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

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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. Endoplasmic reticulum stress response: The unfolded protein response, an evolutionarily conserved Bortezomib in Combination with Novel adaptive response, is overwhelmed in response to Targeted Therapies the combined insults of bortezomib (increased unfolded proteins, ref. 22; NF-κB inactivation) and Combinations of bortezomib and novel targeted thera- HDACi. This response triggers events leading to a pies may act synergistically to increase antitumor activity striking increase in mitochondrial injury, caspase and overcome specific cellular resistance and/or anti- activation, and apoptosis, in some cases character- apoptotic mechanisms. Preclinical data on combinations ized by increased production of Bcl-Xs accompanied of bortezomib and novel targeted therapies currently being by activation of Bid and production of caspase- investigated are summarized in Supplementary Table S1, 8 and -3 (23). together with possible mechanisms responsible for the en- The combination of bortezomib and vorinostat has hanced activity of each combination. As yet, few resistant been the most extensively studied. A phase III trial

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Fig. 1. The intracellular pathways and proteins affected by proteasome inhibition with bortezomib. Abbreviations: JNK, c-Jun N-terminal kinase; Ros, reactive oxygen species. Adapted from Boccadoro et al. (6).

(NCT00773747) of this doublet is evaluating a conven- Two other HDACi, panobinostat and romidepsin, are also tional bortezomib dose and schedule with 400 mg of vor- being assessed in combination with bortezomib in phase I inostat on days 1 through 14 of a 21-day cycle in patients trials enrolling patients with relapsed and/or refractory with relapsed and/or refractory MM (one to two prior MM (NCT00431990). Both trials included dexamethasone treatments). This definitive study was initiated after two at some point in the treatment, and accrued patients pre- phase I dose-escalation trials (24, 25) of bortezomib-vor- viously treated with bortezomib. Several responses includ- inostat in relapsed and/or refractory MM (NCT00310024 ing one immunofixation negative complete response and NCT00111813) established that vorinostat and borte- (CR), one VGPR, and three PR were noted in 14 patients zomib were well tolerated (nausea, diarrhea, thrombocy- entered in early cohorts of the panobinostat trial (27). topenia most common toxicities), and 18 out of 55 Bortezomib-romidepsin and dexamethasone treatment in- evaluable patients (33%) achieved a very good partial re- duced a CR in one patient and at least a PR in 7 out of 10 sponse (VGPR) or partial response (PR). Approximately patients (70%), although transient thrombocytopenia was 40% of patients with prior bortezomib therapy also had problematic (28). a response (24). In total, five phase I dose-escalation studies of bortezomib-vorinostat in MM or solid tumor pa- Kinase inhibitors tients, assessing a variety of administration schedules for Cyclin-dependent kinase inhibitors alvocidib and both agents, are ongoing or completed. In a phase I study PD0332991. Alvocidib is a small molecule, pan-cyclin– of patients with unresectable or metastatic solid tumors dependent kinase (CDK) inhibitor that can induce cell (NCT00227513), objective responses were noted in two cycle arrest and apoptosis, as well as downregulate cyclin patients, one with a soft tissue sarcoma (PR lasting >9 D1 and vascular endothelial growth factor (VEGF). Alvo- months) and an NSCLC patient. Because this study sug- cidib was the first potent CDK inhibitor to enter clinical gested that the bortezomib-vorinostat combination may trials and has shown promising activity in patients with be efficacious in solid tumors, a number of phase II trials CLL (29). are evaluating the regimen in NSCLC (NCT00798720), gli- The combination of bortezomib and alvocidib has been oma (NCT00641706), and non-Hodgkins lymphomas evaluated in hematopoietic cell lines using clinically (NHL; NCT00703664). achievable levels of both agents. In Bcr/Abl-positive chron- Bortezomib-belinostat is being investigated in a phase I ic myelogenous leukemia cell lines, sensitive and resistant trial of patients with advanced solid tumors or lympho- to imatinib, bortezomib-alvocidib synergistically in- mas (NCT00348985). The maximum tolerated dose creased mitochondrial dysfunction and apoptosis through (MTD) for this combination has not yet been established, inactivation of the NF-êB and signal transducer and activa- although modest antitumor activity has been reported tor of transcription 3 and 5 (STAT3 and STAT5) pathways (26). A phase II study evaluating bortezomib-belinostat (30). Only the combination, not the single agents, in- in relapsed and/or refractory MM (NCT00431340) was duced apoptosis, decreased myeloid cell leukemia 1 pro- stopped early because of dose-limiting toxicity (DLT). tein (Mcl-1) expression, and increased proapoptotic Bak

