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Dive into the research topics where Fred Harbinski is active.

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Featured researches published by Fred Harbinski.


Nature Cell Biology | 2014

Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo

William E. Dowdle; Beat Nyfeler; Jane Nagel; Robert Elling; Shanming Liu; Ellen Triantafellow; Suchithra Menon; Zuncai Wang; Ayako Honda; Gwynn Pardee; John Cantwell; Catherine Luu; Ivan Cornella-Taracido; Edmund Harrington; Peter Fekkes; Hong Lei; Qing Fang; Mary Ellen Digan; Debra Burdick; Andrew F. Powers; Stephen B. Helliwell; Simon D’Aquin; Julie Bastien; Henry Wang; Dmitri Wiederschain; Jenny Kuerth; Philip Bergman; David Schwalb; Jason R. Thomas; Savuth Ugwonali

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4−/− mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo.


Cancer Discovery | 2012

Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth

Fred Harbinski; Vanessa J. Craig; Sneha Sanghavi; Douglas Jeffery; Lijuan Liu; Kelly Ann Sheppard; Sabrina Wagner; Christelle Stamm; Andreas Buness; Christian Chatenay-Rivauday; Yao Yao; Feng He; Chris Lu; Vito Guagnano; Thomas Metz; Peter Finan; Francesco Hofmann; William R. Sellers; Jeffrey A. Porter; Vic E. Myer; Diana Graus-Porta; Christopher J. Wilson; Alan J. Buckler; Ralph Tiedt

The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.


Cancer Research | 2016

High order drug combinations are required to effectively kill colorectal cancer cells

Thomas Horn; Stephane Ferretti; Nicolas Ebel; Angela Tam; Samuel Ho; Fred Harbinski; Ali Farsidjani; Matthew Zubrowski; William R. Sellers; Robert Schlegel; Dale Porter; Erick Morris; Jens Wuerthner; Sébastien Jeay; Joel Greshock; Ensar Halilovic; Levi A. Garraway; Giordano Caponigro; Joseph Lehar

Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. Cancer Res; 76(23); 6950-63. ©2016 AACR.


Journal of Biological Chemistry | 2014

Identification of mixed lineage leukemia 1(MLL1) protein as a coactivator of heat shock factor 1(HSF1) protein in response to heat shock protein 90 (HSP90) inhibition.

Yaoyu Chen; Jinyun Chen; Jianjun Yu; Guizhi Yang; Emilia Temple; Fred Harbinski; Hui Gao; Christopher Wilson; Raymond Pagliarini; Wenlai Zhou

Background: The efficacy of HSP90 inhibitors may be limited by HSF1-mediated feedback mechanisms. Results: MLL1 regulates HSF1-target genes upon HSP90 inhibition, and MLL1 depletion shows a striking combination effect in human cancer. Conclusion: MLL1 functions as a coactivator of HSF1 upon HSP90 inhibition. Significance: This is the first report of MLL1 as a coactivator of HSF1 upon HSP90 inhibition. Heat shock protein 90 (HSP90) inhibition inhibits cancer cell proliferation through depleting client oncoproteins and shutting down multiple oncogenic pathways. Therefore, it is an attractive strategy for targeting human cancers. Several HSP90 inhibitors, including AUY922 and STA9090, show promising effects in clinical trials. However, the efficacy of HSP90 inhibitors may be limited by heat shock factor 1 (HSF1)-mediated feedback mechanisms. Here, we identify, through an siRNA screen, that the histone H3 lysine 4 methyltransferase MLL1 functions as a coactivator of HSF1 in response to HSP90 inhibition. MLL1 is recruited to the promoters of HSF1 target genes and regulates their expression in response to HSP90 inhibition. In addition, a striking combination effect is observed when MLL1 depletion is combined with HSP90 inhibition in various human cancer cell lines and tumor models. Thus, targeting MLL1 may block a HSF1-mediated feedback mechanism induced by HSP90 inhibition and provide a new avenue to enhance HSP90 inhibitor activity in human cancers.


