Kenneth <span>H.</span> Shain, MD, PhD
Researcher

Kenneth H. Shain, MD, PhD

Academic Rank: Assistant Member

Overview

To date, Dr. Shain has been actively participating in translation research in multiple myeloma and other hematologic malignancies, with 40 publications as well as a number of book chapters. Clinically, Dr. Shain is/has been the principal investigator and co-investigator of a number of clinical trials in multiple myeloma. His translational research has focused on the mechanisms by which components of the bone marrow microenvironment influence myeloma biology, survival, and drug response. He is currently collaborating with a wide range of Moffitt and non-Moffitt researchers, mathematicians, clinicians and other groups to carry out his research goals.  

Discipline

    • Malignant Hematology
    • Tumor Biology
    • Myeloma
    • Systems Medicine Working Group
    • Chemical Biology and Molecular Medicine Program

Education & Training

    • University of South Florida, PhD - Biochemistry & Molecular Biology
    • University of South Florida College of Medicine , MD
    • University of South Florida College of Medicine, Resident - Internal Medicine
    • University of South Florida College of Medicine, Moffitt Cancer Center, - Hematology/Oncology
Research

This research goal and desire to bring personalized therapy to the forefront of myeloma therapy involves several projects – (1) Personalized care of multiple myeloma: A) EMMA (evolutionary mathematical myeloma advisor) - a novel collaboration with critical alliance with our integrated mathematical oncology department (Dr. Robert Gatenby, Dr. Robert Gilles and Dr. Ariosto Silva among others) characterizing aspects of the evolution of drug response. This collaboration has led the development of a novel mathematically-based model to predict patient response to therapy; thus, facilitating potential for the design of patient-specific/optimized therapeutic strategies that could extend survival in patients. B) GEP (gene expression profiling) - under a sponsored research agreement with Signal Genetics we will develop GEP signatures to better define risk of progression for antecedent conditions and to better inform key patient management decisions in multiple myeloma. (2) Targeting mediators of plasma cell development: Using three different mouse models we have identified a heretofore uncharacterized role of the histone deacetylase (HDAC), HDAC11, in plasma cell differentiation and biology. Our preliminary data indicate that HDAC11, the most recently identified HDAC, is critical for B cell development, more specifically plasma cell differentiation in vivo. Ongoing research will hopefully lead to the development of targeted therapeutics and clinical trials in myeloma patients. (3) Microenvironment-modulated synthetic lethality: Microenvironmental determinants alter tumor drug response; thereby, conferring myeloma survival and drug resistance. To this end, major questions remain: A) Can we identify key environmental determinants facilitating this survival phenotype to combat EMDR, MRD (minimal residual disease), and relapse? B) Can we identify drug targets that exhibit a TME-induced “synthetic lethality” (e.g. drugs with increased activity within the context of the TME)? We have recently identified PYK2/FAK2 as a target meeting this criteria and are working on translating this into clinical trials in collaboration with Verastem.

