Photo of Thomas M. Roberts,  PhD

Thomas M. Roberts, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3049
Fax: (617) 632-4770


thomas_roberts@dfci.harvard.edu

Thomas M. Roberts, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
  • Chair, Cancer Biology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Signaling Mechanisms and Cancer

Through the process of signal transduction, cells communicate what is happening on their surfaces to the regulatory machinery inside. This process is facilitated by a class of enzymes called kinases, which help activate specific genes in the long strands of DNA in a cell's nucleus. An overactive kinase can lead to an overactive gene and, ultimately, to cancer. Our laboratory is researching the role of these catalysts of cell growth and division and has discovered how several work. Our discoveries have become the basis of new drugs that target the actions of specific kinases. This class of drugs, called kinase inhibitors, offers extraordinary hope for the future of cancer care.

Research in the laboratory currently focuses on three areas. One is how particular kinases are involved in cancer. For instance, the kinase termed PI3K blocks the orderly process of cell death, called apoptosis. Thus, inhibiting PI3K should lead to tumor cell death. We are also exploring new ways to measure kinase activity in tumors. Every tumor is unique, with its own pattern of activated kinases. Because there are more than 600 different kinases in a given tumor, it is important to find which ones are activated so that we know which ones to inhibit. Finally, our laboratory is developing murine model systems to study kinases in tumors.

Once kinases have been pinpointed, our laboratory develops the techniques and technology that allow pharmaceutical companies to make new drugs that target them. We supply the company with the reagents necessary to test the effect of drugs on the action of tyrosine kinases. In addition, DFCI scientists have developed the means to make kinases for testing. This collaboration has led to the creation of several new drugs. In particular, the drug Gleevec has been approved by the FDA against chronic myeloid leukemia (CML). More recently we have been working with Novartis on PI3k inhibitors. PI3K inhbitors from Novartis and other companies are now entering Phase 2 trials.

