Person: Pepin, David
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Pepin
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David
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Pepin, David
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Publication Publisher Correction: Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer(Nature Publishing Group UK, 2018) Qi, Ruogu; Wang, Yongheng; Bruno, Peter M.; Xiao, Haihua; Yu, Yingjie; Li, Ting; Lauffer, Sam; Wei, Wei; Chen, Qixian; Kang, Xiang; Song, Haiqin; Yang, Xi; Huang, Xing; Detappe, Alexandre; Matulonis, Ursula; Pepin, David; Hemann, Michael T.; Birrer, Michael J.; Ghoroghchian, P. PeterPublication PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation(Impact Journals LLC, 2014) Sabbatino, Francesco; Wang, YangYang; Wang, Xinhui; Flaherty, Keith; Yu, Ling; Pepin, David; Scognamiglio, Giosue'; Pepe, Stefano; Kirkwood, John M.; Cooper, Zachary A.; Frederick, Dennie T.; Wargo, Jennifer Ann; Ferrone, Soldano; Ferrone, CristinaControl of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.Publication CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis(Public Library of Science, 2016) Sosulski, Amanda; Horn, Heiko; Zhang, Lihua; Coletti, Caroline; Vathipadiekal, Vinod; Castro, Cesar; Birrer, Michael J.; Nagano, Osamu; Saya, Hideyuki; Lage, Kasper; Donahoe, Patricia; Pepin, DavidCD44 is a transmembrane hyaluronic acid receptor gene that encodes over 100 different tissue-specific protein isoforms. The most ubiquitous, CD44 standard, has been used as a cancer stem cell marker in ovarian and other cancers. Expression of the epithelial CD44 variant containing exons v8-10 (CD44v8-10) has been associated with more chemoresistant and metastatic tumors in gastrointestinal and breast cancers, but its role in ovarian cancer is unknown; we therefore investigated its use as a prognostic marker in this disease. The gene expression profiles of 254 tumor samples from The Cancer Genome Atlas RNAseqV2 were analyzed for the presence of CD44 isoforms. A trend for longer survival was observed in patients with high expression of CD44 isoforms that include exons v8-10. Immunohistochemical (IHC) analysis of tumors for presence of CD44v8-10 was performed on an independent cohort of 210 patients with high-grade serous ovarian cancer using a tumor tissue microarray. Patient stratification based on software analysis of staining revealed a statistically significant increase in survival in patients with the highest levels of transmembrane protein expression (top 10 or 20%) compared to those with the lowest expression (bottom 10 and 20%) (p = 0.0181, p = 0.0262 respectively). Expression of CD44v8-10 in primary ovarian cancer cell lines was correlated with a predominantly epithelial phenotype characterized by high expression of epithelial markers and low expression of mesenchymal markers by qPCR, Western blot, and IHC. Conversely, detection of proteolytically cleaved and soluble extracellular domain of CD44v8-10 in patient ascites samples was correlated with significantly worse prognosis (p<0.05). Therefore, presence of transmembrane CD44v8-10 on the surface of primary tumor cells may be a marker of a highly epithelial tumor with better prognosis while enzymatic cleavage of CD44v8-10, as detected by presence of the soluble extracellular domain in ascites fluid, may be indicative of a more metastatic disease and worse prognosis.Publication Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance(Proceedings of the National Academy of Sciences, 2012) Meirelles, K.; Benedict, Lance Mitchell; Dombkowski, D.; Pepin, David; Preffer, Frederic; Teixeira, J; Tanwar, Pradeep; Young, Robert; MacLaughlin, D. T.; Donahoe, Patricia; Wei, X.Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad−) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad− cells. Similarly, proliferation of the 3+Ecad− cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3−Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad− subpopulation through the induction of cyclin-dependent kinase inhibitors. 3+Ecad− cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics.Publication Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer(Nature Publishing Group UK, 2017) Qi, Ruogu; Wang, Yongheng; Bruno, Peter M.; Xiao, Haihua; Yingjie, Yu; Li, Ting; Lauffer, Sam; Wei, Wei; Chen, Qixian; Kang, Xiang; Song, Haiqin; Yang, Xi; Huang, Xing; Detappe, Alexandre; Matulonis, Ursula; Pepin, David; Hemann, Michael T.; Birrer, Michael J.; Ghoroghchian, P. PeterAdvanced-stage epithelial ovarian cancers are amongst the most difficult to treat tumors and have proven to be refractory to most cytotoxic, molecularly targeted, or immunotherapeutic approaches. Here, we report that nanoparticle-drug conjugates (NDCs) of monomethyl auristatin E (MMAE) significantly increase loading on a per-vehicle basis as compared to antibody-drug conjugates (ADCs). Their intraperitoneal administration enabled triggered release of the active MMAE toxin to inhibit tumor growth and to extend animal survival to >90 days in a cell-line xenograft model of disseminated ovarian cancer. In a patient-derived xenograft model of advanced-stage and platinum-resistant ovarian cancer, an MMAE-based NDC doubled the duration of tumor growth inhibition as compared to cisplatin. NDCs of highly potent toxins thus introduce a translatable platform that may be exploited to maximize the safety and efficacy of cytotoxic chemotherapies, combining the best features of ADCs with those of nanoparticle-based therapeutics.