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Levi A. Garraway

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https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#1
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#2
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28794284/genomic-profiling-of-er-breast-cancers-after-short-term-estrogen-suppression-reveals-alterations-associated-with-endocrine-resistance
#3
Jennifer M Giltnane, Katherine E Hutchinson, Thomas P Stricker, Luigi Formisano, Christian D Young, Monica V Estrada, Mellissa J Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G Kuba, Melinda E Sanders, Xinmeng J Mu, Eliezer M Van Allen, Nikhil Wagle, Ingrid A Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S Ross, Vincent A Miller, Phillip J Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M Balko, Carlos L Arteaga
Inhibition of proliferation in estrogen receptor-positive (ER(+)) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER(+)/human epidermal growth factor receptor 2-negative (HER2(-)) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28757884/the-fuzzy-world-of-precision-medicine-deliberations-of-a-precision-medicine-tumor-board
#4
Sarah A McGraw, Judy Garber, Pasi A Jänne, Neal Lindeman, Nelly Oliver, Lynette M Sholl, Eliezer M Van Allen, Nikhil Wagle, Levi A Garraway, Steven Joffe, Stacy W Gray
AIM: To understand how a cancer precision medicine tumor board (CPM-TB) made choices about return of results. MATERIALS & METHODS: Observed CPM-TB deliberations and completed in-depth interviews with committee members. RESULTS: Responding to complex evidence of ambiguous significance, deliberations of the CPM-TB were predicated on analytic validity and clinical utility. Members had concerns both about potential harms due to returning results based on weak evidence and about withholding potentially meaningful results...
January 2017: Personalized Medicine
https://www.readbyqxmd.com/read/28753430/defining-a-cancer-dependency-map
#5
Aviad Tsherniak, Francisca Vazquez, Phil G Montgomery, Barbara A Weir, Gregory Kryukov, Glenn S Cowley, Stanley Gill, William F Harrington, Sasha Pantel, John M Krill-Burger, Robin M Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Guozhi Jiang, Jessica Hsiao, William F J Gerath, Sara Howell, Erin Merkel, Mahmoud Ghandi, Levi A Garraway, David E Root, Todd R Golub, Jesse S Boehm, William C Hahn
Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features...
July 27, 2017: Cell
https://www.readbyqxmd.com/read/28666115/ifn%C3%AE-dependent-tissue-immune-homeostasis-is-co-opted-in-the-tumor-microenvironment
#6
Christopher J Nirschl, Mayte Suárez-Fariñas, Benjamin Izar, Sanjay Prakadan, Ruth Dannenfelser, Itay Tirosh, Yong Liu, Qian Zhu, K Sanjana P Devi, Shaina L Carroll, David Chau, Melika Rezaee, Tae-Gyun Kim, Ruiqi Huang, Judilyn Fuentes-Duculan, George X Song-Zhao, Nicholas Gulati, Michelle A Lowes, Sandra L King, Francisco J Quintana, Young-Suk Lee, James G Krueger, Kavita Y Sarin, Charles H Yoon, Levi Garraway, Aviv Regev, Alex K Shalek, Olga Troyanskaya, Niroshana Anandasabapathy
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28594900/systematic-genomic-and-translational-efficiency-studies-of-uveal-melanoma
#7
Chelsea Place Johnson, Ivana K Kim, Bita Esmaeli, Ali Amin-Mansour, Daniel J Treacy, Scott L Carter, Eran Hodis, Nikhil Wagle, Sara Seepo, Xiaoxing Yu, Anne Marie Lane, Evangelos S Gragoudas, Francisca Vazquez, Elizabeth Nickerson, Kristian Cibulskis, Aaron McKenna, Stacey B Gabriel, Gad Getz, Eliezer M Van Allen, Peter A C 't Hoen, Levi A Garraway, Scott E Woodman
To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX...
