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: Brain metastases are among the most feared complications in cancer, because even small satellite tumors can be incapacitating. About 20% of breast cancer patients are diagnosed with brain metastases, and autopsy data suggests a true incidence of nearly 30%. Thus, breast cancer is a frighteningly common source of brain metastases. The median survival time for breast cancer patients with untreated brain metastases is 4 weeks, and can be increased to 4-6 months with whole-brain radiotherapy and stereotactic radiosurgery, or up to 16 months if solitary metastases can be removed surgically. Thus, novel approaches to treat this form of breast cancer spread are desperately needed. 
 
 
 
 
 
 
 
 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. The feasibility of this approach is based on our previous work 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) demonstrated that treatment with these antibodies can interfere with established metastatic disease.
 
 
 
 
 
 
 
 Our specific aims for this CBCRP-funded project include to
 
 l. Investigate if treatment with single chain Fv (scFv) fragments of human antibodies against the activated conformer of adhesion receptor integrin ?v?3, the identified functional target, can interfere with brain metastases caused by breast cancer.
 
 2. Modify the display and formats of the existing, disease-fighting antibodies to optimize their application and localization to breast cancer cells in the brain.
 
 3. Search combinatorial antibody libraries of cancer patient immunoglobulins for new, potentially therapeutic antibodies that seek out breast cancer cells in the brain with high efficiency and which interfere with the viability specifically of these cells.
 
 
 
 
 
 
 
 Metastasis directed scFv antibodies are displayed on coat protein pIII of filamentous bacteriophage, which have the capacity to penetrate into the brain when administered through the nose as a spray. Mice with brain metastases, caused by human beast cancer cells, will be treated with scFv-phage constructs, and response will be monitored by repeated non-invasive imaging of tumors in the brain. Antibody reactivity and specificity as well as neurotoxicity will be analyzed by histology. To optimize treatment, we will increase the number of scFv copies per phage particle. New inhibitory antibodies against breast cancer brain metastases will be isolated and tested in our system.
 
 
 
 
 
 
 
 This work carries a high risk, as it addresses a complex clinical situation that has been understudied in basic and clinical research. But, the project also has a realistic potential to trigger a much needed breakthrough.