Kenneth H. Shain, MD, PhD

Dr. Shain and colleagues propose that characterization of signaling incited by the bone marrow niche and of novel mechanisms of resistance (both de novo and acquired multidrug resistance) will facilitate development of therapeutic regimens for multiple myeloma and other malignancies.They demonstrated that interleukin (IL)-6 and FN adhesion collaborate to specifically enhance STAT3 activity with resultant increase in malignant potential via a novel ß1 integrin-mediated preloading of gp130 with non-phosphorylated STAT3, priming gp130 for signaling. The researchers continue to elucidate the mechanism(s) mediating this novel regulation of STAT3 in co-stimulated cells and have proposed that the enhanced STAT3 activity facilitated by the collaboration of IL-6 and FN-adhesion involves adhesion-mediated raft formation and redistribution of ß1 integrins, gp130 and STAT3 to lipid raft signaling microdomains. These studies may identify novel targets for the development of therapeutic strategies focusing on the abrogation of proliferative and survival effects of the bone marrow niche.In another research effort, Dr. Shain and colleagues demonstrated that transcriptional regulation of the Fanconi anemia (FA)/BRCA DNA repair pathway is an important mediator of resistance to melphalan in myeloma cells.

• 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 Apr. Pubmedid: 23542223.
• 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.
• Shain K. Metastatic myeloma?. Blood. 2012 Jun;119(24):5612-5613. Pubmedid: 22700691.
• 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. Br J Haematol. 2012 Jun;157(5):553-563. Pubmedid: 22449149.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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;63(22):7900-7906. Pubmedid: 14633719.
• 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.
• 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 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.
• 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.
• 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, 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.
• Shain K, Jove R, Olashaw N. Constitutive Rel B activity in v-Src transformed fibroblasts: requirement for lkB degradation. J Cell Biochem. 1999;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;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.