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Hahn, William

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Hahn

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William

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Hahn, William
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    Biologically Informed Deep Neural Network for Prostate Cancer Discovery
    (Springer Science and Business Media LLC, 2021-09-22) Elmarakeby, Haitham A.; Hwang, Justin; Arafeh, Rand; Crowdis, Jett; Gang, Sydney; Liu, David; AlDubayan, Saud H.; Salari, Keyan; Kregel, Steven; Richter, Camden; Arnoff, Taylor E.; Park, Jihye; Hahn, William; Van Allen, Eliezer
    Determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge [1,2]. Recent advances in machine learning interpretability as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics [3–5]. Here, we developed a biologically informed deep learning model (P-NET) to stratify prostate cancer patients by treatment resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modeling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, that were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
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    Small-Molecule Targeting of Brachyury Transcription Factor Addiction in Chordoma
    (Springer Science and Business Media LLC, 2019-01-21) Sharifnia, Tanaz; Wawer, Mathias J.; Chen, Ting; Huang, Qing-Yuan; Weir, Barbara A.; Sizemore, Ann; Lawlor, Matthew A.; Goodale, Amy; Cowley, Glenn S.; Vazquez, Francisca; Ott, Christopher; Francis, Joshua M.; Sassi, Slim; Cogswell, Patricia; Sheppard, Hadley E.; Zhang, Tinghu; Gray, Nathanael; Clarke, Paul A.; Blagg, Julian; Workman, Paul; Sommer, Josh; Hornicek, Francis; Root, David E.; Hahn, William; Bradner, James E.; Wong, Kwok-Kin; Clemons, Paul A.; Lin, Charles Y.; Kotz, Joanne D.; Schreiber, Stuart
    Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors. In chordoma, we find that T is associated with a 1.5-Mb region containing ‘super-enhancers’ and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
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    Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
    (eLife Sciences Publications, Ltd, 2017) Paolella, Brenton R.; Gibson, William; Urbanski, Laura M; Alberta, John; Zack, Travis Ian; Bandopadhayay, Pratiti; Nichols, Caitlin; Agarwalla, Pankaj Kumar; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara Ann; Root, David E; Cowley, Glenn S; Buhrlage, Sara; Stiles, Charles; Ebert, Benjamin; Hahn, William; Reed, Robin; Beroukhim, Rameen
    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. DOI: http://dx.doi.org/10.7554/eLife.23268.001
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    NetSig: network-based discovery from cancer genomes
    (2018) Horn, Heiko; Lawrence, Michael; Chouinard, Candace R.; Shrestha, Yashaswi; Hu, Jessica Xin; Worstell, Elizabeth; Shea, Emily; Ilic, Nina; Kim, Eejung; Kamburov, Atanas; Kashani, Alireza; Hahn, William; Campbell, Joshua D.; Boehm, Jesse S.; Getz, Gad; Lage, Kasper
    Approaches that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes, but are challenging to validate at scale and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks and data from 4,742 tumor exomes and used it to accurately classify known driver genes in 60% of tested tumor types and to predict 62 new candidates. We designed a quantitative experimental framework to compare the in vivo tumorigenic potential of NetSig candidates, known oncogenes and random genes in mice showing that NetSig candidates induce tumors at rates comparable to known oncogenes and 10-fold higher than random genes. By reanalyzing nine tumor-inducing NetSig candidates in 242 patients with oncogene-negative lung adenocarcinomas, we find that two (AKT2 and TFDP2) are significantly amplified. Overall, we illustrate a scalable integrated computational and experimental workflow to expand discovery from cancer genomes.
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    Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
