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Trever Bivona, MD, PhD

Trever Bivona, MD, PhD
Associate Professor, Department of Medicine
Division of Hematology/Oncology
Research Summary:
Molecular characterization and precision treatment of solid cancers.

Our group aims to use the tools of precision medicine to improve the molecular diagnosis and targeted therapy of patients with solid cancers, including lung cancer which is the leading cause of cancer mortality in both men and women in the United States and globally. Our basic and translational research program is focused on obtaining and functionally characterizing the molecular drivers of tumor growth in individual patients. We study patient samples and clinical data to identify novel potential drivers of tumor initiation, progression, and therapy resistance. We functionally annotate the putative molecular drivers using an integrated approach of genetic and pharmacologic tools and methods to identify the key functional drivers of cancer initiation, progression, and drug resistance. This precision approach to understanding the molecular pathogenesis of lung cancer (and other cancers) has led to the discovery of new biomarkers and targets that provide rationale for novel clinical trials that we are launching to improve patient survival. Our research program has been fortunate to receive support from several sources, including the NIH Director’s New Innovator Award Program, NCI, Howard Hughes Medical Institute Collaborative Innovation Award Program, the American Lung Association, and the Searle, Doris Duke, Kimmel, and Pew Foundations, among others. This generous support has enabled us to address challenges preventing progress toward transforming lung cancer (and other solid cancers) from a lethal disease into a chronic or curable condition. We welcome anyone interested in our basic and translational research program to contact us.

Selected Publications

Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, Okimoto RA, Lin L, Neel DS, Sabnis A, Flanagan J, Chan E, Varella-Garcia M, Aisner DL, Vaishnavi A, Ou SH, Collisson EA, Ichihara E, Mack PC, Lovly CM, Karachaliou N, Rosell R, Riess JW, Doebele RC, Bivona TG. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med. 2015 Sep;21(9):1038-47. doi: 10.1038/nm.3930. Epub 2015 Aug 24. PubMed PMID: 26301689.

Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, Hendifar AE, Wang Z, Atreya CE, Kelley RK, Loon KV, Ko AH, Tempero MA, Bivona TG, Munster PN, Talasaz A, Collisson EA. Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas. Cancer Discov. 2015 Jun 24. [Epub ahead of print] PubMed PMID:26109333.

Flaherty KT, Wargo JA, Bivona TG. YAP in MAPK pathway targeted therapy resistance. Cell Cycle. 2015;14(12):1765-6. doi: 10.1080/15384101.2015.1032644. PubMed PMID: 26036142.

Pazarentzos E, Giannikopoulos P, Hrustanovic G, St John J, Olivas VR, Gubens MA, Balassanian R, Weissman J, Polkinghorn W, Bivona TG. Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3CβD1067V kinase domain mutation. Oncogene. 2015 May 18. doi: 10.1038/onc.2015.173. [Epub ahead of print] PMID: 25982275

Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, Benzaken AO, Rodon J, Morse N, Yan JJ, Liu M, Das R, Chen Y, Tam A, Wang H, Liang J, Gurski JM, Kerr DA, Rosell R, Teixidó C, Huang A, Ghossein RA, Rosen N, Bivona TG, Scaltriti M, Baselga J. AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas. Cancer Cell. 2015 Apr 13;27(4):533-46. doi:10.1016/j.ccell.2015.03.010. PubMed PMID: 25873175; PubMed Central PMCID: PMC4398915. 

Blakely CM, Pazarentzos E, Olivas V, Asthana S, Yan JJ, Tan I, Hrustanovic G, Chan E, Lin L, Neel DS, Newton W, Bobb KL, Fouts TR, Meshulam J, Gubens MA,Jablons DM, Johnson JR, Bandyopadhyay S, Krogan NJ, Bivona TG. NF-κB-ActivatingComplex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer. Cell Rep. 2015 Apr 7;11(1):98-110.  doi: 10.1016/j.celrep.2015.03.012. Epub 2015 Apr 2. PubMed PMID: 25843712; PubMed Central PMCID: PMC4394036.

Choi YJ, Kim SY, So KS, Baek IJ, Kim WS, Choi SH, Lee JC, Bivona TG, Rho JK,Choi CM. AUY922 Effectively Overcomes MET- and AXL-Mediated Resistance to EGFR-TKI in Lung Cancer Cells. PLoS One. 2015 Mar 17;10(3):e0119832. doi: 10.1371/journal.pone.0119832. eCollection 2015. PubMed PMID: 25780909; PubMed Central PMCID: PMC4363657.

