Inhibition of Brain Metastases in Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Brunhilde  Felding , Ph.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11IB-0077 Award: $278,850
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2005)
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.

Final Report (2006)
We have established unique new human breast cancer cell models and analytical systems to follow the development of breast cancer brain metastases step-by-step and evaluate the response of such lesions to treatment. Having identified the activated conformer of integrin avŖ3 (a widely distributed cell adhesion receptor that links cells to specific components of the extracellular matrix, or ECM) as a new molecular target on metastatic breast cancer cells, we now showed that expression of this form of the adhesion receptor very strongly promotes breast cancer cell survival, expansion and invasive dissemination in the brain and central nervous system. To develop a new therapeutic approach against metastatic breast cancer, particularly lesions in the brain, we isolated function-blocking antibodies against activated avŖ3 from combinatorial libraries of cancer patient leukocytes. We showed that these antibodies behave like natural ligands of the receptor, but are much more specific, and can pinpoint metastatic breast cancer cells, including those that home to the brain. Most importantly, we established that treatment with these antibodies can interfere with early metastatic disease, and we generated proof-of-principle evidence that systemic treatment of experimental mice with our patient derived antibody phage preparations can stop, or significantly slow down, progression of even very advanced breast cancer metastases in the lungs, liver or kidney. When displayed on phage particles and administered as a nasal spray or injected into the peritoneal cavity, our antibodies can reach target organs of breast cancer metastasis, including the brain. To optimize the efficacy of the antibodies and prolong their half-life in the patientís body, we have generated different combinations of the effective regions of the antibodies to increase their stability and potential to penetrate cancer lesions. With these developments we have overcome a major hurdle that has been a stumbling block for research on breast cancer brain metastases. Our findings and developments will allow us rigorously investigate and optimize new treatment approaches with patient derived antibodies directed against breast cancer metastases in the brain.

If successful, our approach could lead to the development of a new therapy for brain metastases in breast cancer patients. Our antibodies against the molecular target that we identified as critical for breast cancer brain metastasis, and new antibodies that we are selecting, are fully human and their functional portions could be directly used in the clinic.

Adaptation of energy metabolism in breast cancer brain metastases.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Chen EI, et al, and Felding-Habermann B
Yr: 2007 Vol: 67 Nbr: 4 Abs: Pg:1472-86

The biology of metastasis to a sanctuary site.
Periodical:Clinical Cancer Research
Index Medicus: Clin Cancer Res
Authors: Palmieri D, Chambers AF, Felding-Habermann B, Huang S, Steeg PS.
Yr: 2007 Vol: 13 Nbr: 6 Abs: Pg:1656-62