American Association for Cancer Research

Translational Breast Cancer Research Grant
BCRF funds are supporting two-year BCRF-AACR Grants in Translational Breast Cancer Research. AACR's research grant program highlights promising and innovative new research selected through a flexible, rigorous and transparent peer review process.

The 2007-2009 BCRF-AACR grant recipients are:

Ingrid Mayer, MD, Vanderbilt University, Nashville, TN
Systemic therapies for breast cancer should be guided by biologic features of the tumor, such as hormone-sensitivity or HER2-overexpression. An unfortunate problem with breast cancers is that they tend to become resistant to endocrine therapies over time, and both de novo and acquired resistance to anti-HER2 therapy occur. EGFR (epidermal growth factor receptor) and/or HER2 (ErbB) receptors become important for the tumor cell at the time of escape from hormone deprivation.

Dr. Mayer has proposed a phase II neoadjuvant study of the aromatase inhibitor letrozole (Femara®) combined with the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib (Tykerb®) in post-menopausal patients with newly diagnosed ER+/HER2+ operable breast cancer, to identify optimal biological markers of ER/ErbB inhibition and to correlate the changes in these markers with biological endpoints such as cell proliferation and cell death. Letrozole and lapatinib are drugs with known efficacy against breast cancer.

Dr. Mayer proposes that this approach will allow researchers to establish biomarkers predictive of response and/or lack of benefit. In turn, these biomarkers should permit the better selection of patients into subsequent trials with this combination, avoid costly and lengthy clinical trials in the metastatic setting, and provide a platform for prioritization of novel combinations.

Alana Welm, PhD, University of Utah, Salt Lake City, UT
Dr. Welm has developed new in vitro and in vivo approaches to better understand breast cancer and metastasis. She is working to validate MSP/MT-SP1/MST1R expression as a biomarker for high-risk breast cancer and has developed a diagnostic test for its expression. She hopes to carry out pre-clinical studies to test inhibitors of the MSP pathway for the ability to block tumor growth and/or invasion.

Douglas Yee, MD, Director of the Cancer Center, University of Minnesota, Minneapolis, MN
Dr. Yee's research focuses on focus on the regulation of breast cancer cells by peptide growth factors. His laboratory is examining the insulin-like growth factor signaling system with the hope of developing new therapies to disrupt breast cancer cell growth and metastasis.

The 2008-2010 BCRF-AACR grant recipients are:

Virginia F. Borges, MD, Assistant Professor, Medical Oncology, University of Colorado, Aurora, CO
"Targeting the Inflammatory Milieu of Pregnancy-Associated Breast Cancer"
Pregnancy exerts complex effects on the risk of breast cancer. The risk of breast cancer diagnosis increases immediately following the completion of a pregnancy and this risk persists for approximately 10 years. The diagnosis of invasive breast cancer in temporal proximity to a completed pregnancy is associated with an increased risk of subsequent metastatic spread and a significant decrease in breast cancer survival for reasons unrelated to standard breast cancer prognostic markers. Pregnancy-associated breast cancer (PABC) is defined as a breast cancer diagnosed within 6 years of a completed pregnancy, reflecting this period of increased risk. Among women under the age 40 diagnosed with breast cancer, almost 50% fulfill the definition of PABC. As many American women continue to delay childbearing until later ages, this proportion will continue to increase.

Dr. Borges and her colleagues have reported that an inflammatory background arises in the breast tissue in setting of post-pregnancy, post-weaning breast involution and that this inflammation associated with weaning is promotional of metastasis in PABC. Increasingly, the interaction between the pro-inflammatory tumor microenvironment and the different arms of the immune system is recognized as a critical factor in breast cancer progression and as a potential area for therapeutic targeting. Therefore, the researchers will investigate the immune response to the pro-inflammatory tumor microenvironment in PABC as it compares to non-PABC and to target this pro-inflammatory environment with a short term anti-inflammatory intervention that they hypothesize will result in a decrease in inflammation, a decrease immune suppression and pro-tumor-immune responses and a decrease potential for metastasis in newly diagnosed PABC.

David A. Frank, MD, PhD, Associate Professor of Medicine, Dana-Farber Cancer Institute, Boston, MA
"Targeting STAT3 for the Molecular Therapy of Breast Cancer"

This project aims to develop new drugs for the targeted therapy of advanced breast cancer. Research in Dr. Frank's laboratory over the last several years has focused on understanding the molecular abnormalities that distinguish a breast cancer cell from a normal cell, and devising rational strategies to target these specifically. In this way, he hopes to develop drugs that are much more effective at inhibiting breast cancer cells, and much less toxic.

Dr. Frank's team has found that a protein called STAT3, which regulates expression of genes that control cellular function, is turned on inappropriately in the majority of breast cancers. Furthermore, this abnormality drives the malignant behavior of breast cancer, as inhibition of STAT3 leads to a loss of the ability of tumor cells to grow and spread. They have also found that normal cells can tolerate inhibition of STAT3 with little consequence, due to the presence of back-up systems that are lost in cancer cells. Based on these findings, they have focused on STAT3 as a key molecular target for the rational therapy of breast cancer.

To date the researchers have identified three drugs that are selective inhibitors of STAT3 function. Their goal is to evaluate the ability of these drugs to inhibit the growth and malignant behavior of human breast cancer cells in tissue culture-based and laboratory models.

Yvonne J. Patterson, PhD, Professor of Microbiology and Associate Dean, University of Pennsylvania, Philadelphia, PA
"Anti-Angiogenesis Immunotherapy for Treatment of Metastatic Breast Cancer"

The ideal therapy for breast cancer would require limited administrations, be specific, non-toxic, inexpensive and would provide lifelong protection from multiple cancer types. Immunotherapy is a type of therapy that tells your immune system to specifically attack only cancer cells. Researchers use bacteria to carry and disguise tumor protein as a bacterial protein, to trick the immune system into thinking that it needs to attack all cells expressing this particular protein. Since only tumor cells express this protein then only cancer cells will be targeted.

The immune system is very specific, is not toxic, and will provide lifelong immunity. Dr. Patterson's lab is focused on expressing these tumor proteins in Listeria monocytogenes, a bacteria commonly found in dairy products which causes disease in immuno-compromised individuals, like AIDS patients, and pregnant women. Here, the investigators target the tumor's blood supply which makes their therapy applicable to more than just breast cancer; it could be used to treat all sorts of cancers because all tumors need a constant supply of blood to carry nutrients, oxygen, and remove wastes. This therapy targets blood vessels that are newly forming (called angiogenesis), so that tumors that are growing for the first time (like after metastasis) will be most affected by this therapy. Since new blood vessels do not usually form in adults unless during pregnancy or wound healing, the only source of rapidly dividing vessel cells would be growing tumors. Thus targeting angiogenesis using immunotherapy will provide lifelong immunity against rapidly dividing tumors by attacking their food supply. The investigators hope this approach will provide a possible alternative therapy against breast cancer that may also provide additional protection against metastasis and could impact other cancers.