The Breast Cancer Research Foundation-AACR Grants for Translational Breast Cancer Research were established in 2007 to provide support for innovative cancer research projects designed to accelerate the discovery, development and application of new agents to treat breast cancer and/or for preclinical research with direct therapeutic intent.
- Carey Anders, M.D. (2010)
- Charles V. Clevenger, M.D., Ph.D. (2010)
- Heide L. Ford, Ph.D. (2010)
- Virginia F. Borges, M.D. (2009)
- Wilson H. Miller, Jr., M.D., Ph.D. (2009)
- Yvonne J. Paterson, Ph.D. (2009)
- Ingrid A. Mayer, M.D. (2007)
2010 GRANTEES
Carey Anders, M.D.Assistant Professor, University of North Carolina Chapel Hill, Chapel Hill, NC
PARP Inhibition and Nanoparticles to Treat Breast Cancer Brain Metastases
"It is estimated that 200,000 women are diagnosed annually and world-wide with triple-negative breast cancer. Triple-negative breast cancer is an aggressive subset of breast cancer that lacks expression of the estrogen and progesterone receptors and the HER2 protein and is over-represented among women with advanced breast cancer. Moreover, recent studies illustrate half of women with advanced triple-negative breast cancer recur within the central nervous system. Systemic therapies capable of treating triple-negative breast cancer brain metastases are limited by the paucity of anti-cancer agents capable of crossing the blood brain barrier. Presently, there is no effective chemotherapeutic approved to treat patients with triple-negative breast cancer brain metastases and women with recurrence to the central nervous system are frequently excluded from promising clinical trials. Triple-negative breast cancer brain metastases represents a clinically-unmet need.
"Poly (ADP-Ribose) polymerase (PARP) inhibitors, a class of drugs which inhibit DNA repair, have emerged as one of the most exciting classes of agents to partner with chemotherapy to treat advanced extracranial triple-negative breast cancer. The physical properties of many of the clinically-available PARP inhibitors allow blood brain barrier penetration. Moreover, nanoparticle formulations of anti-cancer agents have been shown in preclinical and clinical studies to enhance central nervous system delivery. Thus, we have hypothesized that PARP inhibition in combination with nanoparticle anti-cancer agents will prove efficacious in the treatment of triple-negative breast cancer brain metastases. In this proposal, we have designed a series of preclinical studies in an established intracranial triple-negative breast cancer mouse model. We propose to compare the pharmacologic distribution and efficacy of PARP inhibition in combination with nanoparticle versus non-nanoparticle formulations of chemotherapies known to be active in breast cancer.
"The overarching goal of our research program is to improve therapeutic options, and ultimately survival, for women diagnosed with triple-negative breast cancer brain metastases. We believe that the results anticipated from this innovative proposal have the potential to refine our ability to select chemotherapeutic partners to combine with PARP inhibitors to more effectively treat patients with triple-negative breast cancer brain metastases. Importantly, results from this translational project will provide an informed foundation for the design of clinical trials evaluating PARP inhibitors in combination with nanoparticle chemotherapeutics aimed at improving survival for patients with triple-negative breast cancer brain metastases. “I would like to personally thank my co-primary mentors, Drs. Lisa A. Carey and Charles M. Perou, who are both part of the collaborative and supportive environment at the University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center."