Pazarentzos E, Bivona TG. Adaptive stress signaling in targeted cancer therapy resistance. Oncogene. 2015 Feb 23. doi: 10.1038/onc.2015.26. [Epub ahead of print] Review. PubMed PMID: 25703329.

Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, Asthana S, Neel D,  Yan JJ, Lu X, Pham L, Wang MM, Karachaliou N, Cao MG, Manzano JL, Ramirez JL, Torres JM, Buttitta F, Rudin CM, Collisson EA, Algazi A, Robinson E, Osman I, Muñoz-Couselo E, Cortes J, Frederick DT, Cooper ZA, McMahon M, Marchetti A, Rosell R, Flaherty KT, Wargo JA, Bivona TG. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 2015 Mar;47(3):250-6. doi: 10.1038/ng.3218. Epub 2015 Feb 9. PubMed PMID: 25665005. 

Okimoto RA, Bivona TG. Recent advances in personalized lung cancer medicine. Per Med. 2014;11(3):309-321. PubMed PMID: 25506379; PubMed Central PMCID: PMC4263209.

Shen J, Wei J, Guan W, Wang H, Ding Y, Qian X, Yu L, Zou Z, Xie L, Costa C, Bivona T, Rosell R, Liu B. Plasma mRNA expression levels of BRCA1 and TS as potential predictive biomarkers for chemotherapy in gastric cancer. J Transl Med. 2014 Dec 14;12(1):355. [Epub ahead of print] PubMed PMID: 25496700; PubMed Central PMCID: PMC4302091.

Rolfo C, Giovannetti E, Hong DS, Bivona T, Raez LE, Bronte G, Buffoni L, Reguart N, Santos ES, Germonpre P, Taron M, Passiglia F, Van Meerbeeck JP, Russo  A, Peeters M, Gil-Bazo I, Pauwels P, Rosell R. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev. 2014 Sep;40(8):990-1004. doi: 10.1016/j.ctrv.2014.05.009. Epub 2014 Jun 6. Review. PubMed PMID: 24953979.

Lin L, Asthana S, Chan E, Bandyopadhyay S, Martins MM, Olivas V, Yan JJ, Pham L, Wang MM, Bollag G, Solit DB, Collisson EA, Rudin CM, Taylor BS, Bivona TG. Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):E748-57. doi: 10.1073/pnas.1320956111. Epub 2014 Feb 3. PubMed PMID: 24550319; PubMed Central PMCID: PMC3932924.

Costa C, Molina MA, Drozdowskyj A, Giménez-Capitán A, Bertran-Alamillo J, Karachaliou N, Gervais R, Massuti B, Wei J, Moran T, Majem M, Felip E, Carcereny E, Garcia-Campelo R, Viteri S, Taron M, Ono M, Giannikopoulos P, Bivona T, RosellR. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014 Apr 1;20(7):2001-10. doi: 10.1158/1078-0432.CCR-13-2233. Epub 2014 Feb 3. PubMed PMID: 24493829.

Molina-Vila MA, Nabau-Moretó N, Tornador C, Sabnis AJ, Rosell R, Estivill X,  Bivona TG, Marino-Buslje C. Activating mutations cluster in the "molecular brake" regions of protein kinases and do not associate with conserved or catalytic residues. Hum Mutat. 2014 Mar;35(3):318-28. doi: 10.1002/humu.22493. Epub 2014 Jan 8. PubMed PMID: 24323975.

Rosell R, Bivona TG, Karachaliou N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet. 2013 Aug 24;382(9893):720-31. doi: 10.1016/S0140-6736(13)61715-8. Review. PubMed PMID: 23972815.

Sabnis AJ, Bivona TG. FGFR fusions in the driver's seat. Cancer Discov. 2013  Jun;3(6):607-9. doi: 10.1158/2159-8290.CD-13-0185. PubMed PMID: 23749526.

Hrustanovic G, Lee BJ, Bivona TG. Mechanisms of resistance to EGFR targeted therapies. Cancer Biol Ther. 2013 Apr;14(4):304-14. doi: 10.4161/cbt.23627. Epub 2013 Jan 28. Review. PubMed PMID: 23358468; PubMed Central PMCID: PMC3667869.

