Toward the objective of Growth Control in MM, Project 1 continues its path of translational research based on the concept that control of a malignancy with enornnous genomic instability requires effective interference with redundant escape mechanisms via multi-targeted combination therapy as delivered in Total Therapy (TT). Unprecedented success in gene expression profiling (GEP)-defined low-risk and lack of substantive progress in high-risk MM provided the rationale for adopting a risk-based treatment approach in Aim 1, hypothesizing that overall progress in MM growth control can be accelerated by GEP-defined riskbased therapies. TT4 for low-risk MM emphasizes reduction of morbidity while retaining TT3 efficacy with 4- yr continuous CR estimates of 90%. Appreciating MM re-growth during prolonged treatment recovery phases of TT3 as a mechanism of treatment failure, TT5 for high-risk MM will apply dose-dense but less doseintense therapy to provide quasi-continuous exposure to 8-drug synergistic combinations as a means of avoiding host exhaustion. Translational research emphasizes pharmacogenomic studies into the mechanisms of action of bortezomib and, for the first time, of melphalan, whose synergistic interaction with novel agents will be maximally exploited. Taking full advantage of the enormous repository of protocolspecified serial GEP samples and imaging studies in TT2 and TT3, follow-up over the next 5 years will enable us to test the hypothesis that therapeutic success in TT3 compared with TT2 can be explained in the context of MM-microenvironment (ME) interaction revealed by GEP studies of both MM and the ME.
Aim 2 will interrogate the MM-ME interaction viewed as critical toward disease manifestation, progression, and therapeutic response. We expect to unravel resistance mechanisms due to expansion of primary resistant tumor subpopulations or secondary transformation events with high LDH and human myeloma cell line (HMCL) signatures; derive 'cure signatures' for patients in continuous CR for more than 7 yr; identify thalidomide and bortezomib beneficiaries toward future individualized therapy; determine whether drug (bortezomib, melphalan) test-dose induced GEP alterations provide insight into molecular disease evolution; determine whether reactivation of tumor dormancy at focal lesion sites is responsible for late and unexpected relapses; and elucidate whether and how myeloma cells may uniquely interact, in a molecular subtype-specific fashion, with the ME and thus contribute to disease manifestation and progression events.
This will be the first time in MM clinical trial research that a prognostic tool as powerful as gene expression profiling will be used for selecting patients for two separate risk-based protocols. Toward truly individualized therapies in the future, single institution resources generated during 2 decades of comprehensively conducted and translationally directed therapy will be crucial toward identifying more generally applicable simpler surrogate tools for selecting maximally effective therapies tailored to the individual patient.
|Alagpulinsa, David A; Ayyadevara, Srinivas; Yaccoby, Shmuel et al. (2016) A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition. Mol Cancer Ther 15:241-50|
|McDonald, James E; Kessler, Marcus M; Gardner, Michael W et al. (2016) Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma. Clin Cancer Res :|
|VÃ¥tsveen, Thea Kristin; Sponaas, Anne-Marit; Tian, Erming et al. (2016) Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro. J Hematol Oncol 9:75|
|Pawlyn, Charlotte; Kaiser, Martin F; Heuck, Christoph et al. (2016) The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. Clin Cancer Res 22:5783-5794|
|Weinhold, Niels; Ashby, Cody; Rasche, Leo et al. (2016) Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 128:1735-44|
|Jethava, Yogesh; Mitchell, Alan; Epstein, Joshua et al. (2016) Adverse metaphase cytogenetics can be overcome by adding bortezomib and thalidomide to fractionated melphalan transplants. Clin Cancer Res :|
|Weinhold, N; Heuck, C J; Rosenthal, A et al. (2016) Clinical value of molecular subtyping multiple myeloma using gene expression profiling. Leukemia 30:423-30|
|Pawlyn, C; Fowkes, L; Otero, S et al. (2016) Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? Leukemia 30:1446-8|
|Heuck, C J; Jethava, Y; Khan, R et al. (2016) Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 30:976-80|
|Mitchell, Jonathan S; Li, Ni; Weinhold, Niels et al. (2016) Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun 7:12050|
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