Journal of Clinical Investigation | 2017

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Alexia T. Kedves; Scott Gleim; Xiaoyou Liang; Dennis M. Bonal; Frederic Sigoillot; Fred Harbinski; Sneha Sanghavi; Christina Benander; Elizabeth L. George; Prafulla C. Gokhale; Quang-Dé Nguyen; Paul Kirschmeier; Robert J. Distel; Jeremy L. Jenkins; Michael Goldberg; William C. Forrester

Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC-targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing.


Journal of Biomolecular Screening | 2017

Jenkins-CI, an Open-Source Continuous Integration System, as a Scientific Data and Image-Processing Platform

Ioannis K. Moutsatsos; Imtiaz Hossain; Claudia Agarinis; Fred Harbinski; Yann Abraham; Luc Dobler; Xian Zhang; C. Wilson; Jeremy L. Jenkins; Nicholas Holway; John A. Tallarico; Christian N. Parker

High-throughput screening generates large volumes of heterogeneous data that require a diverse set of computational tools for management, processing, and analysis. Building integrated, scalable, and robust computational workflows for such applications is challenging but highly valuable. Scientific data integration and pipelining facilitate standardized data processing, collaboration, and reuse of best practices. We describe how Jenkins-CI, an “off-the-shelf,” open-source, continuous integration system, is used to build pipelines for processing images and associated data from high-content screening (HCS). Jenkins-CI provides numerous plugins for standard compute tasks, and its design allows the quick integration of external scientific applications. Using Jenkins-CI, we integrated CellProfiler, an open-source image-processing platform, with various HCS utilities and a high-performance Linux cluster. The platform is web-accessible, facilitates access and sharing of high-performance compute resources, and automates previously cumbersome data and image-processing tasks. Imaging pipelines developed using the desktop CellProfiler client can be managed and shared through a centralized Jenkins-CI repository. Pipelines and managed data are annotated to facilitate collaboration and reuse. Limitations with Jenkins-CI (primarily around the user interface) were addressed through the selection of helper plugins from the Jenkins-CI community.


Chemistry & Biology | 2015

Metabolic Enzyme Sulfotransferase 1A1 Is the Trigger for N-Benzyl Indole Carbinol Tumor Growth Suppression

Deborah M. Rothman; Xiaolin Gao; Elizabeth George; Timothy Rasmusson; Diksha Bhatia; Irina Alimov; Louis Wang; Amin Kamel; Panagiotis Hatsis; Yan Feng; Antonin Tutter; Gregory A. Michaud; Earl Robert Mcdonald Iii; Kavitha Venkatesan; David Farley; Mary Ellen Digan; Yucheng Ni; Fred Harbinski; Mithat Gunduz; Christopher J. Wilson; Alan J. Buckler; Mark Labow; John A. Tallarico; Vic E. Myer; Jeffrey A. Porter; Shaowen Wang

In an attempt to identify novel therapeutics and mechanisms to differentially kill tumor cells using phenotypic screening, we identified N-benzyl indole carbinols (N-BICs), synthetic analogs of the natural product indole-3-carbinol (I3C). To understand the mode of action for the molecules we employed Cancer Cell Line Encyclopedia viability profiling and correlative informatics analysis to identify and ultimately confirm the phase II metabolic enzyme sulfotransferase 1A1 (SULT1A1) as the essential factor for compound selectivity. Further studies demonstrate that SULT1A1 activates the N-BICs by rendering the compounds strong electrophiles which can alkylate cellular proteins and thereby induce cell death. This study demonstrates that the selectivity profile for N-BICs is through conversion by SULT1A1 from an inactive prodrug to an active species that induces cell death and tumor suppression.


