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Trever Bivona, MD, PhD

Trever Bivona, MD, PhD
Assistant Professor, Department of Medicine
Division of Hematology/Oncology
Research Summary:
Molecular Pathogenesis and Targeted Therapy of Lung Cancer

Our overarching goal is to discover new strategies to enhance responses in cancer patients to treatments that target aberrant signal transduction pathways that drive tumor growth.  We engage in studies linking the bench and the bedside investigating the molecular pathogenesis of human cancers with a primary focus on lung cancer, the leading cause of cancer mortality.  We use interdisciplinary approaches and next-generation functional genomics methodologies, relevant human lung cancer cell line and tumor model systems, and human lung cancer specimens and clinical data to define the molecular events that drive the growth human lung cancers (e.g. please see Bivona TG, et al Nature 471, 523-526, 24 March 2011; Zheng ZZ, et al, Bivona TG, Nature Genetics 2012).  Based on our discoveries, we design novel, rational therapeutic strategies and translate our findings into clinical applications. Our laboratory investigations often lead to clinical trials testing novel, molecularly targeted cancer therapies that are aimed at improving the survival of genetically defined subsets of patients with lung and other lethal cancers. 

There are several ongoing projects in the lab that are focused on functionally characterizing the lung cancer genome to develop new strategies to enhance the survival of lung cancer patients.  In our studies, we leverage a conceptually and technically innovative and multidisciplinary approach using unbiased systems biology and chemical genetic screening strategies and detailed mechanistic studies in human lung cancer models.

1) Defining the underlying molecular mechanisms by which tumor cells become dependent upon mutant, activated forms of the epidermal growth factor receptor (EGFR) for their growth and survival (“oncogene dependence”).

2) Elucidating genetic and epigenetic determinants of driver oncogene dependence in genetically defined subsets of human lung cancers that are characterized by expression of an oncogenic kinase such as mutant BRAF or the EML4-ALK gene fusion.

3) Uncovering mechanisms of primary and secondary resistance to driver oncogene inhibition in lung cancers using cell line and mouse models of lung cancer to define molecular biomarkers and rational therapeutic targets to overcome treatment resistance in lung cancer patients.

4) Developing quantitative genetic interaction maps of signaling networks driving resistance to oncogene-targeted therapy in human lung cancers to develop synergistic cocktail therapies that could enhance the survival of appropriately selected, molecularly defined subsets of lung cancer patients.

Honors:
1998  Vanderbilt University Honors Degree in Molecular Biology
1998  Vanderbilt University Research Excellence Award
1998-2005  NIH Medical Scientist Training Program Award
2005  Medical Science Writing Award, NYU School of Medicine
2007  US Patent 20060083742 Prenyl-electrostatic Switch
2008-2010  Charles A. Dana Foundation Clinical Scholars Research Fellowship
2009  Julia Zelmanovich Young Alumnus Award, NYU School of Medicine
2010  American Society of Clinical Oncology Young Investigator Award
2010  Uniting Against Lung Cancer Research Award
2011  NIH/NCI Clinical Investigator Career Development Award (K08)
2012  National Lung Cancer Partnership Young Investigator Award
2012  Sidney Kimmel Foundation Kimmel Scholar Award    
2012  Damon Runyon Clinical Investigator Award Finalist
2012  American Lung Association Lung Cancer Discovery Award
2012  Doris Duke Charitable Foundation Clinical Scientist Development Award
2012  Visiting Scholar Howard Hughes Medical Institute (HHMI) Scholars Program at California State University-Fullerton
2012  NIH Director’s New Innovator Award (DP2) more information

Selected Publications

Robibaro B, Stedman TT, Coppens I, Ngo HM, Pypaert M, Bivona T, Nam HW, Joiner KA.  Toxoplasma gondii Rab5 enhances cholesterol acquisition from hos  cells.Cell Microbiol. 2002 Mar;4(3):139-52. PMID:11906451

Chiu VK*, Bivona T*, Hach A, Sajous JB, Silletti J, Wiener H, Johnson RL 2nd, Cox AD,  Philips MR.  Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell  Biol. 2002 May;4(5):343-50. * Equal Contribution  PMID:11988737

Bivona TG, Philips MR. Ras pathway signaling on endomembranes. Curr Opin Cell  Biol. 2003 Apr;15(2):136-42. PMID:12648668

Bivona TG, Perez De Castro I, Ahearn IM, Grana TM, Chiu VK, Lockyer PJ, Cullen PJ,  Pellicer A, Cox AD, Philips MR. Phospholipase Cg activates Ras on the Golgi apparatus by means of RasGRP1.  Nature. 2003 Aug 7;424(6949):694-8. PMID:12845332

