Translational research, adapting new laboratory findings quickly to improve prevention, quality of life, and survival for breast cancer patients, hs been the focus of the team now forming the Baylor Breast Center for over 30 years. In the early years of our previous SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemotherapy resistance, breast cancer prevention, metastasis, and development of premalignant lesions. Developmental projects ranged even further in seeking new translational possibilities. In this new SPORE proposal, we build on our earlier results and on new findings and technologies, in four projects and several support components. (1) We have discovered that the mevalonate pathway is upregulated by anti-HER2 therapy and can serve as an escape pathway, leading to treatment failure. But several already approved agents (statins and bisphosphonates) can inhibit this pathway, and we will explore their mechanisms and their potential to overcome this treatment failure, both in preclinical studies and a clinical trial. (2)The steroid receptor coactivator SRC-3 is frequently overexpressed in breast cancer and promotes growth and endocrine resistance, especially when HER2 is also active. Finding that inhibiting upstream kinases PKC and PKD that support SRC-3 activity can suppress tumor growth and restore endocrine sensitivity, we propose to dissect the functions of these kinases on SRC-3 in defined preclinical models, and test the efficacy and safety of a PKC inhibitor added to endocrine therapy in a clinical trial. (3) Chemoprevention of breast cancer has had limited acceptance due to expense and concerns about side effects of long-term continuous treatment with existing agents. But we have now discovered that activated pSTAT5 blocks the apoptosis that is typically induced as a protective mechanism by activation of oncogenes, and that even short-term suppression of pSTAT5 with agents like ruxolitinib can cause regression of premalignant breast lesions and prevent progression to cancer in mice. In both mouse models and an early clinical trial, we will investigate this approach for effective intermittent chemoprevention. (4) Though immunotherapy promises exquisite specificity and safety, results have been disappointing as tumor cells alter targeted antigens and generate an immunosuppressive environment to escape. Here we propose to adoptively transfer T cells engineered to attack two tumor-associated antigens rather than one, and to express a chimeric receptor that causes the repressive cytokine 1L4 to promote T cell cytotoxicity instead. Our unique, widely used breast Tissue Resource/Pathology Core, along with Biostatistics and Administrative Cores give key support to this SPORE. Our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research.
SPOREs exist to bring the best bench science and the best clinical science together, to optimize the application of what we know and explore the most profitable parts of what we don't yet know, to improve our outcomes in treating and hopefully preventing breast cancer. We've made strides in defining effective combinations of therapy and circumventing resistance that now affect patient treatment every day, and we will continue to make more in this proposed new SPORE while also researching the farther limits to find new and better ways to do promising things like chemoprevention and immunotherapy.
|Yu, L; Liang, Y; Cao, X et al. (2017) Identification of MYST3 as a novel epigenetic activator of ER? frequently amplified in breast cancer. Oncogene 36:2910-2918|
|Mohammed, Somala; Sukumaran, Sujita; Bajgain, Pradip et al. (2017) Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer. Mol Ther 25:249-258|
|Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609|
|Dong, J; Zhao, W; Shi, A et al. (2016) The PR status of the originating cell of ER/PR-negative mouse mammary tumors. Oncogene 35:4149-54|
|Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G et al. (2016) Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev 35:547-573|
|Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81|
|Eedunuri, Vijay Kumar; Rajapakshe, Kimal; Fiskus, Warren et al. (2015) miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation. Mol Endocrinol 29:1170-83|
|Shi, Aiping; Dong, Jie; Hilsenbeck, Susan et al. (2015) The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia. PLoS One 10:e0132214|
|Sine, Jessica; Urban, Cordula; Thayer, Derek et al. (2015) Photo activation of HPPH encapsulated in ""Pocket"" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine 10:125-45|
|Dowst, Heidi; Pew, Benjamin; Watkins, Chris et al. (2015) Acquire: an open-source comprehensive cancer biobanking system. Bioinformatics 31:1655-62|
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