Providence Regional Cancer Partnership

Simple SummaryHuman breast tissue extracellular matrix (ECM) is a microenvironment essential for the survival and biological activities of mammary epithelial cells. The ECM structural features of human breast tissues remain poorly defined. In this study, we identified the structural and mechanical properties of human normal breast and invasive ductal carcinoma tissue ECM using histological methods and atomic force microscopy. Additionally, a protein hydrogel was generated using human breast tissue ECM and defined for its microstructural features using immunofluorescence imaging and machine learning. Furthermore, we examined the three-dimensional growth of normal mammary epithelial cells or breast cancer cells cultured on the ECM protein hydrogel, where the cells exhibited biological phenotypes like those seen in native breast tissues. Our data provide novel insights into cancer cell biology, tissue microenvironment mimicry and engineering, and native tissue ECM-based biomedical and pharmaceutical applications.Tissue extracellular matrix (ECM) is a structurally and compositionally unique microenvironment within which native cells can perform their natural biological activities. Cells grown on artificial substrata differ biologically and phenotypically from those grown within their native tissue microenvironment. Studies examining human tissue ECM structures and the biology of human tissue cells in their corresponding tissue ECM are lacking. Such investigations will improve our understanding about human pathophysiological conditions for better clinical care. We report here human normal breast tissue and invasive ductal carcinoma tissue ECM structural features. For the first time, a hydrogel was successfully fabricated using whole protein extracts of human normal breast ECM. Using immunofluorescence staining of type I collagen (Col I) and machine learning of its fibrous patterns in the polymerized human breast ECM hydrogel, we have defined the microstructural characteristics of the hydrogel and compared the microstructures with those of other native ECM hydrogels. Importantly, the ECM hydrogel supported 3D growth and cell-ECM interaction of both normal and cancerous mammary epithelial cells. This work represents further advancement toward full reconstitution of the human breast tissue microenvironment, an accomplishment that will accelerate the use of human pathophysiological tissue-derived matrices for individualized biomedical research and therapeutic development.

Abstract BACKGROUND: We established the olaparib tablet maximum tolerated dose (MTD) at 150 mg bid, dose limiting toxicities (DLT's) and response to therapy or carboplatin, paclitaxel and olaparib tablet given simultaneously, reported at ASCO 2014. This abstract will include data from both the phase 1b and the phase 2 expansion. METHODS: A total of 54 subjects were evaluated in this trial, 14 in phase 1b and 40 in phase 2. Eligibility required measurable disease, adequate organ function and ECOG performance status of ~ 2. Subjects had to have failed first line platinum containing chemotherapy. BRCA testing was conducted as available. Subjects received the metronomic therapy of paclitaxel 60mg/m2 IV and carboplatin AUC 2 IV weekly, 3 weeks out of 4, and olaparib tablets at 150 mg bid administered orally for 3 consecutive days (D1-D3) every week for each cycle. Subjects were assessed for toxicity and response according to the protocol. Subjects that reached a confirmed complete remission were transitioned to olaparib tablets only, 300 mg bid until disease progression. RESULTS: Median age was 58 and median number of prior regimens was 4. There have been no deaths due to the study regimen. One patient had grade 4 neutropenia and an allergic reaction to carboplatin. The common grade 3/4 toxicities were caused by the chemotherapy (neutropenia. anemia and thrombocytopenia). Two patients had mild GI toxicities. One patient had a skin rash. There was no evidence of cardiac, hepatic, or pulmonary toxicities in any of these patients. 25% of subjects had a complete remission (CR), 31% had PR, 23% had SD and 21% had PD. Of the 13 CRs, 4 were BRCA negative. PFS median for BRCA positive subjects is 12.6 months vs 4.8 months for BRCA negative subjects. OS median for BRCA positive subjects is 24 months vs 16 months for BRCA negative subjects. All of the CR's are alive. CONCLUSION: Olaparib tablet can be safely administered simultaneously with a weekly regimen of carboplatin and paclitaxel in heavily pretreated ovarian cancer patients. Olaparib appears to be highly effective in BRCA positive subjects. This is the first successful combination of olaparib tablets with carboplatin and paclitaxel that has been well tolerated. Citation Format: Rivkin SE, Moon J, Iriarte D, Sloan H, Wiseman C, Klee M, Ference K, Drescher C, Veljovich D, Bondurant A, Peters W, Jiang P, Goodman G, Park M, Fer M, Shah C, Johnston E, Kaplan H, Wahl T, Ellis E. PHASE IB/II WITH EXPANSION OF PATIENTS AT THE MTD STUDY OF OLAPARIB PLUS WEEKLY (METRONOMIC) CARBOPLATIN AND PACLITAXEL IN RELAPSED OVARIAN CANCER PATIENTS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP30.