Combination Therapy of Bortezomib with Novel Targeted Agents: an Emerging Treatment Strategy

Published OnlineFirst August 3, 2010; DOI: 10.1158/1078-0432.CCR-09-2882 Review Clinical Cancer Research Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy John J. Wright Abstract Clinical trials evaluating combinations of targeted agents with bortezomib, the first-in-class proteasome inhibitor, have been initiated, with the objective of enhancing its single agent activity in hematologic malignancies (myeloma, mantle cell lymphoma), as well as expanding its efficacy in solid tumors. In most cases, preclinical studies have provided a supportive rationale for designing these doublet combination studies. Novel, small molecule–targeted agents being investigated with bortezomib in clinical trials include protein deacetylase inhibitors, kinase inhibitors, farnesyltransferase inhibitors, heat-shock protein 90 inhibitors, pan-Bcl-2 family inhibitors, and other classes of targeted inhibitors. Preliminary clinical data, available from a number of ongoing trials, suggest that most of these combinations are well tolerated and some have promising clinical efficacy that will require subsequent confirmation. Translational studies, conducted as part of the trials, may provide important insights into the putative mechanism of action delineated by preclinical studies of the combinations. The emergence of novel proteasome inhibitors may also expand the opportunities for optimizing these combination therapies. There is potential for an increasingly broad clinical trials program to investigate this therapeutic approach in a range of tumor types, as well as to consider additional agents in sequence or in combination. Clin Cancer Res; 16(16); 4094–104. ©2010 AACR. The complex and heterogeneous array of genomic and Pharmaceuticals Research & Development, L.L.C.). Bortezo- epigenetic alterations that has been identified in many tu- mib has been approved by the U.S. Food and Drug Admin- mors, and is associated with a multitude of processes (pro- istration (FDA) for multiple myeloma (MM; refs. 1–3), and liferation, metastasis, chemoresistance) critical for cancer recently for relapsed mantle cell lymphoma (MCL; ref. 4). progression, has shaped an emerging consensus that com- It has generally been ineffective as monotherapy for the bination strategies employing multiple targeted agents treatmentofawidevarietyofsolidtumors.Bortezomib, warrant evaluation as an important therapeutic strategy. through inhibition of the 26S proteasome and subsequent Numerous small molecule–targeted therapies with inde- effect on multiple key cellular pathways, has shown pendent mechanisms of action that inhibit key cellular increased and/or synergistic activity with several novel tar- proteins or signaling pathways in various cancers are cur- geted agents, indicating its potential to substantially en- rently in development. Doublet combinations of targeted hance the clinical activity of these novel therapies. Most of therapies are being assessed in a variety of tumors, usually the clinical trials of these combinations were initiated as a testing two agents that have different targets, nonoverlap- result of relevant in vitro studies, which have provided a sup- ping toxicity, and some rationale for evaluation (preclini- portive scientific rationale. An increase in the number of cal activity or clinical efficacy). these studies is expected in coming years, on the basis of This review focuses on the clinical development pro- emerging data with new agents, which is expanding our un- gram assessing combinations of targeted agents with the derstanding of the molecular pathways important in cancer first-in-class proteasome inhibitor bortezomib (VELCADE, progression. Millennium Pharmaceuticals, Inc. and Johnson & Johnson Bortezomib Author's Affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland Bortezomib is a dipeptidyl boronic acid analog that Note: Supplementary data for this article are available at Clinical Cancer reversibly inhibits the 26S proteasome by binding to N- Research Online (http://clincancerres.aacrjournals.org/). terminal threonine residues in the active site of the chymo- Corresponding Author: John J. Wright, Investigational Drug Branch, trypsin-like catalytic region (5). As reviewed elsewhere, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 6130 Executive Boulevard, EPN proteasome inhibition results in anticancer activity 7122, Bethesda, MD 20892. Phone: 301-496-1196; Fax: 301-402-0428; through several different mechanisms, including disrup- E-mail: [email protected]. tion of cell cycle progression, induction of apoptosis, inhi- doi: 10.1158/1078-0432.CCR-09-2882 bition of proliferation, and anti-angiogenesis (6). The key ©2010 American