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Ebright, Richard

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Ebright

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Richard

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Ebright, Richard

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2013 - 20163

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Author's Publications: search.filters.isAuthorOfPublication.43c0eb14-dbdc-46fa-8f9d-5715b49c31e4

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Now showing 1 - 3 of 3
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    HER2 expression identifies dynamic functional states within circulating breast cancer cells
    (2016) Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K.; Licausi, Joseph A.; Desai, Rushil; O’Keefe, Ryan M.; Ebright, Richard; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela Lika; Iafrate, Anthony; Kapur, Ravi; Sgroi, Dennis; Ting, David; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel
    Circulating tumor cells (CTCs) in women with advanced estrogen receptor-positive/HER2-negative breast cancer acquire a HER2-positive subpopulation following multiple courses of therapy1,2. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here, we analyzed CTCs from 19 ER+/HER2− patients, 84% of whom had acquired CTCs expressing HER2. Cultured CTCs maintain discrete HER2+ and HER2− subpopulations: HER2+ CTCs are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways. HER2− CTCs show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2− CTCs interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. While HER2+ and HER2− CTCs have comparable tumor initiating potential, differential proliferation favors the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2− phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic CTC-derived tumor models. Together, these results point to distinct yet interconverting phenotypes within patient-derived CTCs, contributing to progression of breast cancer and acquisition of drug resistance.
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    An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules
    (Elsevier BV, 2013) Basu, Amrita; Bodycombe, Nicole E.; Cheah, Jaime H.; Price, Edmund V.; Liu, Ke; Schaefer, Giannina Ines; Ebright, Richard; Stewart, Michelle L.; Ito, Daisuke; Wang, Stephanie; Bracha, Abigail L.; Liefeld, Ted; Wawer, Mathias; Gilbert, Joshua C.; Wilson, Andrew J.; Stransky, Nicolas; Kryukov, Gregory V.; Dancik, Vlado; Barretina, Jordi; Garraway, Levi; Hon, C. Suk-Yee; Munoz, Benito; Bittker, Joshua A.; Stockwell, Brent R.; Khabele, Dineo; Stern, Andrew M.; Clemons, Paul A.; Shamji, Alykhan F.; Schreiber, Stuart
    The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.
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    Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma
    (2016) Powers, John T.; Tsanov, Kaloyan M; Pearson, Daniel; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theiβen, Jessica; Tu, Ho-Chou; Han, A Reum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan; Ross, Samantha J; Cesana, Marcella; Collins, James; Berthold, Frank; Daley, George
    Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.