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.
Dennis E. Hallahan, M.D.
Elizabeth and James McDonnell Distinguished Professor and Head, Department of Radiation Oncology, Washington University, Siteman Cancer Center, St. Louis, MO
Antibodies to Novel Inducible Antigens in Breast Cancer
"Presently, therapeutic antibodies for breast cancer are limited to antigens that are either specific to cancer or are over-expressed in breast cancers. Not only are the number of antigens limited, they also tend to be over-expressed in a small percentage of patients (e.g. 30 percent breast cancers express Her2/neu). In contrast, inducible antigens are expressed in nearly all cancers and expand the number of therapeutic targets for antibody development. The principles of inducible neoantigens are that cancer cells over-express intracellular proteins including TIP1 and GRP78 [6,7]. Breast cancer cells respond to ionization by transporting these proteins to the cell surface in response to DNA damage response and ATM activation. We developed monoclonal antibodies to TIP1 and GRP78.
"We will test the hypothesis that these antigens are selectively induced within breast cancers during irradiation. TIP1 and GRP78 are radiation inducible neoantigens that were discovered by phage displayed peptide libraries, proteomics and genomic analysis. We recently found that TIP1 and GRP78 undergo radiation induced translocation to the cell surface. Breast cancer specific binding is achieved for several days by anti-TIP1 and anti-GRP78 monoclonal antibodies after irradiation. Optical imaging and immunohistochemical staining indicated that the TIP1 and GRP78 specific antibodies achieve specific binding to irradiated breast cancer in mouse models. Like IgG1 in humans, these IgG2b isotype monoclonal antibodies are the most potent isotypes to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in mouse models of breast cancer. FcγRIIIA is the primary activating FcγR expressed by natural killer (NK) cells, DCs and macrophages, and is required for NK cell-mediated ADCC. FcγRI is a high-affinity receptor expressed by macrophages, and dendritic cells (DCs)-mediated antibody-dependent cell-mediated phagocytosis (ADCP).
"The objective of this research is to test the hypothesis that radiation can be used to induce antibody-dependent activation of immune effector cells in breast cancer. We will study the efficacy of therapeutic antibodies to multiple radiation inducible neo-antigens and study immune effector cell activation to control breast cancer. This new paradigm in cancer therapy complements therapeutic antibodies by inducing additional antigens for antibody binding to the surface of breast cancer."
Mark M. Moasser, M.D.
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, Professor in Residence, University of California, San Francisco, CA
A Next-Generation Approach for Inactivation of the HER2-HER3 Tumor Driver
"More than 20 percent of breast cancers are characterized by amplification of the HER2 oncogene and two decades of experimental studies strongly suggest that this subtype of breast cancer is driven by the pathologic function of the overexpressed HER2 oncoprotein. This has led to the very promising hypothesis that patients with the HER2-positive subtype of breast cancer can be treated highly effectively through the singular use of drugs that effectively inactivate HER2 functions. Several such drugs have now been developed and entered the clinical arena. An important lesson learned from this first generation of drugs has been the unexpected resiliency of the HER2 target and mechanistic insights that lay the groundwork for a next generation of agents with, hopefully, much higher anti-cancer efficacies. This work has highlighted the role of HER3 as a critical partner for HER2. Although HER3 is catalytically inactive, it is an important activator of the HER2 kinase, and its signaling functions are intimately connected with the downstream Akt/mTor signaling pathway, so critical for tumorigenic growth. The highly adaptive nature of the network topology downstream of HER3 provide robust feedback functions to ensure continued HER3 signaling required for growth and survival. Consequently, the functionally relevant HER2-HER3 tumor driver is endowed with a signal buffering capacity that protects it against all but the complete inactivation of the HER2 kinase, placing this target beyond the therapeutic range of even the most potent HER2 or HER3 targeting agents currently available. The highly effective treatment of HER2-driven breast cancers awaits the development of next-generation drugs with much higher potencies than the current classes of antibody therapeutics or kinase inhibitors currently in the pharmaceutical platforms. In this AACR-BCRF project, we propose to lay the groundwork for such an endeavor.
"The exquisite sensitivity of HER2 to inhibitors of Hsp90 proves that such potency is possible and provides a promising avenue for exploration. Despite massive overexpression in cancer cells, HER2 undergoes rapid and near complete degradation when exposed to inhibitors of Hsp90, identifying an Achilles heel attribute in this high value target. Its partner HER3 is also dependent on Hsp90 function. However, the large size of the Hsp90 client repertoire significantly limits the potential of Hsp90 as a clinically useful target for loss-of-function drugs and an inescapable limitation of all current classes of Hsp90 inhibitors. We believe that the chaperone functions of Hsp90 can be inhibited in a client-selective fashion with drugs that target Hsp90 allosteric sites critical for mediating HER2 and HER3 stability, and tumor-driving HER2-HER3 complex formation. This belief is based on recent insights into the mode of interaction between Hsp90 and its clients, and the recent discovery of a prototype compound that inhibits Hsp90 interaction with some but not other clients. In contrast to all current Hsp90 inhibitors in clinical trials, drugs developed with this mechanism of action would forsake the loss-of-function of Hsp90, instead affecting only a restricted scope of client proteins, affording a much wider therapeutic index and more potent clinical activity in the treatment of HER2-amplified breast cancers. We will pursue this concept through two non-redundant but complimentary approaches; a mutation-based structure-function analysis and a small molecule screening effort. The ultimate goal of our work is to develop therapies that can effectively inactivate the HER2-HER3 tumor driver with the requisite potency and selectivity to mediate the complete clinical remission of cancer in patients with even advanced stages of HER2-driven breast cancer."
