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David A. Barbie, MD


Medical Oncology

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Physician

  • Associate Director of the Robert and Renée Belfer Center for Applied Cancer Research
  • Physician
  • Associate Professor of Medicine, Harvard Medical School

Centers/Programs

Clinical Interests

  • KRAS targeted therapy
  • Lung cancer
  • Translational oncology

Contact Information

  • Appointments877-332-4294 (new)
    617-632-6190 (established)
  • Office Phone Number617-632-6049
  • Fax617-632-5786

Board Certification:

  • Internal Medicine, 2005
  • Medical Oncology, 2008

Fellowship:

  • Dana-Farber/Partners CancerCare, Medical Oncology

Residency:

  • Massachusetts General Hospital, Chief Resident in Internal Medicine
  • Massachusetts General Hospital, Internal Medicine

Medical School:

  • Harvard Medical School

Recent Awards:

  • NIH R01 Award 2015
  • V Foundation Scholar Award 2012
  • ASCO Young Investigator Award 2009
  • NIH K08 Award 2010

Research

Translational Oncology/KRAS Targeted Therapy

My interest as a medical oncologist and cancer biologist is to identify novel targets for cancer therapy. Specifically, I have focused on lung cancer clinically with a particular interest in targeting KRAS mutations, which have remained refractory to current therapies.

We previously found that TBK1, a kinase that is normally involved in immune cell signaling, prevents apoptosis in cancer cells driven by oncogenic KRAS. Others have found that inhibition of the NF-kB and STAT pathways, in which TBK1 is involved, also results in impaired tumor growth in KRAS-driven mouse lung cancer. Recently, we discovered that a kinase inhibitor, momelotinib, inhibits TBK1 and JAK signaling and has activity in mouse models of Kras-driven lung cancer. Based on these findings, we have opened a trial together with Gilead Sciences combining momelotinib with the MEK inhibitor trametinib in treatment refractory KRAS mutant lung cancer.

My overall goal is to continue this effort clinically and in the lab to refine combination therapy for KRAS-driven lung cancer and improve outcomes for this challenging disease.

