Inhibiting Breast Cancer Brain Metastasis with Cilengitide
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 because they severely impact the quality of life and can be managed in the clinic only for a few weeks or months. The incidence is rising as the brain is emerging as a major site of isolated recurrence. There is no standard treatment for breast cancer patients with brain metastases, and most lesions do not respond to chemotherapeutics. Surgery, stereotactic radio surgery and whole brain radiation can prolong patient survival, but often with severe side effects. Thus, new therapies are urgently needed. We recently identified an “activated” form of the adhesion receptor integrin ?v?3 on human breast cancer cells as critical for brain metastatic growth and identified ?v?3 as a new therapeutic target for brain metastases. 
 
 
 
 
 
 
 
 Our goal is now to investigate if an existing drug against αvβ3 inhibits brain metastasis in breast cancer. The drug, called Cilengitide, is currently in Phase III clinical trial for glioblastoma multiforme, a very aggressive primary brain tumor. The drug is safe and patient survival data are promising. If our studies indicate that Cilengitide affects breast cancer brain lesions, this will provide a rationale and design information for a clinical trial. We will work closely with Dr. Burt Nabors, the lead of the Cilengitide trial against primary brain tumors.
 
 
 
 
 
 
 
 Our specific aims are: 
 
 
 
 • Investigate Cilengitide effects on ?αvβ3-positive breast cancer brain metastases and analyze if the drug interferes with tumor cell αvβ3-mediated VEGF expression. To assess how frequently αvβ3-positive brain lesions are seen in the clinic, αvβ3 expression will be analyzed in patient samples.
 
 
 
 • Investigate Cilengitide effects on ?αvβ3-negative breast cancer brain metastases, which depend on the Her-2 oncogene for intracranial growth. Treatment impact on Her-2 survival pathways will be analyzed. If this approach is promising, a combination of Cilengitide and Lapatinib to interrupt Her2 and EGFR1 (Her-1) signaling will be evaluated.
 
 
 
 
 
 
 
 All investigations will be performed in mouse models of human breast cancer. Treatment responses will be analyzed in immune deficient mice that developed brain lesions after human breast cancer cells were either implanted into the brain, or injected into the carotid artery to seed widespread brain lesions as seen in breast cancer patients. We will use unique new cell models that we established from breast cancer patient brain lesions. Treatment effects will be measured at the cellular and molecular levels. This will be achieved by non-invasive imaging of the animals followed by detailed histological and pathology, and by investigating molecular mechanisms involved and new blood vessel formation. We will also analyze if the therapy normalizes animal behavior to assess if it can improve the quality of life. 
 
 
 
 
 
 
 
 Results from this study could directly lead to a clinical trial against breast cancer brain metastasis. If indicated, a trial can be implemented immediately.