2017: PloS One
https://www.readbyqxmd.com/read/28515055/exome-sequencing-of-african-american-prostate-cancer-reveals-loss-of-function-erf-mutations
#8
Franklin W Huang, Juan Miguel Mosquera, Andrea Garofalo, Coyin Oh, Maria Baco, Ali Amin-Mansour, Bokang Rabasha, Samira Bahl, Stephanie A Mullane, Brian D Robinson, Saud Aldubayan, Francesca Khani, Beerinder Karir, Eejung Kim, Jeremy Chimene-Weiss, Matan Hofree, Alessandro Romanel, Joseph R Osborne, Jong Wook Kim, Gissou Azabdaftari, Anna Woloszynska-Read, Karen Sfanos, Angelo M De Marzo, Francesca Demichelis, Stacey Gabriel, Eliezer M Van Allen, Jill Mesirov, Pablo Tamayo, Mark A Rubin, Isaac J Powell, Levi A Garraway
African-American men have the highest incidence and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n=102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3-5% of lethal castration-resistant prostate cancers...
May 17, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28464947/erratum-to-unraveling-the-clonal-hierarchy-of-somatic-genomic-aberrations
#9
Davide Prandi, Sylvan C Baca, Alessandro Romanel, Christopher E Barbieri, Juan-Miguel Mosquera, Jacqueline Fontugne, Himisha Beltran, Andrea Sboner, Levi A Garraway, Mark A Rubin, Francesca Demichelis
No abstract text is available yet for this article.
May 2, 2017: Genome Biology
https://www.readbyqxmd.com/read/28420421/analysis-of-100-000-human-cancer-genomes-reveals-the-landscape-of-tumor-mutational-burden
#10
Zachary R Chalmers, Caitlin F Connelly, David Fabrizio, Laurie Gay, Siraj M Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S Lieber, Steven Roels, Jared White, Geoffrey A Otto, Jeffrey S Ross, Levi Garraway, Vincent A Miller, Phillip J Stephens, Garrett M Frampton
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome...
April 19, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28125075/assigning-clinical-meaning-to-somatic-and-germ-line-whole-exome-sequencing-data-in-a-prospective-cancer-precision-medicine-study
#11
Arezou A Ghazani, Nelly M Oliver, Joseph P St Pierre, Andrea Garofalo, Irene R Rainville, Elaine Hiller, Daniel J Treacy, Vanesa Rojas-Rudilla, Sam Wood, Elizabeth Bair, Michael Parello, Franklin Huang, Marios Giannakis, Frederick H Wilson, Elizabeth H Stover, Steven M Corsello, Tom Nguyen, Huma Q Rana, Alanna J Church, Carol Lowenstein, Carrie Cibulskis, Ali Amin-Mansour, Jennifer Heng, Lauren Brais, Abigail Santos, Patrick Bauer, Amanda Waldron, Peter Lo, Megan Gorman, Christine A Lydon, Marisa Welch, Philip McNamara, Stacey Gabriel, Lynette M Sholl, Neal I Lindeman, Judy E Garber, Steven Joffe, Eliezer M Van Allen, Stacy W Gray, Pasi A Ja Nne, Levi A Garraway, Nikhil Wagle
PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples...
July 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#12
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28062669/people
#13
(no author information available yet)
Charles S. Fuchs, MD, MPH; Levi A. Garraway, MD, PhD; and Laurie H. Glimcher, MD, are featured.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28028240/suppression-of-19s-proteasome-subunits-marks-emergence-of-an-altered-cell-state-in-diverse-cancers
#14
Peter Tsvetkov, Ethan Sokol, Dexter Jin, Zarina Brune, Prathapan Thiru, Mahmoud Ghandi, Levi A Garraway, Piyush B Gupta, Sandro Santagata, Luke Whitesell, Susan Lindquist
The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27906693/believe-the-miracles-of-biomedical-science-and-human-suffering
#15
Levi A Garraway
No abstract text is available yet for this article.