Mohney RP, Das M, Bivona TG, Hanes R, Adams AG, Philips MR, O'Bryan JP. Intersectin activates Ras but stimulates transcription through an independent pathway involving  JNK.  J Biol Chem. 2003 Nov 21;278(47):47038-45. PMID:12970366

Bivona TG, Wiener HH, Ahearn IM, Silletti J, Chiu VK, Philips MR. Rap1 up-regulation and activation on plasma membrane regulates T cell adhesion. J Cell Biol. 2004 Feb 2;164(3):461-70. PMID:14757755

Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T, Luo J, Thompson JA,  Schraven BL, Philips MR, Neel BG.  Shp2 regulates SRC family kinase activity and ras/erk  activation by controlling csk recruitment. Molecular Cell. 2004 Feb 13;(3):341-55.   PMID:14967142

Walker SA, Kupzig S, Bouyoucef D, Davies LC, Tsuboi T, Bivona TG, Cozier GE,  Lockyer PJ, Buckler A, Rutter GA, Allen MJ, Philips MR, Cullen PJ. Identification of a Ras  GTPase-activating protein regulated by receptor-mediated Ca(2+) oscillations. EMBO J. 2004 Apr 21;23(8):1749-60. PMID:15057271

Dustin ML, Bivona TG and Philips MR. Membranes as messengers in T cell adhesion signaling. Nat Immunol. 2004 Apr;5(4):363-72. PMID:15052266

Perez De Castro I, Bivona TG, Philips MR, Pellicer A.  Ras Activation in Jurkat T cells  following Low- Grade Stimulation of the T-Cell Receptor Is Specific to N-Ras and Occurs Only on the Golgi Apparatus. Mol Cell Biol. 2004 Apr;24(8):3485-96. PMID:15060167

Jordan JD, He JC, Eungdamrong NJ, Gomes I, Ali W, Nhuyen T, Bivona TG, Philips  MR,  Devi LA, Iyengar R. Cannabinoid receptor-induced neurite outgrowth is mediated by  Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII. J  Biol Chem. 2005 Mar 25;280(12):11413- 21. PMID:15657046

Bivona TG, Philips MR. Analysis of Ras and Rap activation in living cells using fluorescent Ras binding domains. Methods. 2005 Oct;37(2):138-45.PMID: 16289969

Bivona TG, Quatela S, Bodemann BO, Ahearn IM, Soskis MJ, Weiner HH, Saba SG, Yim D,  Perez de Castro I, Thompson CR, Cox AD, Philips MR. PKC regulates a farnesyl  electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis.  Mol Cell. 2006 Feb 17;21(4):481-93. PMID:16483930

Bivona TG, Quatela S, Philips MR. Analysis of Ras activation in living cells with GFP-RBD. Methods Enzymol. 2006;407:128-43. PMID:16757320

Quatela SE, Sung PJ, Ahearn IM, Bivona TG, Philips MR. Analysis of K-Ras  phosphorylation, translocation, and induction of apoptosis. Methods Enzymol. 2008;439:87- 102. PMID:18374158

Rosell R, et al, Bivona TG, Sawyers CL, Taron M. Pre-treatment EGFR T790M mutation   and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer  patients with EGFR mutations. Clin Cancer Res. 2011 Mar 1;17(5):1160-1168.  PMID:21233402

Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, Moonsamy P, Dahlman K, Miller V, Costa C, Hannon G, Sawyers C.  FAS and NF-kB, Signalling Modulate Dependence of  Lung Cancers on Mutant EGFR.  Nature. 2011 Mar 24;471: 523-526. PMID:2143078

Morris LGT, Taylor BT, Bivona TG, Gong Y, Eng S, Brennan C, Kaufman A, Kastenhuber E, Banuchi V, Singh B, Heguy A, Viale A, Mellinghoff A, Huse J, Ganly I, Chan T. Genomic dissection of the EGFR/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers. PNAS. 2011 Nov 22;108(47):19024-9. PMID:22065749

Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine A, Rho J, Choi Y, Choi CM, Kim SW, Jang SJ, Park YS, Miller VA, Arcila M, Ladanyi M, Moonsamy P, Sawyers C, Ma PC, Costa C, Taron M, Rosell R, Halmos B, Bivona TG. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics 2012 Jul 1;44(8):852-860. PMID:22751098

Lin L & Bivona TG. Mechanisms of resistance to epidermal growth factor receptor inhibitors and novel therapeutic strategies to overcome resistance in NSCLC patients. Chemotherapy Research and Practice. 2012. vol. 2012, Article ID 817297, 2012. doi:10.1155/2012/817297

Blakely C & Bivona TG. Resiliency of lung cancers to EGFR inhibitor treatment unveiled offering opportunities to divide and conquer EGFR inhibitor resistance.  Cancer Discovery. 2012. In press.