    (Nature Publishing Group UK, 2018) Ng, Samuel Y.; Yoshida, Noriaki; Christie, Amanda L.; Ghandi, Mahmoud; Dharia, Neekesh; Dempster, Joshua; Murakami, Mark; Shigemori, Kay; Morrow, Sara N.; Van Scoyk, Alexandria; Cordero, Nicolas A.; Stevenson, Kristen E.; Puligandla, Maneka; Haas, Brian; Lo, Christopher; Meyers, Robin; Gao, Galen; Cherniack, Andrew; Louissaint, Abner; Nardi, Valentina; Thorner, Aaron R.; Long, Henry; Qiu, Xintao; Morgan, Elizabeth; Dorfman, David; Fiore, Danilo; Jang, Julie; Epstein, Alan L.; Dogan, Ahmet; Zhang, Yanming; Horwitz, Steven M.; Jacobsen, Eric; Santiago, Solimar; Ren, Jian-Guo; Guerlavais, Vincent; Annis, D. Allen; Aivado, Manuel; Saleh, Mansoor N.; Mehta, Amitkumar; Tsherniak, Aviad; Root, David; Vazquez, Francisca; Hahn, William; Inghirami, Giorgio; Aster, Jon; Weinstock, David; Koch, Raphael
    T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.
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    Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations
    (2013) Brastianos, Priscilla; Horowitz, Peleg; Santagata, Sandro; Jones, Robert T.; McKenna, Aaron; Getz, Gad; Ligon, Keith; Palescandolo, Emanuele; Van Hummelen, Paul; Ducar, Matthew D.; Raza, Alina; Sunkavalli, Ashwini; MacConaill, Laura E.; Stemmer-Rachamimov, Anat; Louis, David; Hahn, William; Dunn, Ian; Beroukhim, Rameen
    Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
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    Colorectal Cancers from Distinct Ancestral Populations Show Variations in BRAF Mutation Frequency
    (Public Library of Science, 2013) Hanna, Megan C.; Go, Christina; Roden, Christine; Jones, Robert T.; Pochanard, Panisa; Javed, Ahmed Yasir; Javed, Awais; Mondal, Chandrani; Palescandolo, Emanuele; Van Hummelen, Paul; Hatton, Charles; Bass, Adam; Chun, Sung Min; Na, Deuk Chae; Kim, Tae-Im; Jang, Se Jin; Osarogiagbon, Raymond U.; Hahn, William; Meyerson, Matthew; Garraway, Levi; MacConaill, Laura
    It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer.
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    The Bromodomain Protein Brd4 Insulates Chromatin from DNA Damage Signaling
    (2013) Floyd, Scott R.; Pacold, Michael E.; Huang, Qiuying; Clarke, Scott M.; Lam, Fred C.; Cannell, Ian G.; Bryson, Bryan D.; Rameseder, Jonathan; Lee, Michael J.; Blake, Emily J.; Fydrych, Anna; Ho, Richard; Greenberger, Benjamin A.; Chen, Grace C.; Maffa, Amanda; Del Rosario, Amanda M.; Root, David E.; Carpenter, Anne E.; Hahn, William; Sabatini, David M.; Chen, Clark C.; White, Forest M.; Bradner, James E; Yaffe, Michael
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    Integrated genetic and pharmacologic interrogation of rare cancers
    (Nature Publishing Group, 2016) Hong, Andrew; Tseng, Yuen-Yi; Cowley, Glenn S.; Jonas, Oliver; Cheah, Jaime H.; Kynnap, Bryan D.; Doshi, Mihir B.; Oh, Coyin; Meyer, Stephanie C.; Church, Alanna J.; Gill, Shubhroz; Bielski, Craig M.; Keskula, Paula; Imamovic, Alma; Howell, Sara; Kryukov, Gregory V.; Clemons, Paul A.; Tsherniak, Aviad; Vazquez, Francisca; Crompton, Brian D.; Shamji, Alykhan; Rodriguez-Galindo, Carlos; Janeway, Katherine A.; Roberts, Charles W. M.; Stegmaier, Kimberly; van Hummelen, Paul; Cima, Michael J.; Langer, Robert S.; Garraway, Levi; Schreiber, Stuart; Root, David E.; Hahn, William; Boehm, Jesse S.
    Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.
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    TRAF2 is an NF-κB activating oncogene in epithelial cancers
    (2014) Shen, Rhine R.; Zhou, Alicia Y.; Kim, Eejung; O’Connell, Joyce T.; Hagerstrand, Daniel; Beroukhim, Rameen; Hahn, William
    Aberrant NF-κB activation is frequently observed in human cancers. Genome characterization efforts have identified genetic alterations in multiple components of the NF-κB pathway, some of which have been shown to be essential for cancer initiation and tumor maintenance. Here using patient tumors and cancer cell lines, we identify the NF-κB regulator, TRAF2 as an oncogene that is recurrently amplified and rearranged in 15% of human epithelial cancers. Suppression of TRAF2 in cancer cells harboring TRAF2 copy number gain inhibits proliferation, NF-κB activation, anchorage-independent growth and tumorigenesis. Cancer cells that are dependent on TRAF2 also require NF-κB for survival. The phosphorylation of TRAF2 at serine 11 is essential for the survival of cancer cells harboring TRAF2 amplification. Together these observations identify TRAF2 as a frequently amplified oncogene.