3d-models for high-throughput screening drug discovery and development

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The invention provides high throughput screening methodologies for identifying agents that can modulate Epithelial-Mesenchymal Transition (EMT) and/or Mesenchymal-Epithelial Transition (MET) phenotypes of a cell, uses of such agents and methods of identifying a patient that is likely to respond or unlikely to respond to treatment with such agents.

This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 61/285,539 filed Dec. 10, 2009, which is incorporated herein by reference.

TECHNICAL FIELD：The invention relates to drug discovery and development and particularly 3D models that may be used in high throughput screening techniques.

BACKGROUND OF INVENTION：In 1968 Elizabeth D. Hay first described the concept that epithelial cells undergo a phenotypic change to become motile or mesenchymal. This reversible transformation now described as Epithelial-Mesenchymal Transition (EMT) has been shown to be an important mechanism in human biological processes including: embryonic development, wound healing, and cancer progression and metastasis. A recent review series on EMT, prompted by the EMT research community, has further categorized EMT into three types including: embryonic development and organ formation (type 1), wound healing and fibrosis (type 2), and cancer progression and metastasis (type 3). As a result, type 3 EMT is emerging as a valid target for drug development in the treatment of cancer and fibrosis.

Currently, there remain gaps in our understanding of the signaling events that govern EMT, and the reversion, Mesenchymal-Epithelial Transition (MET). For example, in 1987 Nagafuchi et al. showed that exogenous expression of wild type E-cadherin into L-fibroblasts (devoid of E-cadherin) showed a morphological change resulting in the formation of tight juctions. Since this report, it has been well documented that when E-cadherin is exogenously expressed in mesenchymal cells, there is a phenotypic reversion resembling an epithelial phenotype. More recently Wang et al. demonstrated that inhibiting signaling pathways such as Ras-MAPKinase, or PI3Kinase led to moderate inhibition of in vitro cell invasion with no morpholocial changes indicative of a phenotypic reversion. However, this study did not measure the changes in expression of specific EMT markers.

Around the world approximately 1 million women are diagnosed with breast cancer each year. In the United States, the probability of developing invasive breast cancer in women is 1 in 8 from birth to death and there are about 180,000 (about 72%) out of 250,000 new cases of invasive breast cancer each year. The 5-year survival rate for women diagnosed with in situ or localized breast cancer is 98%, which decreases significantly for women diagnosed with invasive metastatic breast cancer to only 27%. Therefore, metastatic dissemination remains to be the primary cause of mortality in breast cancer patients. In particular, 15-20% of breast cancers display basal-like (EGFR, vimentin positive) and or triple negative (TN) (HR-negative and HER2-negative) phenotypes, which are associated with aggressive metastatic breast cancer, resistance to chemotherapy and an overall poor prognosis.

The pathogenesis of basal-like and TN breast cancers is still poorly understood and it remains unclear as to what mechanisms drive these tumor cells to proliferate and metastasize. As a result, there are no specific targeted therapeutic systemic regimens for the treatment of these types of cancer, which ultimately contributes to the overall poor prognosis. However, growing evidence indicates that these types of cancer undergo EMT resulting in metastasis.