Host Hypoxia to Treat Breast Cancer Brain Metastasis
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: Brain metastases are among the most feared complications in breast cancer and do not respond to conventional chemo- or immunotherapies. They are treated with surgery, if individual metastases are found at operable sites in the brain, and with radiation. Approximately 30% of patients with advanced breast cancer are diagnosed with brain metastases, and these are found more frequently as improved treatments often reduce metastases in the rest of the body. For example, with the success of Herceptin, an antibody therapy against breast cancers that carry the Her-2 marker, an alarming 40% of patients with Her-2 positive tumors develop brain lesions. 
 
 
 
 
 
 
 
 Our goal is to investigate a new approach to treating breast cancer brain metastases effectively, and ultimately provide patients with brain lesions with a reliable therapy that enhances survival and quality of life. We discovered that exposing experimental mice bearing human breast cancer brain lesions to reduced levels of oxygen (host hypoxia) equivalent to high mountain altitude, profoundly inhibits brain metastatic growth without affecting overall health. 
 
 
 
 
 
 
 
 In this project, we will use mouse models of breast cancer brain metastasis and determine if host hypoxia inhibits brain metastatic growth. This includes the disease subtypes: Her-2 positive, triple negative, and ER/PR positive breast cancers. We will determine whether hypoxic treatment generally opens a “window” for enhanced response to chemo- or radiation therapy. We developed a procedure to apply whole brain radiation to mice, and we chose two FDA approved drugs, lapatinib (blocks Her2 growth receptor pathway) and SAHA (Vorinostat, a histone deacetylase inhibitor), which are currently considered for breast cancer patients with brain metastases. We will evaluate whether host hypoxia can improve the efficacy of radiation in combination with these drugs. And, we will determine whether brain metastases are permanently inhibited, even after patients return to normal oxygen levels. Next, we will analyze how the adaptation of the brain to reduced oxygen affects metastases in the central nervous system. While the hypoxia conditions we found effective against brain metastases are mild and comparable to those used by athletes during high altitude training, they still produce profound responses that help the brain cells, but apparently not the tumor cells, to stay active and get enough oxygen. The molecular mechanisms involved will be investigated in the mouse brain tissues, based on how blood vessels and other cell types of the normal brain respond to reduced levels of oxygen and the presence of tumor cells in the brain. 
 
 
 
 
 
 
 
 Our results may lead to a break-through toward an effective standard therapy for breast cancer patients with brain metastases. If our planned experiments show that host hypoxia generally inhibits brain metastatic growth regardless of the breast cancer type, and that hypoxic treatment opens a window for enhanced response to radiation or chemotherapy, the proposed combination approach could directly lead to a clinical trial.