Cancer Research | 2016

Abstract 1311: High order drug combinations are required to effectively kill colorectal cancer cells

Thomas Horn; Stephane Ferretti; Nicolas Ebel; Angela Tam; Samuel Ho; Fred Harbinski; Ali Farsidjani; Matt Zubrowski; William R. Sellers; Robert Schlegel; Dale Porter; Erick Morris; Jens Wuerthner; Sébastien Jeay; Joel Greshock; Ensar Halilovic; Levi A. Garraway; Giordano Caponigro; Joseph Lehár

Tumors are complex biological systems that often retain proliferative capacity even when challenged with drug treatment. Given this resiliency, drug combinations may provide greater therapeutic benefit, however, which molecules to combine and how many to include in combinations for effective responses is not clear yet. Using image-based proliferation and apoptosis assays in colorectal cancer cell lines we systematically investigated combinations that ranged in number from two to six drugs and targeted critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In many cases, where cell lines were resistant to two- and three-way drug combinations, increased expression of anti-apoptotic proteins was observed and induction of cytotoxic responses required up to fourth-order combinations. Our results demonstrate that high-order drug combinations might be needed to kill cancers and show how systematic drug combination screening together with a molecular understanding of drug responses can guide their identification. Citation Format: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matt Zubrowski, William R. Sellers, Robert Schlegel, Dale Porter, Erick Morris, Jens Wuerthner, Sebastien Jeay, Joel Greshock, Ensar Halilovic, Levi A. Garraway, Giordano Caponigro, Joseph Lehar. High order drug combinations are required to effectively kill colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1311.


Molecular Cancer Therapeutics | 2015

Abstract LB-B04: Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells

Thomas Horn; Stephane Ferretti; Nicolas Ebel; Angela Tam; Samuel Ho; Fred Harbinski; Ali Farsidjani; Matthew Zubrowski; Ensar Halilovic; Erick Morris; William R. Sellers; Robert Schlegel; Jens Wuerthner; Levi A. Garraway; Sébastien Jeay; Joel Greshock; Giordano Caponigro; Joseph Lehár

Tumors are complex and robust biological systems that harbor the potential to proliferate against various drug treatments. Drug combinations provide a promising therapeutic strategy, but it is not clear which and how many drugs are required to overcome cancers. Using image-based proliferation and apoptosis assays in colorectal cancer cells we systematically investigated complex treatments composed of two to six drugs targeting critical oncogenic pathways. Drug pairs targeting growth signaling resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded cytostatic responses and failed to induce apoptosis. Enhanced, and sometimes genotype-specific cytotoxicity was seen after targeting additional mechanisms including apoptosis or cell cycle. Cells that resisted all tested drug pairs and drug triples were protected by a mechanism that prevented apoptosis. Targeted inhibition of this mechanism using combinations of up to four compounds induced cytotoxic responses in cells in vitro and in vivo. Our results demonstrate that complex combinations of targeted drugs might be required to induce killing in cancers and show how the cells9 genetic alterations and a molecular understanding of drug responses can guide their identification. The identification of resistance mechanisms that are pre-existing in subpopulations of tumor cells also opens the exciting avenue of sequenced treatments, with each drug or drug combination targeting and eradicating a specific cell population. Citation Format: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matthew Zubrowski, Ensar Halilovic, Erick Morris, William R. Sellers, Robert Schlegel, Jens Wuerthner, Levi A. Garraway, Sebastien Jeay, Joel Greshock, Giordano Caponigro, Joseph Lehar. Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B04.


Nature Chemical Biology | 2014

Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39

Frederic Bassilana; Adam Carlson; Jennifer DaSilva; Bianka Grosshans; Solange Vidal; Valérie Beck; Barbara Wilmeringwetter; Luis Llamas; Todd B Showalter; Pascal Rigollier; Aaron Bourret; Arun Ramamurthy; Xu Wu; Fred Harbinski; Samantha Plonsky; Lac Lee; Heinz Ruffner; Paola Grandi; Markus Schirle; Jeremy L. Jenkins; Andreas W. Sailer; Tewis Bouwmeester; Jeffrey A. Porter; Vic E. Myer; Peter Finan; John A. Tallarico; Joseph F. Kelleher; Klaus Seuwen; Rishi K. Jain; Sarah J Luchansky

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