Person:
Golub, Todd

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Golub

First Name

Todd

Name

Golub, Todd
Author's Publications: search.filters.isAuthorOfPublication.63230eb9-3d10-4761-b5c0-767718e87385

Search Results

Now showing 1 - 10 of 36
  • Thumbnail Image
    Publication
    Patient-derived xenografts undergo murine-specific tumor evolution
    (2017) Ben-David, Uri; Ha, Gavin; Tseng, Yuen-Yi; Greenwald, Noah; Oh, Coyin; Shih, Juliann; McFarland, James M.; Wong, Bang; Boehm, Jesse S.; Beroukhim, Rameen; Golub, Todd
    Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer.
  • Thumbnail Image
    Publication
    A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity
    (2017) Bachovchin, Daniel A.; Koblan, Luke W.; Wu, Wengen; Liu, Yuxin; Li, Youhua; Zhao, Peng; Woznica, Iwona; Shu, Ying; Lai, Jack H.; Poplawski, Sarah E.; Kiritsy, Christopher P.; Healey, Sarah E.; DiMare, Matthew; Sanford, David G.; Munford, Robert S.; Bachovchin, William W.; Golub, Todd
    The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely even in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acid- and nitrile-containing compounds provided dual potency/selectivity structure-activity relationships from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 (DPP4) inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling, and suggest such profiling can be incorporated into the earliest stages of drug discovery.
  • Thumbnail Image
    Publication
    Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity
    (2013) Dulak, Austin M.; Stojanov, Petar; Peng, Shouyong; Lawrence, Michael S.; Fox, Cameron; Stewart, Chip; Bandla, Santhoshi; Imamura, Yu; Schumacher, Steven E.; Shefler, Erica; McKenna, Aaron; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Saksena, Gordon; Voet, Douglas; Ramos, Alex H.; Auclair, Daniel; Thompson, Kristin; Sougnez, Carrie; Onofrio, Robert C.; Guiducci, Candace; Beroukhim, Rameen; Zhou, David; Lin, Lin; Lin, Jules; Reddy, Rishindra; Chang, Andrew; Luketich, James D.; Pennathur, Arjun; Ogino, Shuji; Golub, Todd; Gabriel, Stacey B.; Lander, Eric; Beer, David G.; Godfrey, Tony E.; Getz, Gad; Bass, Adam
    The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a five-year survival rate of 15%, identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole exome sequencing of 149 EAC tumors/normal pairs, 15 of which have also been subjected to whole genome sequencing. We identify a mutational signature defined by a high prevalence of A to C transversions at AA dinucleotides. Statistical analysis of exome data identified significantly mutated 26 genes. Of these genes, four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 reveal increased cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis.
  • Thumbnail Image
    Publication
    Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion
    (2012) Straussman, Ravid; Morikawa, Teppei; Shee, Kevin; Barzily-Rokni, Michal; Qian, Zhi Rong; Du, Jinyan; Davis, Ashli; Mongare, Margaret M.; Gould, Joshua; Frederick, Dennie T.; Cooper, Zachary A.; Chapman, Paul B.; Solit, David B.; Ribas, Antoni; Lo, Roger S.; Flaherty, Keith; Ogino, Shuji; Wargo, Jennifer Ann; Golub, Todd
    Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anti-cancer drugs. We found that stroma-mediated resistance is surprisingly common – particularly to targeted agents. We further characterized the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most of these patients exhibit some degree of innate resistance1-4. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed stromal HGF expression in patients with BRAF-mutant melanoma and a statistically significant correlation between stromal HGF expression and innate resistance to treatment. Dual inhibition of RAF and MET resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance.
  • Thumbnail Image
    Publication
    Mutational heterogeneity in cancer and the search for new cancer genes
    (2014) Lawrence, Michael S.; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Stewart, Chip; Mermel, Craig; Roberts, Steven A.; Kiezun, Adam; Hammerman, Peter S.; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortés, Maria L.; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I.; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine; Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo; Koren, Amnon; McCarroll, Steven; Mora, Jaume; Crompton, Brian; Onofrio, Robert; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Roberts, Charles W. M.; Biegel, Jaclyn A.; Stegmaier, Kimberly; Bass, Adam; Garraway, Levi; Meyerson, Matthew; Golub, Todd; Gordenin, Dmitry A.; Sunyaev, Shamil; Lander, Eric; Getz, Gad
    Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
  • Thumbnail Image
    Publication
    Identification of RPS14 as a 5q- syndrome gene by RNA interference screen
    (2013) Ebert, Benjamin; Pretz, Jennifer; Bosco, Jocelyn; Chang, Cindy Y.; Tamayo, Pablo; Galili, Naomi; Raza, Azra; Root, David E.; Attar, Eyal Chai; Ellis, Steven R.; Golub, Todd
    Somatic chromosomal deletions in cancer are thought to indicate the location of tumor suppressor genes, whereby complete loss of gene function occurs through biallelic deletion, point mutation, or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis.1 In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome (MDS) characterized by a defect in erythroid differentiation.2 Here, we describe an RNA interference (RNAi)-based approach to discovery of the 5q- disease gene. We find that partial loss of function of the ribosomal protein RPS14 phenocopies the disease in normal hematopoietic progenitor cells, and moreover that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-rRNA in RPS14 deficient cells that is highly analogous to the functional defect in Diamond Blackfan Anemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital bone marrow failure syndrome. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function, and suggests that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.
  • Thumbnail Image
    Publication
    Multiplex Cytological Profiling Assay to Measure Diverse Cellular States
    (Public Library of Science, 2013) Gustafsdottir, Sigrun M.; Ljosa, Vebjorn; Sokolnicki, Katherine L.; Anthony Wilson, J.; Walpita, Deepika; Kemp, Melissa M.; Petri Seiler, Kathleen; Carrel, Hyman A.; Golub, Todd; Schreiber, Stuart; Clemons, Paul A.; Carpenter, Anne E.; Shamji, Alykhan F.
    Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological profiling assay that “paints the cell” with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.
  • Thumbnail Image
    Publication
    Discovery and saturation analysis of cancer genes across 21 tumor types
    (2014) Lawrence, Michael S.; Stojanov, Petar; Mermel, Craig; Garraway, Levi; Golub, Todd; Meyerson, Matthew; Gabriel, Stacey B.; Lander, Eric; Getz, Gad
    Summary While a few cancer genes are mutated in a high proportion of tumors of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalog of cancer genes, we analyzed somatic point mutations in exome sequence from 4,742 tumor-normal pairs across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumor types. Our analysis also identified 33 genes not previously known to be significantly mutated, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes, mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5000 samples per tumor type, depending on background mutation rate. The results help guide the next stage of cancer genomics.
  • Thumbnail Image
    Publication
    Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer
    (2014) Lohr, Jens; Adalsteinsson, Viktor A.; Cibulskis, Kristian; Choudhury, Atish; Rosenberg, Mara; Cruz-Gordillo, Peter; Francis, Joshua; Zhang, Cheng-Zhong; Shalek, Alex K.; Satija, Rahul; Trombetta, John T.; Lu, Diana; Tallapragada, Naren; Tahirova, Narmin; Kim, Sora; Blumenstiel, Brendan; Sougnez, Carrie; Lowe, Alarice; Wong, Bang; Auclair, Daniel; Van Allen, Eliezer; Nakabayashi, Mari; Lis, Rosina T.; Lee, Gwo-Shu M.; Li, Tiantian; Chabot, Matthew S.; Ly, Amy; Taplin, Mary-Ellen; Clancy, Thomas; Loda, Massimo; Regev, Aviv; Meyerson, Matthew; Hahn, William; Kantoff, Philip; Golub, Todd; Getz, Gad; Boehm, Jesse S.; Love, J. Christopher
    Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
  • Thumbnail Image
    Publication
    The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis
    (Nature Publishing Group, 2016) Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd
    Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tumorigenesis, and observe marked differences in CNA prevalence between mouse mammary tumours initiated with distinct drivers. Some aberrations are recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumorigenesis. Synteny-based comparison of mouse and human tumours narrows critical regions in CNAs, thereby identifying candidate driver genes. We experimentally validate that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis to inform the pathogenesis of human cancer.