KRAS G12C inhibition and innate immune targeting. Expert Opin Ther Targets. 2021 Mar 11.
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Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity. Cancer Discov. 2021 Mar 11.
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Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade. J Clin Invest. 2021 Jan 19; 131(2).
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Targeting the mutant p53 secretome. J Clin Invest. 2021 Jan 04; 131(1).
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Engineering approaches for studying immune-tumor cell interactions and immunotherapy. iScience. 2021 Jan 22; 24(1):101985.
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Turnaround Time of Plasma Next-Generation Sequencing in Thoracic Oncology Patients: A Quality Improvement Analysis. JCO Precis Oncol. 2020; 4.
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Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer. Genet Epidemiol. 2021 Feb; 45(1):99-114.
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Tumor-Derived cGAMP Regulates Activation of the Vasculature. Front Immunol. 2020; 11:2090.
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Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade. Cancer Discov. 2020 Sep; 10(9):1296-1311.
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TBK1 Activation by VHL Loss in Renal Cell Carcinoma: A Novel HIF-Independent Vulnerability. Cancer Discov. 2020 03; 10(3):348-350.
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Use of ExVivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 05 15; 26(10):2393-2403.
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Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. Cancer Cell. 2020 01 13; 37(1):104-122.e12.
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Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases. Nat Struct Mol Biol. 2020 01; 27(1):92-104.
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Clonal Selection Drives NF-?B Activation in Recurrent Nasopharyngeal Carcinoma. Cancer Res. 2019 12 01; 79(23):5915-5916.
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Phosphorylation of RAB7 by TBK1/IKKe Regulates Innate Immune Signaling in Triple-Negative Breast Cancer. Cancer Res. 2020 01 01; 80(1):44-56.
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Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer. Cancer Discov. 2019 10; 9(10):1372-1387.
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Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion. Cancer Res. 2019 08 01; 79(15):3903-3915.
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Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2019 Jan 10; 176(1-2):404.
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The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy. Blood Adv. 2018 12 11; 2(23):3428-3442.
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A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell. 2018 11 01; 175(4):984-997.e24.
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Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018 11 01; 175(4):998-1013.e20.
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Tumor cGAMP Awakens the Natural Killers. Immunity. 2018 10 16; 49(4):585-587.
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3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Lab Chip. 2018 10 09; 18(20):3129-3143.
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Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer. Cancer Discov. 2019 01; 9(1):34-45.
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A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing. Cancer Immunol Res. 2018 12; 6(12):1511-1523.
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Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS. Cancer Cell. 2018 09 10; 34(3):439-452.e6.
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Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet. 2018 09; 50(9):1271-1281.
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Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure. Clin Lung Cancer. 2018 11; 19(6):e853-e859.
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Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. Invest New Drugs. 2019 02; 37(1):159-165.
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Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med. 2018 08; 24(8):1143-1150.
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Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer. Clin Cancer Res. 2018 10 01; 24(19):4854-4864.
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Plasma inflammatory cytokines and survival of pancreatic cancer patients. Clin Transl Gastroenterol. 2018 04 25; 9(4):145.
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RASA1/NF1-Mutant Lung Cancer: Racing to the Clinic? Clin Cancer Res. 2018 03 15; 24(6):1243-1245.
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Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018 01; 118(1):9-16.
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ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors. Cancer Res. 2018 02 15; 78(4):1044-1057.
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Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov. 2018 02; 8(2):196-215.
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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2018 02; 8(2):216-233.
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Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in Cancer. Annu Rev Med. 2018 01 29; 69:333-347.
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Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. Cell Syst. 2017 08 23; 5(2):105-118.e9.
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Refining Targeted Therapy Opportunities for BRAF-Mutant Melanoma. Cancer Discov. 2017 08; 7(8):799-801.
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The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. Oncogene. 2017 09 07; 36(36):5145-5157.
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Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. Cancer Discov. 2017 08; 7(8):852-867.
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MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. Oncotarget. 2017 Feb 21; 8(8):13872-13885.
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Tumor SQSTM1 (p62) expression and T cells in colorectal cancer. Oncoimmunology. 2017; 6(3):e1284720.
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Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors. Cancer Immunol Res. 2016 12; 4(12):1038-1048.
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Fine needle aspirate flow cytometric phenotyping characterizes immunosuppressive nature of the mesothelioma microenvironment. Sci Rep. 2016 08 19; 6:31745.
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Inflammation as a driver and vulnerability of KRAS mediated oncogenesis. Semin Cell Dev Biol. 2016 10; 58:127-35.
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Characterizing genomic alterations in cancer by complementary functional associations. Nat Biotechnol. 2016 05; 34(5):539-46.
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Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer Immunol Res. 2016 06; 4(6):520-30.
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STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. Cancer Res. 2016 Mar 01; 76(5):999-1008.
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Doxycycline: new tricks for an old drug. Oncotarget. 2015 Aug 14; 6(23):19336-7.
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Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell. 2015 Aug 06; 59(3):345-358.
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Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation. Cancer Immunol Res. 2015 Aug; 3(8):855-63.
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Response to Crizotinib in a Patient With Lung Adenocarcinoma Harboring a MET Splice Site Mutation. Clin Lung Cancer. 2015 Sep; 16(5):e101-4.
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Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014 Dec 08; 26(6):909-922.
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Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. J Clin Invest. 2014 Dec; 124(12):5411-23.
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Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc Natl Acad Sci U S A. 2014 Nov 11; 111(45):E4869-77.
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Targeting pathways downstream of KRAS in lung adenocarcinoma. Pharmacogenomics. 2014 Aug; 15(11):1507-18.
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Targeting cytokine networks in KRAS-driven tumorigenesis. Expert Rev Anticancer Ther. 2014 Aug; 14(8):869-71.
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Interactive Medical case. Off balance. N Engl J Med. 2014 Jun 12; 370(24):e37.
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Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine. Nat Med. 2014 Jun; 20(6):682-8.
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Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood. 2014 Jul 03; 124(1):13-23.
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Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 2014 Apr; 4(4):452-65.
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Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers. Cancer Discov. 2013 Sep; 3(9):1044-57.
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Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28; 3(3):747-58.
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Functional genomics and cancer drug target discovery. Curr Opin Mol Ther. 2010 Jun; 12(3):284-93.
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Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009 Nov 05; 462(7269):108-12.
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AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009 Jul 07; 16(1):21-32.
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Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009 May 29; 137(5):821-34.
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Highly parallel identification of essential genes in cancer cells. Proc Natl Acad Sci U S A. 2008 Dec 23; 105(51):20380-5.
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Destablization of the Cancer Genome. DeVita, Hellman & Rosenberg's Cancer: Principle and Practice of Oncology. 2008; 35-51.

Destablization of the Cancer Genome. DeVita, Hellman & Rosenberg's Cancer: Principle and Practice of Oncology. 2008; 35-51.

Pharmacology of Cancer: Genome Synthesis, Stability, and Maintenance. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 2008; 675-699.

Pharmacology of Cancer: Signal Transduction. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 2008; 701-717.

Hematology-Oncology. Pocket Medicine. 2008; 5.1-5.36.

Pharmacology of Cancer: Genome Synthesis, Stability, and Maintenance. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 2008; 675-699.

Pharmacology of Cancer: Signal Transduction. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 2008; 701-717.

Hematology-Oncology. Pocket Medicine. 2008; 5.1-5.36.

Systemic mastocytosis: current classification and novel therapeutic options. Clin Adv Hematol Oncol. 2006 Oct; 4(10):768-75.
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Nuclear tumor suppressors in space and time. Trends Cell Biol. 2005 Jul; 15(7):378-85.
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Eosinophilic gastroenteritis associated with systemic lupus erythematosus. J Clin Gastroenterol. 2004 Nov-Dec; 38(10):883-6.
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A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc Natl Acad Sci U S A. 2004 Jun 29; 101(26):9677-82.
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Nuclear reorganization of mammalian DNA synthesis prior to cell cycle exit. Mol Cell Biol. 2004 Jan; 24(2):595-607.
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Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107. Proc Natl Acad Sci U S A. 2003 Dec 23; 100(26):15601-6.
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Nuclear Organization of Mammalian DNA Replication. 2002.

RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Mol Cell Biol. 2001 Apr; 21(8):2918-32.
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Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism. J Biol Chem. 2000 Nov 24; 275(47):37101-9.
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Nuclear organization of DNA replication in primary mammalian cells. Genes Dev. 2000 Nov 15; 14(22):2855-68.
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NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. Genes Dev. 2000 Sep 15; 14(18):2283-97.
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Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol. 1996 Sep; 16(9):5210-8.
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