential impact: Our study will pioneer the testing of this approach on metastatic TNBC. Following the testing of this technology for the treatment of stroke and brain cancer, our study presents a real opportunity for this treatment to be of high clinical significance for the treatment of TNBC patients in the very near future. Moreover, as metastatic disease has no cure, our new treatment offers great promise as it could potentially prevent the development of metastasis using naturally occurring metabolite. It can also be potentially effective against BC metastasis in other organs apart from brain (as bone). This will significantly improve the survival of thousands of patients suffering from metastatic TNBC.