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Stephanie C. Pero, Ph.D.
Research Assistant Professor, Department of Surgery, University of Vermont College of Medicine, Burlington, VT
A Novel Ultra HTS Cytotoxic Assay for Discovery of Human Cancer Antibodies
"The funding from the Breast Cancer Research Foundation-AACR Grant for Translational Breast Cancer Research will be used to generate an ultra high throughput cytotoxic assay to identify antibodies from individual cancer patients’ tumor-infiltrating B cells that are able to kill the patient’s own tumor. Dr. Pero is focusing her efforts on this aim because rapid identification of antibodies that exhibit a particular set of characteristics among a heterogeneous population remains a challenge for basic biomedical research and drug discovery. Anti-cancer monoclonal antibodies that target specific antigens on the tumor surfaces are being used with increasing frequency to treat solid and hematologic malignancies. Advantages of these antibodies include their long half-life, low toxicity, high affinity and specificity. Patient-derived antibodies are a rich source of high-affinity target-specific antibodies. These antibodies already exist in the circulation of cancer patients, and, as self-derived antibodies, are in a format ideal for clinical use.
"Dr. Pero will collaborate with Christopher Love at the Koch Institute for Integrative Cancer Research at MIT to develop an assay that uses a limited number of tumor cells to screen tens of thousands of different antibodies for bioactivity using their microengraved slides. The microengraving process creates an array of 84,672 microwells in subnanoliter volumes in which to test the functional capability of B cells isolated from patients on cell-mediated cytotoxicity.
"Dr. Pero works in conjunction with David Krag, M.D., and Girja Shukla, Ph.D., at the University of Vermont College of Medicine to greatly expand the portfolio of therapeutic anti-cancer antibodies for cancer patients. Our approach has the real possibility of rapidly generating clinically useful antibodies by developing new screening methods so that we can screen the full repertoire of a patient’s B cells. Several drug development steps can be bypassed if the pre-existing antibodies generated by a patient can be determined to be specific for tumor binding and functionally inhibit tumor progression. No further in vivo manipulation of the patient’s immune system is necessary. It is necessary that their immune system be primed to make B cell clones with tumor-binding antibodies. The rest is done outside the patient, leading to unrestricted production of therapeutic antibodies. This research strategy will enable a new screening tool to identify B cells producing anti-tumor antibodies.
"This outcome will provide useful information of the natural response to the tumor generated by affected patients, and may suggest new strategies for therapeutic vaccines designed to elicit similar antibodies in others. More importantly, this approach would suggest a potential new paradigm for personalized treatment."
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Shizhen Emily Wang, Ph.D.
Assistant Professor, Department of Cancer Biology, Beckman Research Institute in the City of Hope, Duarte, CA
Identify Blood-Borne microRNAs Associated with Breast Cancer Metastasis
"Metastasis is the leading cause of mortality in breast cancer patients. Understanding the molecular mechanisms that influence distant metastasis of breast cancer and identifying biomarkers associated with metastatic disease progression will enhance our ability to optimize and individualize anti-breast cancer treatment at an early stage to prospectively prevent metastasis and protect the target organs. The recently discovered miRNAs play a crucial role in multiple cellular functions by regulating expression of their target genes, and are frequently dysregulated in breast cancer. Cancer-secreted miRNAs, encapsulated in microvesicles shed by cancer cells, are stably present in the extracellular environment of cancer cells and in the blood of cancer patients. In this project funded by Breast Cancer Research Foundation-AACR Grant in Translational Breast Cancer Research, we will identify the blood-borne miRNAs associated with breast cancer metastasis, and will explore their role in the metastatic progression of breast cancer through affecting cancer and niche cells. Studies will be carried out using high-throughput deep sequencing approach and established cell and animal models. The immediate outcome of this project is the identification of blood-borne miRNA signatures that reflect the potential for or presence of metastasis in breast cancer patients. These may enable accurate prediction and early diagnosis of metastasis in breast cancer patients, allowing for preventive or therapeutic early treatments. Another major significance of our study is to provide fundamental groundwork and preclinical evidence for a novel strategy to prevent breast cancer metastasis by therapeutically targeting the malignant miRNA signals released by cancer cells."