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Dharia, Neekesh

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Dharia

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Neekesh

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Dharia, Neekesh

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2017 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.dfba3f9c-9cdd-4baf-98d2-a20af4c64f51

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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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    Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells
    (2017) Meyers, Robin M.; Bryan, Jordan G.; McFarland, James M.; Weir, Barbara A.; Sizemore, Ann E.; Xu, Han; Dharia, Neekesh; Montgomery, Phillip G.; Cowley, Glenn S.; Pantel, Sasha; Goodale, Amy; Lee, Yenarae; Ali, Levi D.; Jiang, Guozhi; Lubonja, Rakela; Harrington, William F.; Strickland, Matthew; Wu, Ting; Hawes, Derek; Zhivich, Victor A.; Wyatt, Meghan R.; Kalani, Zohra; Chang, Jaime J.; Okamoto, Michael; Stegmaier, Kimberly; Golub, Todd; Boehm, Jesse S.; Vazquez, Francisca; Root, David E.; Hahn, William; Tsherniak, Aviad
    The CRISPR-Cas9 system has revolutionized gene editing both on single genes and in multiplexed loss-of-function screens, enabling precise genome-scale identification of genes essential to proliferation and survival of cancer cells1,2. However, previous studies reported that a gene-independent anti-proliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, leading to false positive results in copy number amplified regions3,4. We developed CERES, a computational method to estimate gene dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy-number-specific effect. As part of our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this dataset. We found that CERES reduced false positive results and estimated sgRNA activity for both this dataset and previously published screens performed with different sgRNA libraries. Here, we demonstrate the utility of this collection of screens, upon CERES correction, in revealing cancer-type-specific vulnerabilities.