Association for Cancer Research. proteins and signaling pathways affected, and subsequent 4094 Clin Cancer Res; 16(16) August 15, 2010 Downloaded from clincancerres.aacrjournals.org on October 8, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst August 3, 2010; DOI: 10.1158/1078-0432.CCR-09-2882 Bortezomib in Combination with Novel Targeted Agents models have been tested with the various novel combina- Translational Relevance tions (10). Table 1 provides an overview, and Supplemen- tary Table S2 provides a detailed summary, of the ongoing The expanding early-phase clinical trial program of early-phase clinical trial program of these combination re- a broad range of bortezomib-based combinations gimens, which are reviewed below. with novel targeted agents, including histone deacetylase inhibitors, kinase inhibitors, farnesyltransferase Histone deacetylase inhibitors inhibitors, heat-shock protein 90 inhibitors, and the Histone deacetylase inhibitors (HDACi) are a class of pan-Bcl-2 family inhibitors, is reviewed. Early clinical cancer therapeutic agents that regulate gene expression data may identify new therapeutic strategies and pro- by globally increasing histone acetylation (11). The anti- vide an opportunity for an increasingly broad clinical tumor activity of HDACi involves multiple mechanisms, trials program to investigate this therapeutic approach including transcriptional upregulation of genes involved in a range of tumor types, particularly hematologic in apoptosis, cell cycle control, DNA repair, and differen- malignancies. tiation (12). HDACi also induce acetylation of nonhistone Ongoing translational research will help validate proteins, which may contribute to antitumor activity (13). preclinical findings and improve our understanding A structurally diverse group of compounds with varying of the molecular mechanisms of various cancer types, specificity against the spectrum of identified histone dea- the relevance of pathways to cancer survival, and the cetylases has been identified, and preclinical studies indi- molecular and/or genetic markers associated with re- cate that these agents have potent anticancer activities sponse and/or outcome with bortezomib and novel (11). One HDACi, vorinostat, has been approved by the targeted therapies. Such information may allow devel- FDA for the treatment of cutaneous T-cell lymphoma opment of combination regimens optimized for spe- (14). Clinical trials are currently evaluating the combina- cific tumor subtypes, providing tailored therapy for tion of bortezomib with at least four HDACi: vorinostat, individual patients on the basis of the molecular belinostat, panobinostat, and romidepsin (Table 2). and/or genetic characteristics of their disease. Preclinical assessments of combinations of bortezomib and HDACi have identified several potential mechanisms resulting in synergistic antitumor activity: cellular effects, are summarized in Fig. 1. Bortezomib is 1. Nuclear factor-κB (NF-κB) effects: Bortezomib blocks preclinically active in many hematologic and solid malig- IκBα degradation, inhibiting NF-κB activation and nancies as a single agent and enhances the activity of many diminishing expression of NF-κB target genes. These chemotherapy agents in models of MM, acute leukemia, effects enhance the antitumor lethality of HDACi as and lung and pancreatic cancers (6). manifested by enhanced HDACi-mediated reactive Bortezomib can overcome or reverse chemoresistance oxygen species and apoptosis in MM (15), non– and increase sensitivity to specific agents, including mel- small cell lung carcinoma (NSCLC; ref. 16), chronic phalan, doxorubicin, mitoxantrone, and dexamethasone lymphocytic leukemia (17), MCL (18) cell lines, and (7). Such enhanced activity in combination has translated imatinib-resistant leukemia cells (19). into substantial clinical activity in large clinical trials; for 2. Aggresome disruption: Aggresome formation, depen- example, bortezomib plus liposomal doxorubicin has dent on HDAC 6, is induced as a cytoprotective re- been approved in relapsed MM (8), and on the basis of sponse to the increasing burden of misfolded the pivotal VISTA trial with bortezomib, melphalan, and proteins created by bortezomib treatment of cancer prednisone in newly diagnosed MM, bortezomib has cells. Inhibition of HDAC 6 activity by HDACi, like recently been approved for the treatment of newly diag- vorinostat or tubacin leads to aggresome disruption nosed MM patients (9). These findings indicate the broad and inactivation with subsequent onset of apoptosis value of proteasome inhibition as a strategy for substan- in pancreatic cancer cells (20) and MM cells (21). tially increasing antitumor activity. 3.

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