Publications

  • Rollison DE, Komrokji R, Lee JH, Hampras S, Fulp W, Fisher K, Baz R, Nishihori T, Xu Q, Olesnyckyj M, Kenvin L, Knight R, Sullivan D, Alsina M, Dalton W, Shain KH. Subsequent primary malignancies among multiple myeloma patients treated with or without lenalidomide. Leuk Lymphoma. 2017 Mar;58(3):560-568. Pubmedid: 27424609.
  • Silva AS, Silva MC, Sudalagunta P, Distler AI, Jacobson T, Collins A, Nguyen T, Song J, Chen DT, Chen L, Cubitt CL, Baz R, Perez L, Rebatchouk D, Dalton W, Greene J, Gatenby RA, Gillies RJ, Sontag E, Meads MB, Shain K. An Ex Vivo Platform for the Prediction of Clinical Response in Multiple Myeloma. Cancer Res. 2017 Jun;77(12):3336-3351. Pubmedid: 28400475.
  • Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, Balasis ME, Mesa TE, Sallman DA, Lancet JE, Komrokji RS, List AF, McLeod HL, Alsina M, Baz R, Shain KH, Rollison DE, Padron E. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017 Jan;18(1):112-121. Pubmedid: 27927582.
  • Zhao X, Lwin T, Silva A, Shah B, Tao J, Fang B, Zhang L, Fu K, Bi C, Li J, Jiang H, Meads MB, Jacobson T, Silva M, Distler A, Darville L, Zhang L, Han Y, Rebatchouk D, Di Liberto M, Moscinski LC, Koomen JM, Dalton WS, Shain KH, Wang M, Sotomayor E, Tao J. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun. 2017 Apr;8:14920. Pubmedid: 28416797. Pmcid: PMC5399304.
  • Turner JG, Kashyap T, Dawson JL, Gomez J, Bauer AA, Grant S, Dai Y, Shain KH, Meads M, Landesman Y, Sullivan DM. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma. Oncotarget. 2016 Nov;7(48):78896-78909. Pubmedid: 27806331. Pmcid: PMC5340237.
  • Meads MB, Fang B, Mathews L, Gemmer J, Nong L, Rosado-Lopez I, Nguyen T, Ring JE, Matsui W, MacLeod AR, Pachter JA, Hazlehurst LA, Koomen JM, Shain KH. Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene. 2016 May;35(21):2723-2734. Pubmedid: 26387544. Pmcid: PMC4801703.
  • Baz RC, Martin TG, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May;127(21):2561-2568. Pubmedid: 26932802.
  • Rollison DE, Shain KH, Lee JH, Hampras SS, Fulp W, Fisher K, Al Ali NH, Padron E, Lancet J, Xu Q, Olesnyckyj M, Kenvin L, Knight R, Dalton W, List A, Komrokji RS. Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide. Cancer Med. 2016 Jul;5(7):1694-1701. Pubmedid: 27098006. Pmcid: PMC4944897.
  • Turner JG, Dawson JL, Grant S, Shain KH, Dalton WS, Dai Y, Meads M, Baz R, Kauffman M, Shacham S, Sullivan DM. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors. J Hematol Oncol. 2016 Aug;9(1):73. Pubmedid: 27557643. Pmcid: PMC4997728.
  • Nishihori T, Song J, Shain KH. Minimal Residual Disease Assessment in the Context of Multiple Myeloma Treatment. Curr Hematol Malig Rep. 2016 Apr;11(2):118-126. Pubmedid: 26898557. Pmcid: PMC4819726.
  • Shain KH, Dalton WS, Tao J. The tumor microenvironment shapes hallmarks of mature B-cell malignancies. Oncogene. 2015 Sep;34(36):4673-4682. Pubmedid: 25639873. Pmcid: PMC4688902.
  • Griffin PT, Ho VQ, Fulp W, Nishihori T, Shain KH, Alsina M, Baz RC. A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma. Cancer. 2015 Oct;121(20):3622-3630. Pubmedid: 26149422.
  • Nishihori T, Baz R, Shain K, Kim J, Ochoa-Bayona JL, Yue B, Sullivan D, Dalton W, Alsina M. An open-label phase I/II study of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed myeloma. Eur J Haematol. 2015 Nov;95(5):426-435. Pubmedid: 25600676. Pmcid: PMC4508238.
  • Fang B, Hoffman MA, Mirza AS, Mishall KM, Li J, Peterman SM, Smalley KS, Shain KH, Weinberger PM, Wu J, Rix U, Haura EB, Koomen JM. Evaluating kinase ATP uptake and tyrosine phosphorylation using multiplexed quantification of chemically labeled and post-translationally modified peptides. Methods. 2015 Jun;81:41-49. Pubmedid: 25782629. Pmcid: PMC4460980.