Charles V. Clevenger, M.D., Ph.D.Diana, Princess of Wales Professor of Cancer Research, Robert H. Lurie Comprehensive Cancer Center and Department of Pathology, Northwestern University, Chicago, IL
Cyclophilin A as a Target in Breast Cancer
"Cyclophilins are peptidyl-prolyl isomerases that regulate protein structure and function. In this role, they can serve as signaling switches and regulate the function of cell surface receptors, kinases and transcription factors. Recently our lab has documented a critical role in breast cancer cells for cyclophilin A (CypA) in the receptor-mediated activation of the Jak2 tyrosine kinase. CypA is a pharmacologic target for cyclosporine A (CsA), and its non-immunosuppressive analog, NIM811. Given the importance of the Jak/Stat pathway in the pathogenesis of breast cancer, we initially hypothesized and demonstrated that CsA could inhibit ER+ and ER- breast cancer signaling, growth and in vivo progression. Subsequent in vitro studies have revealed that NIM811 has comparable therapeutic promise. The goal of this proposal is to map the full spectrum of NIM811 actions against breast cancer both in vitro and in vivo, and to translate these findings into a phase I trial. These studies could open the use of NIM811, as a non-immunosuppressive drug with minimal toxicity, as both a therapeutic and a potential chemopreventive."
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Heide L. Ford, Ph.D.Associate Professor, University of Colorado Denver, Aurora, CO
Targeting the Six1/Eya Complex for Anti-Breast Cancer Metastasis Therapies
"Breast cancer remains the second leading cause of cancer-related deaths in women. More than 90 percent of breast cancers occur for unknown reasons (sporadically), accentuating that our knowledge of the pathways involved is still far from complete. However, it is clear that particular genes play important roles in the development of sporadic breast cancer and, as with other cancers, it is thought that therapeutic targeting of important “driver” genes may be the most effective way to treat breast cancer. Recently, Six1 was identified as a critical breast cancer gene. Not only is Six1 overexpressed in a large percentage of breast cancers (50 percent of primary breast cancers and 90 percent of metastatic lesions), where it correlates with poor prognosis, but it can also induce tumor formation (tumorigenesis) and metastasis in mouse models of mammary tumorigenesis. These data suggest that the effects of Six1 are widespread and that an effective method to target this protein would have broad therapeutic utility.
"Importantly, Six1 cannot mediate its effects on gene expression and breast cancer in the absence of a critical co-factor, Eya2. Similar to Six1, Eya2 also is not expressed in most normal adult tissues but is re-expressed in cancers. The unique enzymatic activity of Eya proteins makes them more amenable than Six1 to targeting for anti-cancer therapies. The Six1-Eya interaction is essential for growth during embryonic development, and both Six1 and Eya2 have been independently implicated in the same types of cancer. Furthermore, examination of gene expression patterns from 535 breast cancer patients demonstrates that only when there is high Six1 and Eya expression together in breast tumors do they significantly predict shortened time to relapse, shortened time to metastasis and shortened overall survival. These data strongly suggest that Eya proteins are required for Six1-mediated breast tumorigenesis and/or metastasis. Indeed, Eya2 is necessary for the ability of Six1 to induce many of its pro-tumorigenic and pro-metastatic properties. Most importantly, just as with Six1, Eya’s enzymatic activity has recently been shown to be critical for breast cancer metastasis.
"Thus, the Six1/Eya complex is a novel and important drug target whose inactivation is expected to inhibit tumor cell proliferation and metastasis in breast cancers. In addition, because Six1 and Eya2 are embryonic genes with little to no expression in normal adult tissues, inhibitors of their expression/activity are likely to have limited side effects. Thus, my group, in collaboration with Dr. Rui Zhao, will use the BCRF-AACR funding to identify small molecules that can either inhibit the enzymatic activity of Eya2 or the ability of Eya2 to interact with Six1. Identified small molecule inhibitors will be characterized biochemically, as well as in cell culture and in animal models, to determine whether they can inhibit both breast cancer initiation and progression. Since Six1 and Eya influence multiple stages of the tumorigenic process, targeting the Six1/Eya transcriptional complex can potentially inhibit breast cancer both at early and later stages of disease progression. Furthermore, since Six1 and Eya2 are not expressed in most normal adult tissue, therapeutic agents targeting the Six1-Eya complex should inhibit tumor cell proliferation and metastasis with limited toxicity and may provide significant benefits to the 50 to 90 percent of breast cancer patients respectively whose primary tumors and metastatic disease overexpress Six1."