Neel DS, Bivona TG. Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT. Clin Cancer Res. 2013 Jan 1;19(1):3-5. doi: 10.1158/1078-0432.CCR-12-3232. Epub 2012 Nov 21. PubMed PMID: 23172883; PubMed Central PMCID: PMC3537879.

Blakely CM, Bivona TG. Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance. Cancer Discov. 2012 Oct;2(10):872-5. doi: 10.1158/2159-8290.CD-12-0387. PubMed PMID: 23071030; PubMed Central PMCID: PMC3475614.

Lin L, Bivona TG. Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients. Chemother Res Pract. 2012;2012:817297. doi: 10.1155/2012/817297. Epub 2012 Aug 29. PubMed PMID: 22970367; PubMed Central PMCID: PMC3437267.

Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK, Choi YJ, Choi CM, Kim SW, Jang SJ, Park YS, Kim WS, Lee DH, Lee JS, Miller VA, Arcila M, Ladanyi M, Moonsamy P, Sawyers C, Boggon TJ, 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. Nat Genet. 2012 Jul 1;44(8):852-60. doi: 10.1038/ng.2330. PubMed PMID: 22751098; PubMed Central PMCID: PMC3408577.

Morris LG, Taylor BS, Bivona TG, Gong Y, Eng S, Brennan CW, Kaufman A, Kastenhuber ER, Banuchi VE, Singh B, Heguy A, Viale A, Mellinghoff IK, Huse J, Ganly I, Chan TA. Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):19024-9. doi: 10.1073/pnas.1111963108. Epub 2011 Nov 7. PubMed PMID: 22065749; PubMed Central PMCID: PMC3223475.

Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, Moonsamy P, Dahlman K, Miller VA, Costa C, Hannon G, Sawyers CL. FAS and NF-κB signaling modulate dependence of lung cancers on mutant EGFR. Nature. 2011 Mar 24;471(7339):523-6. doi: 10.1038/nature09870. PubMed PMID: 21430781; PubMed Central PMCID: PMC3541675.

Rosell R, Molina MA, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J, Mayo C, Moran T, Mendez P, Cardenal F, Isla D, Provencio M, Cobo M, Insa A, Garcia-Campelo R, Reguart N, Majem M, Viteri S, Carcereny E, Porta R, Massuti B, Queralt C, de Aguirre I, Sanchez JM, Sanchez-Ronco M, Mate

JL, Ariza A, Benlloch S, Sanchez JJ, Bivona TG, Sawyers CL, Taron M. Pretreatment 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):1160-8. doi: 10.1158/1078-0432.CCR-10-2158. Epub 2011 Jan 13. PubMed PMID: 21233402.

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. doi: 10.1016/S0076-6879(07)00407-7. PubMed PMID: 18374158.

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

Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Pérez de Castro I, Li C, Thompson CB, 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. PubMed PMID: 16483930.

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. PubMed PMID: 16289969.

Jordan JD, He JC, Eungdamrong NJ, Gomes I, Ali W, Nguyen 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. Epub 2005 Jan 18. PubMed PMID: 15657046.

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. PubMed PMID: 15060167; PubMed Central PMCID: PMC381594.

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 Ca2+ oscillations. EMBO J. 2004 Apr 21;23(8):1749-60. Epub 2004 Apr 1. PubMed PMID: 15057271; PubMed Central PMCID: PMC394250.

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

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. Mol Cell. 2004 Feb 13;13(3):341-55. PubMed PMID: 14967142.

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. PubMed PMID: 14757755; PubMed Central PMCID: PMC2172240.

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. Epub 2003 Sep 11. PubMed PMID: 12970366.

Bivona TG, Pérez De Castro I, Ahearn IM, Grana TM, Chiu VK, Lockyer PJ, Cullen PJ, Pellicer A, Cox AD, Philips MR. Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature. 2003 Aug 7;424(6949):694-8. Epub 2003 Jun 29. PubMed PMID: 12845332.

Bivona TG, Philips MR. Ras pathway signaling on endomembranes. Curr Opin Cell Biol. 2003 Apr;15(2):136-42. Review. PubMed PMID: 12648668.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. Nat Cell Biol. 2002 May;4(5):343-50. PubMed PMID: 11988737.

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