  • Silva A, Jacobson T, Meads M, Distler A, Shain K. An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells. J Vis Exp. 2015 Jul;(101):e53070. Pubmedid: 26274375. Pmcid: PMC4544963.
  • Nishihori T, Hassoun Y, Zhang L, Shain K, Alsina M, Kharfan-Dabaja MA. High-dose melphalan produces favorable response in a patient with multiple myeloma and coexisting essential thrombocythemia with JAK2 mutation. Bone Marrow Transplant. 2014 Jan;49(1):148-149. Pubmedid: 23933759.
  • Khin ZP, Ribeiro ML, Jacobson T, Hazlehurst L, Perez L, Baz R, Shain K, Silva AS. A preclinical assay for chemosensitivity in multiple myeloma. Cancer Res. 2014 Jan;74(1):56-67. Pubmedid: 24310398. Pmcid: PMC3915502.
  • Baz RC, Shain KH, Hussein MA, Lee JH, Sullivan DM, Finleyoliver E, Nardelli LA, Nodzon LA, Zhao X, Ochoa-Bayona JL, Nishihori T, Dalton WS, Alsina M. Phase II study of pegylated liposomal doxorubicin, low-dose dexamethasone, and lenalidomide in patients with newly diagnosed multiple myeloma. Am J Hematol. 2014 Jan;89(1):62-67. Pubmedid: 24030918. Pmcid: PMC4522918.
  • Shain KH, Tao J. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies. Oncogene. 2014 Aug;33(32):4107-4113. Pubmedid: 24037527. Pmcid: PMC4669099.
  • Baz R, Miladinovic B, Patel A, Ho VQ, Shain KH, Alsina M, Nishihori T, Ochoa-Bayona JL, Sullivan DM, Dalton WS, Djulbegovic B. Sequence of novel agents in multiple myeloma: an instrumental variable analysis. Leuk Res. 2013 Sep;37(9):1077-1082. Pubmedid: 23809054.
  • Nishihori T, Ochoa-Bayona JL, Kim J, Pidala J, Shain K, Baz R, Sullivan D, Jim HS, Anasetti C, Alsina M. Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma. Bone Marrow Transplant. 2013 Sep;48(9):1179-1184. Pubmedid: 23542223. Pmcid: PMC4500071.
  • Boucher K, Parquet N, Widen R, Shain K, Baz R, Alsina M, Koomen J, Anasetti C, Dalton W, Perez LE. Stemness of B-cell progenitors in multiple myeloma bone marrow. Clin Cancer Res. 2012 Nov;18(22):6155-6168. Pubmedid: 22988056. Pmcid: PMC3500436.
  • Sugimori C, Padron E, Caceres G, Shain K, Sokol L, Zhang L, Tiu R, O'Keefe CL, Afable M, Clemente M, Lee JM, Maciejewski JP, List AF, Epling-Burnette PK, Araten DJ. Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. Blood Cancer J. 2012 Mar;2(3):e63. Pubmedid: 22829258. Pmcid: PMC3317526.
  • Nishihori T, Alekshun TJ, Shain K, Sullivan DM, Baz R, Perez L, Pidala J, Kharfan-Dabaja MA, Ochoa-Bayona JL, Fernandez HF, Yarde DN, Oliveira V, Fulp W, Han G, Kim J, Chen DT, Raychaudhuri J, Dalton W, Anasetti C, Alsina M. Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma. Brit J Haematol. 2012 Jun;157(5):553-563. Pubmedid: 22449149. Pmcid: PMC4030553.
  • Shain K. Metastatic myeloma?. Blood. 2012 Jun;119(24):5612-5613. Pubmedid: 22700691.
  • Xiang Y, Remily-Wood ER, Oliveira V, Yarde D, He L, Cheng JQ, Mathews L, Boucher K, Cubitt C, Perez L, Gauthier TJ, Eschrich SA, Shain KH, Dalton WS, Hazlehurst L, Koomen JM. Monitoring a nuclear factor-κB signature of drug resistance in multiple myeloma. Mol Cell Proteomics. 2011 Nov;10(11):M110.005520. Pubmedid: 21846842. Pmcid: PMC3226396.
  • Lebovic D, Zhang L, Alsina M, Nishihori T, Shain KH, Sullivan D, Ochoa-Bayona JL, Kharfan-Dabaja MA, Baz R. Clinical outcomes of patients with plasma cell leukemia in the era of novel therapies and hematopoietic stem cell transplantation strategies: a single-institution experience. Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):507-511. Pubmedid: 21813352.
  • Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA, Dalton WS. Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res. 2009 Feb;69(3):1009-1015. Pubmedid: 19155309. Pmcid: PMC2680075.
  • Yarde DN, Oliveira V, Mathews L, Wang X, Villagra A, Boulware D, Shain KH, Hazlehurst LA, Alsina M, Chen DT, Beg AA, Dalton WS. Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 2009 Dec;69(24):9367-9375. Pubmedid: 19934314. Pmcid: PMC4519834.
  • Shain KH, Dalton WS. Environmental-mediated drug resistance: a target for multiple myeloma therapy. Expert Rev Hematol. 2009 Dec;2(6):649-662. Pubmedid: 21082957.
  • Perez L, Parquet N, Shain K, Nimmanapalli R, Alsina M, Anasetti C, Dalton W. Bone Marrow Stroma Confers Resistance to Apo2 Ligand/TRAIL in Multiple Myeloma inPart by Regulating c-FLIP. J Immunol. 2008 Feb;180(3):1545-1555. Pubmedid: 18209050.
  • Burdelya L, Kujawski M, Niu G, Zhong B, Wang T, Zhang S, Kortylewski M, Shain K, Kay H, Djeu J, Dalton W, Pardoll D, Wei S, Yu H. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J Immunol. 2005 Apr;174(7):3925-3931. Pubmedid: 15778348. Pmcid: PMC2632804.
  • Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004;10(1):48-54. Pubmedid: 14702634.
  • Dalton W, Hazlehurst L, Shain K, Landowski T, Alsina M. Targeting the bone marrow microenvironment in hematologic malignancies. Semin Hematol. 2004;41(2):1-5. Pubmedid: 15190509.
  • Hazlehurst L, Enkemann S, Beam C, Argilagos R, Painter J, Shain K, Saporta S, Boulware L, Moscinski L, Alsina M, Dalton W. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res. 2003 Nov;63(22):7900-7906. Pubmedid: 14633719.
  • Chen T, Yang I, Irby R, Shain K, Wang H, Quackenbush J, Coppola D, Cheng JQ, Yeatman T. Regulation of caspase expression and apoptosis by adenomatous polyposis coli. Cancer Res. 2003;63(15):4368-4374. Pubmedid: 12907606.
  • Shain K, Landowski T, Dalton W. Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J Immunol. 2002;168(5):2544-2553. Pubmedid: 11859150.
  • Shain K, Dalton W. Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new targets for the prevention of acquired MDR. Mol Cancer Ther. 2001;1(1):69-78. Pubmedid: 12467240.
  • Niu G, Shain K, Huang M, Ravi R, Bedi A, Dalton W, Jove R, Yu H. Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res. 2001;61(8):3276-3280. Pubmedid: 11309279.
  • Shain KH, Landowski TH, Buyuksal I, Cantor AB, Dalton WS. Clonal variability in CD95 expression is the major determinant in Fas-medicated, but not chemotherapy-medicated apoptosis in the RPMI 8226 multiple myeloma cell line. Leukemia. 2000 May;14(5):830-840. Pubmedid: 10803514.
  • Shain K, Landowski T, Dalton W. The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance. Curr Opin Oncol. 2000;12(6):557-563. Pubmedid: 11085455.
  • Anderson K, Kyle R, Dalton W, Landowski T, Shain K, Jove R, Hazlehurst L, Berenson J. Multiple Myeloma: New Insights and Therapeutic Approaches. Hematology Am Soc Hematol Educ Program. 2000;147-165. Pubmedid: 11701540.
  • Shain K, Jove R, Olashaw N. Constitutive Rel B activity in v-Src transformed fibroblasts: requirement for lkB degradation. J Cell Biochem. 1999 May;73(2):237-247. Pubmedid: 10227387.
  • Landowski T, Shain K, Oshiro M, Buyuksal I, Painter J, Dalton W. Myeloma cells selected for resistance to CD95-mediated apoptosis are not cross-resistant to cytotoxic drugs: evidence for independent mechanisms of caspase activation. Blood. 1999 Jul;94(1):265-274. Pubmedid: 10381522.
  • Azizan A, Cong Y, Shain K, Tsai S, Olashaw N, Seto E. Transactivation by expression of the hepatitis B virus X protein with an inducible system. Mol Biol Rep. 1998;25(4):231-236. Pubmedid: 9870613.