Development of Targeted Therapy Strategies for Breast Cancer

Principal Investigator: HORTOBAGYI, GABRIEL N
Program: BCRP
Proposal Number: BC013020
Award Number: DAMD17-02-1-0694
Funding Mechanism: Breast Cancer Center of Excellence Award
Partnering Awards:
Award Amount: $5,972,963.00


Breast cancer is the most common malignancy in Western women. It is predicted that in 2001, one-third of all cancers in this country will be breast cancer. Breast cancer has the unfortunate propensity to metastasize, to spread from the breast to other sites or organ systems of the body. Once it has spread, breast cancer is rarely cured with currently available treatments. Thus, breast cancer is an important public health problem, and there is an urgent need for more effective treatment strategies, particularly for metastatic breast cancer.

We believe that the success in combating cancer first comes from basic research to further understand the mechanisms and pathways of regulation that are required for maintaining normal cell functions, and the identification of the key steps and components whose alterations may result in the development of breast cancer. We also believe that the most promising approach to developing curative therapies for breast cancer is the translation of our improved understanding of the molecular and cellular biology of breast cancer to more effective therapeutic strategies in clinical practice. The strong research expertise and the unique resources that our team of senior investigators can bring to bear on the common goal of developing novel targeted strategies for breast cancer through this Center of Excellence program are likely to have an impact on patient management.

We will target a series of molecules that play key roles in the transformation, proliferation, and metastasis of human breast epithelial cells. Cellular transformation, the initial step in cancer formation, is the consequence of genetic changes in DNA. This in turn leads to uncontrolled cell division and excessive proliferation resulting in tumor formation. This is followed by metastasis or the spread of tumor to other sites. In breast cancer, metastatic spread is almost always fatal. To most effectively accelerate discoveries and advancement in the battle against breast cancer, we have formed a team of established researchers with complementary expertise in both basic laboratory research and clinical research. We will develop novel approaches to target the cellular signaling pathways implicated in breast cancer development and essential for cell proliferation, survival, and metastasis. We will target the PTEN/PI3K signaling pathway that is implicated in breast cancer development and is essential for cell proliferation, survival, and metastasis. We will also target genomic DNA stability regulated by the BRCA1/BRCA2 breast cancer predisposition genes. We will test the hypothesis that selective disruption of the DNA repair process in breast cancer cells with intact BRCA1 and BRCA2 function will render the cells selectively sensitive to radiation or chemotherapy. We will also target the cellular apoptotic, or programmed cell death, pathway, that plays a pivotal role in self-defense against cellular transformation and tumor development by eliminating cells with damaged DNA. We will intravenously inject liposome-coated DNA with the bik and bok tumor-suppressor genes into animal models. In addition, we will develop and validate the usefulness of unique breast cancer animal models in the evaluation and validation of these therapeutic approaches, allowing efficient translation of laboratory research to benefit human patients. Outcomes from this application will provide the scientific basis for developing novel therapeutic approaches for clinical trials that will benefit the breast cancer patient.