Inhibition of Brain Metastases in Breast Cancer
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: Today, nearly 30% of patients with advanced breast cancer are eventually diagnosed with brain lesions, making breast tumors the main source of metastatic brain disease in women. Brain metastases are often seen in younger patients with estrogen receptor negative and Her-2 positive tumors. The incidence brain metastasis is rising, as modern therapy extends the lives of many breast cancer patients but fails to inhibit development and progression of metastatic disease. Therefore, it is imperative to develop new, effective regimens that prevent and control this stage of breast cancer.
 
 
 
 
 
 
 
 The goal of this project is to test the hypothesis that brain metastases in breast cancer can be inhibited with phage-displayed human antibodies against metastatic breast cancer cells. Phage are harmless, virus like particles that help the antibody to penetrate the tumor tissue. The feasibility of this approach is based on our previous work and ongoing study where we: (1) identified a new molecular target on metastatic breast cancer cells,(2) isolated function blocking antibodies against this target from combinatorial immunoglobulin libraries of cancer patients, (3) documented the reactivity of these antibodies with metastatic breast cancer cells regardless of the target organ they came from, and (4) most importantly, demonstrated that treatment with these antibodies can interfere with established metastatic disease.
 
 
 
 
 
 
 
 Based on our progress and expert recommendations, we refined the aims for the continuation of this study as follows:
 
 
 
 • Investigate the inhibition of breast cancer brain metastases by treatment with phage-displayed or monomeric human scFv antibodies against the activated form of integrin ?v?3, the novel target that we identified onmetastatic breast cancer cells. 
 
 
 
 • Evaluate the efficacy of this treatment in an immune competent mouse model and assess treatment safety.
 
 
 
 • Use novel strategies for the selection of potentially therapeutic human antibodies that inhibit breast cancer brain metastases.
 
 
 
 
 
 
 
 Our approach is to administer metastasis-directed scFv antibodies (i.e., the variable heavy and variable light antibody chains connected by a biologically inert linker) are displayed on filamentous phage, which have the capacity to penetrate into the brain when administered intranasally. Immunodeficient (SCID) mice with brain metastases caused by luciferase-tagged human beast cancer cells are treated with scFv-phage, and response is monitored by repeated non-invasive imaging. Antibody reactivity and specificity as well as neurotoxicity will be analyzed by histology. The efficacy of repeated phage antibody treatment is evaluated in immune competent mice. New inhibitory antibodies against breast cancer brain metastases will be isolated from libraries from normal donors and breast cancer survivors.
 
 
 
 
 
 
 
 This project has a realistic potential to trigger a much needed breakthrough, as this therapeutic approach is directed against a particularly grim situation in advanced metastatic breast cancer that causes unspeakable pain and suffering.