Inhibiting Breast Cancer Brain Metastasis with Cilengitide

Institution: Scripps Research Institute
Investigator(s): Brunhilde Felding, Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16IB-0052 Award: $284,435
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2010)

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.




Final Report (2011)

Overview and Topic:
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. 20-30% of breast cancer patients are diagnosed with brain metastases. 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, effective therapies are urgently needed.

We recently identified the activated conformer of adhesion receptor integrin αvβ3 on human breast cancer cells as a new therapeutic target for breast cancer brain metastasis. Based on our in vivo studies of human breast cancer cells in a SCID mouse model, we demonstrated a crucial role for high affinity tumor cell integrin αvβ3 in brain metastatic growth and recruitment of blood vessels. Therefore, targeting activated tumor cell integrin αvβ3 may efficiently interfere with breast cancer brain metastasis. To exploit this possibility and generate information that can be immediately used for the development of a clinical trial, we evaluated the use a small molecule inhibitor of integrin αvβ3 that is already in clinical development for primary brain tumors.

Hypothesis and Aims addressed:
We hypothesize that targeting integrin αvβ3 with Cilengitide can inhibit breast cancer brain metastases. We investigate if the drug directly affects tumor cells that express αvβ3, by blocking mechanisms through which the integrin promotes brain metastatic growth. Cilengitide can also interfere with angiogenesis, a process known to depend on αvβ3 expressed by the vasculature. Based on this two-fold therapeutic potential, Cilengitide may also affect αvβ3-negative breast cancer brain lesions.

  1. We investigated effects of Cilengitide on αvβ3-positive breast cancer brain metastases as a mono-therapy and in combination with whole brain radiation therapy (WBRT).
  2. We studied in vitro effects of Cilengitide on αvβ3 high and αvβ3 low expressing breast cancer cells to obtain information on tumor cell survival and growth pertinent to in vivo analysis of the best possible conditions for analyzing clinical inhibition of breast cancer brain metastasis in the animal model.

Summary and Results:
Combination effects of Cilengitide therapy with whole brain radiation therapy (WBRT) in breast cancer brain metastasis were analyzed in female SCID mice after stereotactic implantation of human breast cancer cells. Our results indicate that it will be very important to define the target tumor cell type and therefore the appropriate patient group to achieve the best possible outcome from Cilengitide and Cilengitide combination therapies. Cilengitide could be a promising supportive drug for treatment of brain metastatic disease. It is likely that onset of treatment at earlier stages of brain lesion development would be most effective. It is also clear that analysis of the responsiveness of the tumor cell type causing brain metastases is best, and should be used to define target patient populations who might respond to Cilengitide encompassing treatments most successfully.

Plans for Continuation and Aspects of Translation:
Results from this study might lead to a clinical trial against breast cancer brain metastasis. Information on the best targeted tumor cell and patient population is forthcoming to achieve the best possible outcome. Advocacy Involvement and Sensitivity to

Advocacy Concerns:
We are working with the San Diego chapter of Susan G. Komen for the Cure and with METAvivor, a Non-Profit volunteer organization for metastatic breast cancer. We are also closely connected with the National Breast Cancer Coalition (NBCC), contributing to Advocate training and to plans for the prevention of breast cancer metastasis. Importantly, we learn about concerns and developments in breast cancer support initiatives, and we share our findings. We received strong encouragement for developing a new treatment for breast cancer brain metastasis, because this is a growing and a devastating condition for patients and their loved ones.



Selective formation of covalent protein heterodimers with an unnatural amino acid.
Periodical:Chemistry and Biology
Index Medicus: Chem Biol
Authors: Hutchins BM, Kazane SA, Staflin K, Forsyth JS, Felding-Habermann B, Smider VV, Schultz PG
Yr: 2011 Vol: 18 Nbr: 3 Abs: Pg:299-303

Comparison of in vitro and in vivo approaches to studying brain colonization by breast cancer cells.
Periodical:Journal of Neurooncology
Index Medicus: J. Neoroonc.
Authors: Lorger M, Lee H, Forsyth JS, Felding-Habermann B
Yr: 2011 Vol: 104 Nbr: 3 Abs: Pg:689-96

Site-specific coupling and sterically controlled formation of multimeric antibody fab fragments with unnatural amino acids.
Periodical:Journal of Molecular Biology
Index Medicus: J Mol Biol
Authors: Hutchins BM, Kazane SA, Staflin K, Forsyth JS, Felding-Habermann B, Schultz PG, Smider VV
Yr: 2011 Vol: 406 Nbr: 4 Abs: Pg:595-603