Advances in Hematologic Malignancies Issue 2 Spring 2013
Multiple myeloma (MM) is a remarkable contemporary example of rapid bench-to-bedside translation in new drug development. Our laboratory and animal studies showed that the proteasome inhibitor bortezomib (Velcade - V) and immunomodulatory drug (IMiD) lenalidomide (Revlimid, R) target MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance. We then translated these studies to clinical trials as initial, consolidation, salvage, and maintenance therapy, which have already extended patient survival two- to three-fold from what it was in the 1990s, before these agents were available.
Combinations of targeted therapies such as RV with dexamethasone (RVD) achieve unprecedented rates and depth of responses, and the role of high-dose therapy and stem cell transplantation is being re-evaluated in the context of these universal responses. Immune-based therapies under development include elotuzumab (anti-CS1) and daratumumab (anti-CD38) monoclonal antibodies (MoAbs), as well as MM cell-dendritic cell vaccines and CD138, CS-1, and XBP-1 peptide vaccines. Next-generation targeted agents include deubiquitinating enzyme inhibitors to target protein degradation upstream of the proteasome and overcome proteasome inhibitor resistance;chymotryptic (carfilzomib, opromazib, ixazomib) and more broad (marizomib) proteasome inhibitors; and next-generation IMiD pomalidomide.
Ubiquitin proteasome system function is mediated via a large number of indicated components, suggesting many potential sites of pharmacological intervention. The schema shows second-generation inhibitors of the ubiquitin proteasome pathways and their targets; these agents are now in pre-clinical and clinical studies.
Rationally-based combination therapies include proteasome inhibitors (carfilzomib, opromazib, ixazomib marizomib) with IMiDs (lenalidomide and pomalidomide) to trigger dual apoptotic signaling; MoAbs elotuzumab and daratumumab with IMiDs, which upregulate antibody dependent cellular cytotoxicity; and proteasome inhibitors (e.g., carfilzomib, opromazib, ixazomib) with histone deacetylase (HDAC) inhibitors (e.g., vorinostat, panobinostat, and ACY1215) to block proteasomal and aggresomal degradation of protein, respectively. Clinical trials with many of these agents and combinations are ongoing at Dana-Farber.
Finally, we are using genomics for both development of personalized therapy and new target discovery. Gene profiling, microRNA profiling, and DNA-based single nucleotide polymorphism array studies can predict prognosis, but no universal signature is established. Gene sequencing studies reveal mutated genes in processes consistent with MM biology, including protein homeostasis, NF-κB signaling, interferon regulatory factor 4 and Blimp, and histone methylating enzymes, as well as unexpected BRAF mutations, as in melanoma.
Oncogenomic studies have identified novel target and targeted therapies which have been validated in our models of MM in the BM milieu, including bromodomain inhibitors and Btk inhibitors, both of which are entering clinical trials. Importantly, personalized medicine must include profiling of patient samples not only at diagnosis but also over time, as our early studies now show continued evolution of genetic changes with progressive MM.
Myeloma therefore represents a paradigm of targeting the tumor in its microenvironment. Exploitation of rational targets identified in myeloma has already markedly improved patient outcome in MM, and has great potential in other hematologic malignancies and solid tumors, as well.
— Dharminder Chauhan, JD, PhD, and Teru Hideshima, MD, PhD, senior scientists in the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) Jerome Lipper Multiple Myeloma Center and LeBow Family Institute for Myeloma Therapeutics, and Kenneth C. Anderson, MD, director of the DF/BWCC Jerome Lipper Multiple Myeloma Center and Lebow Institute for Myeloma Therapeutics
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