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2009 GRANTEES
Virginia F. Borges, M.D., M.M.Sc.Assistant Professor, Medical Oncology, University of Colorado, Aurora, CO
Targeting the Inflammatory Milieu of Pregnancy-Associated Breast Cancer
"Pregnancy-associated breast cancer (PABC) is defined as a breast cancer diagnosed within six years of a completed pregnancy, reflecting this period of increased risk. Among women under the age 40 diagnosed with breast cancer, almost 50 percent fulfill the definition of PABC. As many American women continue to delay childbearing until later ages, this proportion will continue to increase. Therefore, PABC is a high-risk, increasing sub-population of breast cancer in the U.S. with significant negative impact on a vital component to society - young mothers. We have reported that an inflammatory milieu arises in the stromal microenvironment in setting of post-pregnancy, post-lactation breast involution and that this stromal microenvironment of involution is promotional of metastasis in PABC. Increasingly, the interaction between the pro-inflammatory tumor microenvironment and the innate and adaptive arms of the immune system is recognized as a critical factor in breast cancer progression and as a potential area for therapeutic targeting. Our project will investigate the immune response to the proinflammatory tumor microenvironment in PABC as it compares to non-PABC. By utilizing the unique window between initial breast cancer diagnosis and definitive surgery, we will also conduct a randomized, short term, drug intervention study to target this pro-inflammatory environment with a short-term, anti-inflammatory intervention. We hypothesize that the anti-inflammatory interventions will result in a decrease of inflammatory markers in the stromal microenvironment, a decrease immune tolerogenic and tumor-promotional responses and a decrease potential for metastasis in newly diagnosed PABC."
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Wilson H. Miller, Jr., M.D., Ph.D.Professor of Oncology, Lady Davis Institute for Medical Research of the SMBD Jewish General Hospital, Montreal, Canada
Targeting eIF4E with Ribavirin in Poor Prognosis Breast Cancer
An important goal in breast cancer research is to develop less toxic and more effective personalized therapies, based on the clinical and molecular characteristics of the tumor. Two proteins (‘targets’) are routinely tested in the assessment of breast cancer: the estrogen receptor (predicting response to endocrine therapies) and Her2 (predicting response to Herceptin). Dr. Miller’s team will study a new target, eIF4E. eIF4E is found at high levels in about 50 percent of all breast cancers, and these tumors are more aggressive and more resistant to chemotherapy. Therefore, blocking the effects of eIF4E has been proposed as a possible new therapy for advanced breast cancer. Ribavirin, a non-toxic anti-viral drug, inhibits the activity of eIF4E and slows the growth of cancer cells with high levels of eIF4E in the laboratory. A recent clinical trial in leukemia performed by Dr. Miller and collaborators showed that ribavirin can effectively target eIF4E in patients and trigger remission of the cancer. It is important to test if ribavirin will have a similar anti-tumor effect in breast cancer. Dr. Miller and his team will conduct a clinical trial to study the effects of ribavirin in metastatic breast cancer patients who have high levels of eIF4E. To show a link between inhibition of eIF4E and anti-tumor effects, tumor samples will be taken before and after treatment to allow for analysis of eIF4E and other tumor markers. The group will also use breast cancer cells grown in the laboratory to identify possible drug combinations that could improve the effectiveness of ribavirin. They will test the combination of ribavirin with drugs commonly used to treat breast cancer, and will also screen a library of 5000 drugs to find new combinations that could be tested in future clinical trials. This research will help the design of novel therapeutic strategies for a group of patients with poor-prognosis, metastatic breast cancer. eIF4E may be an important drug target in this group and detection of high levels of eIF4E in tumors could potentially be used as a guide to clinical decision making, as is currently the case for the detection of ER or Her2. Thus, while ER-positive patients receive tamoxifen and Her2-positive patients get Herceptin, it is postulated that patients with high eIF4E could be treated with ribavirin. Importantly, ribavirin is easily accessible, commercially available, and no side effects were observed in the previous clinical trial in patients with leukemia. Better understanding the role of eIF4E in breast cancer may thus lead to better, personalized therapy.