Publications

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  • Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 2016; 22:723-6. PubMed
  • Spangle JM, Dreijerink KM, Groner AC, Cheng H, Ohlson CE, Reyes J, Lin CY, Bradner J, Zhao JJ, Roberts TM, Brown M. PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. Cell Rep 2016; 15:2692-704. PubMed
  • Lee SJ, Kim MJ, Kwon IC, Roberts TM. Delivery strategies and potential targets for siRNA in major cancer types. Adv Drug Deliv Rev 2016. PubMed
  • Rouleau C, Pores Fernando AT, Hwang JH, Faure N, Jiang T, White EA, Roberts TM, Schaffhausen BS. Transformation by Polyomavirus Middle T Antigen Involves A Unique Bimodal Interaction with the Hippo Effector YAP. J Virol 2016. PubMed
  • Wang D, Wang M, Jiang N, Zhang Y, Bian X, Wang X, Roberts TM, Zhao JJ, Liu P, Cheng H. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. 2016. PubMed
  • White EA, Kramer RE, Hwang JH, Pores Fernando AT, Naetar N, Hahn WC, Roberts TM, Schaffhausen BS, Livingston DM, Howley PM. Papillomavirus E7 oncoproteins share functions with polyomavirus small T antigens. J Virol 2015; 89:2857-65. PubMed
  • Yuzugullu H, Baitsch L, Von T, Steiner A, Tong H, Ni J, Clayton LK, Bronson R, Roberts TM, Gritsman K, Zhao JJ. A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat Commun 2015; 6:8501. PubMed
  • Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol 2014; 24:2274-80. PubMed
  • Hwang JH, Pores Fernando AT, Faure N, Andrabi S, Adelmant G, Hahn WC, Marto JA, Schaffhausen BS, Roberts TM. Polyomavirus small T antigen interacts with yes-associated protein to regulate cell survival and differentiation. J Virol 2014; 88:12055-64. PubMed
  • Utermark T, Schmit F, Lee SH, Gao X, Schaffhausen BS, Roberts TM. The phosphatidylinositol 3-kinase (PI3K) isoform dependence of tumor formation is determined by the genetic mode of PI3K pathway activation rather than by tissue type. J Virol 2014; 88:10673-9. PubMed
  • Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, Schinzel AC, Sood S, Rosenbluh J, Kim JW, Zwang Y, Roberts TM, Root DE, Jacks T, Hahn WC. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 2014; 158:171-84. PubMed
  • Schmit F, Utermark T, Zhang S, Wang Q, Von T, Roberts TM, Zhao JJ. PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A 2014. PubMed
  • Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C, Maira SM, Hollingworth G, Choi C, Khandan T, Paktinat M, Okabe RO, Roberts TM, Zhao JJ. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α. J Clin Invest 2014; 124:1794-809. PubMed
  • Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J, Kovats SG, Kim S, Cooke VG, Monahan JE, Stegmeier F, Roberts TM, Sellers WR, Zhou W, Zhu P. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). 2013; 3:1030-43. PubMed
  • Jia S, Gao X, Lee SH, Maira SM, Wu X, Stack EC, Signoretti S, Loda M, Zhao JJ, Roberts TM. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. 2013; 3:44-51. PubMed
  • Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012; 488:106-10. PubMed
  • Utermark T, Rao T, Cheng H, Wang Q, Lee SH, Wang ZC, Iglehart JD, Roberts TM, Muller WJ, Zhao JJ. The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev 2012; 26:1573-86. PubMed
  • Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, Riddle S, Benes C, Eck M, Roberts T, Gray N, Zhao J. Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. 2012; 2:425-33. PubMed
  • Hofmann I, Weiss A, Elain G, Schwaederle M, Sterker D, Romanet V, Schmelzle T, Lai A, Brachmann SM, Bentires-Alj M, Roberts TM, Sellers WR, Hofmann F, Maira SM. K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo. PLoS ONE 2012; 7:e44146. PubMed
  • Lee SH, Jia S, Zhu Y, Utermark T, Signoretti S, Loda M, Schaffhausen B, Roberts TM. Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma. J Virol 2011. PubMed
  • Ilić N, Roberts TM. Comparing the Roles of the p110留 and p110硫 Isoforms of PI3K in Signaling and Cancer. Curr Top Microbiol Immunol 2010; 347:55-77. PubMed
  • Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468:968-72. PubMed
  • Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 2010; 466:503-7. PubMed
  • Lee SH, Poulogiannis G, Pyne S, Jia S, Zou L, Signoretti S, Loda M, Cantley LC, Roberts TM. A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc Natl Acad Sci U S A 2010; 107:11002-7. PubMed
  • Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8:627-44. PubMed
  • Yi K,Wang X,Emmett MR,Marshall AG,Stewart M,Roberts TM. Dephosphorylation of MSP Fiber Protein 3 (MFP3) by PP2A during Cell Body Retraction in the MSP-based Amoeboid Motility of Ascaris Sperm. Mol Biol Cell 2009; 20:3200-8. PubMed
  • Jia S,Roberts TM,Zhao JJ. Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 2009; 21:199-208. PubMed
  • Schaffhausen BS,Roberts TM. Lessons from polyoma middle T antigen on signaling and transformation: A DNA tumor virus contribution to the war on cancer. Virology 2008; 384:304-16. PubMed
  • Hein J,Boichuk S,Wu J,Cheng Y,Freire R,Jat PS,Roberts TM,Gjoerup OV. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol 2008; 83:117-27. PubMed
  • Jia S,Liu Z,Zhang S,Liu P,Zhang L,Lee SH,Zhang J,Signoretti S,Loda M,Roberts TM,Zhao JJ. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 2008; 454:776-9. PubMed
  • Kishi S,Bayliss PE,Uchiyama J,Koshimizu E,Qi J,Nanjappa P,Imamura S,Islam A,Neuberg D,Amsterdam A,Roberts TM. The identification of zebrafish mutants showing alterations in senescence-associated biomarkers. PLoS Genet 2008; 4:e1000152. PubMed
  • Imamura S,Uchiyama J,Koshimizu E,Hanai J,Raftopoulou C,Murphey RD,Bayliss PE,Imai Y,Burns CE,Masutomi K,Gagos S,Zon LI,Roberts TM,Kishi S. A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis. PLoS ONE 2008; 3:e3364. PubMed
  • Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B. Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci U S A 2007; 104:19011-6. PubMed
  • Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 2007; 449:689-94. PubMed
  • Utermark T, Schaffhausen BS, Roberts TM, Zhao JJ. The p110{alpha} isoform of PI3K is essential for polyoma middle T antigen mediated transformation. J Virol 2007; 81:7069-76. PubMed
  • Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier JK, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K, Hahn WC. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 2007; 129:1065-79. PubMed
  • Gjoerup OV, Wu J, Chandler-Militello D, Williams GL, Zhao J, Schaffhausen B, Jat PS, Roberts TM. Surveillance mechanism linking Bub1 loss to the p53 pathway. Proc Natl Acad Sci U S A 2007; 104:8334-9. PubMed
  • Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 2007; 128:1077-88. PubMed
  • Zhao JJ, Roberts TM. PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci STKE 2006; 2006:pe52. PubMed
  • Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A, Roberts TM. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A 2006; 103:16296-300. PubMed
  • Lin SS, Bassik MC, Suh H, Nishino M, Arroyo JD, Hahn WC, Korsmeyer SJ, Roberts TM. PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum. J Biol Chem 2006; 281:23003-12. PubMed
  • Bayliss PE, Bellavance KL, Whitehead GG, Abrams JM, Aegerter S, Robbins HS, Cowan DB, Keating MT, O'Reilly T, Wood JM, Roberts TM, Chan J. Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish. Nat Chem Biol 2006; 2:265-73. PubMed
  • Liu Z, Roberts TM. Human tumor mutants in the p110alpha subunit of PI3K. Cell Cycle 2006; 5:675-7. PubMed
  • Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, Zhao JJ, Roberts TM, Mandel G, Hannon GJ, Depinho RA, Chin L, Elledge SJ. A genetic screen for candidate tumor suppressors identifies REST. Cell 2005; 121:837-48. PubMed
  • Chan J, Bayliss PE, Wood JM, Roberts TM. Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell 2002; 1:257-67. PubMed
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