SPORE Program in Breast Cancer
C. Kent Osborne, MD-PI
In 1992, the National Cancer Institute established the Specialized Programs of Research Excellence (SPOREs), specialized cancer center grants to promote and speed up the exchange between interdisciplinary research in the laboratory and the treatment of patients in the clinical care setting. Each SPORE is focused on a specific organ site, such as breast or lung cancer. SPORE grants involve both basic and clinical/applied scientists and support projects that will result in new and diverse approaches to the prevention, early detection, diagnosis, and treatment of human cancers.
Translational research, adapting new laboratory findings quickly to improve prevention, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for over 30 years. This team received one of the first four SPORE grants in breast cancer, which has been funded almost continuously ever since – it is now one of only six breast cancer SPOREs in the country. In the early years, our tumor bank that made much of our 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 our current SPORE, under the continuing leadership of Kent Osborne, we are building on our earlier results and on new findings and technologies, in four projects and several support components.
(Rachel Schiff, C. Kent Osborne, and Mothaffar Rimawi) 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.
(Bert O’Malley and Mothaffar Rimawi) 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.
(Yi Li and C. Kent Osborne) 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.
(Juan Vera and Malcolm Brenner) 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 IL4 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, while our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research.