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Yvonne J. Paterson, Ph.D.Professor of Microbiology and Associate Dean, University of Pennsylvania, Philadelphia, PA
Anti-Angiogenesis Immunotherapy for Treatment of Metastatic Breast Cancer
"Our lab specializes in targeting tumor antigens via the use of a bacterial vector that induces potent anti-tumor CD8+ T cell responses against an engineered product. We engineer Listeria monocytogenes to overexpress fragments of tumor proteins fused to the microbial adjuvant, Listeriolysin-O (LLO), and can successfully treat established tumors. Previous Listeria-based therapies included the targeting of Her-2/neu; here we show that self-tolerance can be broken, thereby inducing immune responses to molecules involved in angiogenesis. The pericyte glycoprotein, high-molecular weight-melanoma-associated-antigen (HMWMAA), and the vascular endothelial growth factor receptor (VEGFR2), are currently being targeted by Lm-vaccines. In addition, we propose the construction of a third vaccine that would target the TGFbeta co-receptor, CD105/Endoglin that has selectively higher expression on tumor vasculature and thus can act as a specific, angiogenesis target. For this we will construct a Listeria that expresses the LLO-CD105 fusion protein. Depending on the effectiveness of the three vaccines we intend on testing one vaccine in combination with current therapies targeting breast cancers. Vaccines will be combined with an anti-Her-2/neu Listeria-vaccine, or anti-Her-2/neu antibodies. Since all tumors require intact vasculature to provide nutrients and remove wastes we expect that damage to this network will cause tumor death and that this tumor death will ultimately lead to epitope spreading. We hypothesize that combining anti-angiogenesis and anti-Her-2/neu vaccinations and therapies will both increase the likelihood of tumor death but also Her-2/neu epitope spreading. We hypothesize that the immunity induced by our listerial vaccine constructs will overcome self-tolerance to the angiogenesis molecules due to the potent inflammatory response against Listeria and evidence from previous Her-2/neu studies."
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2007 GRANTEES
Ingrid A. Mayer, M.D.Assistant Professor of Medicine, Vanderbilt University Medical Center, Nashville, TN
Combined Endocrine and Erbb Inhibition in ER+/HER2+ Breast Cancers
Dr. Mayer serves as a clinical investigator and assistant professor at Vanderbilt University Medical Center. With the funding from the Breast Cancer Research Foundation-AACR Grant for Translational Breast Cancer Research, Dr. Mayer will focus her efforts on trying to find out if the combination of two drugs, Letrozole (Femara®) and Lapatinib (Tykerb®) will work better in preventing failure of these tumors response to an anti-hormonal treatment. Dr. Mayer is focusing her research towards these aims because, "we need more and better choices for treating a form of breast cancer whose growth is both dependent on hormones and HER2, and do not respond well to drugs that stop the growth of cancer cells by decreasing the amount of estrogen that is produced in the body, or drugs that are active against HER2, when given by themselves." Dr. Mayer and her research team will perform a clinical trial using the drugs Letrozole (Femara®) and Lapatinib (Tykerb®) together for 14 weeks, before definitive surgery, in postmenopausal patients with hormone-dependent, HER2-positive breast cancers. By carefully studying these tumors with state-of-the-art techniques from a molecular point of view before and after surgery, she hopes to find a "molecular signature" that will tell which subset of these tumors are more likely to respond to the Letrozole/Lapatinib drug combination, by linking the molecular information to the degree of tumor shrinkage we see prior to surgery. Dr. Mayer hopes that "in the end, the studies proposed here will help reduce the mortality of patients with hormone-responsive, HER2-positive breast cancer."
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