December 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27882345/institutional-implementation-of-clinical-tumor-profiling-on-an-unselected-cancer-population
#16
Lynette M Sholl, Khanh Do, Priyanka Shivdasani, Ethan Cerami, Adrian M Dubuc, Frank C Kuo, Elizabeth P Garcia, Yonghui Jia, Phani Davineni, Ryan P Abo, Trevor J Pugh, Paul van Hummelen, Aaron R Thorner, Matthew Ducar, Alice H Berger, Mizuki Nishino, Katherine A Janeway, Alanna Church, Marian Harris, Lauren L Ritterhouse, Joshua D Campbell, Vanesa Rojas-Rudilla, Azra H Ligon, Shakti Ramkissoon, James M Cleary, Ursula Matulonis, Geoffrey R Oxnard, Richard Chao, Vanessa Tassell, James Christensen, William C Hahn, Philip W Kantoff, David J Kwiatkowski, Bruce E Johnson, Matthew Meyerson, Levi A Garraway, Geoffrey I Shapiro, Barrett J Rollins, Neal I Lindeman, Laura E MacConaill
BACKGROUND. Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27811909/fusobacterium-nucleatum-in-colorectal-carcinoma-tissue-according-to-tumor-location
#17
Kosuke Mima, Yin Cao, Andrew T Chan, Zhi Rong Qian, Jonathan A Nowak, Yohei Masugi, Yan Shi, Mingyang Song, Annacarolina da Silva, Mancang Gu, Wanwan Li, Tsuyoshi Hamada, Keisuke Kosumi, Akiko Hanyuda, Li Liu, Aleksandar D Kostic, Marios Giannakis, Susan Bullman, Caitlin A Brennan, Danny A Milner, Hideo Baba, Levi A Garraway, Jeffrey A Meyerhardt, Wendy S Garrett, Curtis Huttenhower, Matthew Meyerson, Edward L Giovannucci, Charles S Fuchs, Reiko Nishihara, Shuji Ogino
OBJECTIVES: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. METHODS: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study...
November 3, 2016: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/27797976/genomic-heterogeneity-and-exceptional-response-to-dual-pathway-inhibition-in-anaplastic-thyroid-cancer
#18
William J Gibson, Daniel T Ruan, Vera A Paulson, Justine A Barletta, Glenn J Hanna, Stefan Kraft, Antonio Calles, Matthew A Nehs, Francis D Moore, Amaro Taylor-Weiner, Jeremiah A Wala, Travis I Zack, Thomas C Lee, Fiona M Fennessy, Erik K Alexander, Tom Thomas, Pasi A Janne, Levi A Garraway, Scott L Carter, Rameen Beroukhim, Jochen H Lorch, Eliezer M Van Allen
Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed...
May 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27760322/genomic-correlates-of-immune-cell-infiltrates-in-colorectal-carcinoma
#19
Marios Giannakis, Xinmeng Jasmine Mu, Sachet A Shukla, Zhi Rong Qian, Ofir Cohen, Reiko Nishihara, Samira Bahl, Yin Cao, Ali Amin-Mansour, Mai Yamauchi, Yasutaka Sukawa, Chip Stewart, Mara Rosenberg, Kosuke Mima, Kentaro Inamura, Katsuhiko Nosho, Jonathan A Nowak, Michael S Lawrence, Edward L Giovannucci, Andrew T Chan, Kimmie Ng, Jeffrey A Meyerhardt, Eliezer M Van Allen, Gad Getz, Stacey B Gabriel, Eric S Lander, Catherine J Wu, Charles S Fuchs, Shuji Ogino, Levi A Garraway
No abstract text is available yet for this article.
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27760319/phenotypic-characterization-of-a-comprehensive-set-of-mapk1-erk2-missense-mutants
#20
Lisa Brenan, Aleksandr Andreev, Ofir Cohen, Sasha Pantel, Atanas Kamburov, Davide Cacchiarelli, Nicole S Persky, Cong Zhu, Mukta Bagul, Eva M Goetz, Alex B Burgin, Levi A Garraway, Gad Getz, Tarjei S Mikkelsen, Federica Piccioni, David E Root, Cory M Johannessen
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants...
October 18, 2016: Cell Reports
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