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in anaplastic large cell lymphoma cell lines, and similar Other kinase inhibitors. Several other kinase inhibitors results were noted in other leukemic (31) and MCL lines that induce enhanced antitumor activity with bortezomib (32). Sequence-dependent addition of bortezomib prior in preclinical models are also being investigated in early- to alvocidib enhanced apoptosis induction in MM cell phase clinical trials. Bortezomib is being evaluated with lines compared with single agent treatment (33). temsirolimus (CCI-779), which is approved for the treat- The bortezomib-alvocidib combination regimen is be- ment of renal cell cancer (42), and everolimus (RAD001): ing assessed in a phase I, dose-escalation study treating two small molecule inhibitors of the mammalian target of patients with recurrent or refractory indolent B-cell neo- rapamycin (mTOR) kinase, which is an intermediate of plasms (NCT00082784). Twice weekly bolus and hybrid the phosphoinositide 3-kinase (PI3K)/Akt/mTor signaling infusion schedules of alvocidib, following bortezomib pathway. Both temsirolimus and everolimus have shown administration, are being tested. An MTD has been es- significant in vitro antitumor and in vivo cytostatic activity tablished for the bolus administration regimen, and en- in xenograft models of NHL and MM, alone, and in combi- couraging antitumor activity included responses in nation with bortezomib (43, 44). Bortezomib-temsirolimus, bortezomib-refractory patients: two lymphoma patients both administered on a weekly schedule, is being eval- hadaCRandseven(fiveMMandtwoNHL)hada uated in a phase I–II trial in relapsed and/or refractory PR (34). Similar assessment of the hybrid alvocidib ad- MM (NCT00483262). The identified MTD was temsiroli- ministration schedule is ongoing. mus 25 mg and bortezomib 1.6 mg/m2, and the overall PD0332991 is an orally bioavailable selective inhibitor response (CR + PR + minimal response) was 33% (5 out of CDK 4 and CDK 6. Proteasome inhibitors and of 15 patients) in patients who had all been previously PD032991 have synergistic antitumor activity in MM treated with bortezomib (45). Bortezomib is also being models (35). A phase I study in relapsed and/or refractory evaluated in combination with the orally bioavailable MM patients evaluating two different administration sche- mTor inhibitor everolimus, in a phase I study of patients dules is underway (36). with relapsed and/or refractory MCL and other indolent Sorafenib and sunitinib. Sorafenib is an oral multikinase lymphomas (NCT0067112). inhibitor of RAF kinase, VEGF receptors 1, 2, and 3, Proteasome inhibition may activate epidermal growth platelet-derived growth factor receptor β (PDGFRβ), Flt-3, factor receptor (EGFR)–dependent mitogenic signaling c-Kit, and RET receptor tyrosine kinases, which is approved and sensitize cells to EGFR inhibition. The effects of co- for the treatment of advanced renal cell carcinoma (37) treating NSCLC cell lines with bortezomib and either gefi- and hepatocellular carcinoma (38). Sorafenib can inhibit tinib, erlotinib, or cetuximab have been examined in tumor growth and angiogenesis, as well as induce apopto- EGFR-expressing cell line models, and, in some cases, sis in a cell context-specific manner, through either Raf- the combinations have shown synergistic activity (46, MAP/ERK kinase (MEK)-mitogen-activated protein kinase 47). A phase I clinical trial combining bortezomib with ce- (MAPK)–dependent or –independent pathways. The bor- tuximab in advanced solid tumors (NCT00622674) and a tezomib-sorafenib combination synergistically induced a phase II study of bortezomib-erlotinib in relapsed and/or marked increase in mitochondrial injury and apoptosis, refractory NSCLC (NCT00283634) have been initiated. requiring Akt inhibition, in multiple human tumor cell The latter trial was closed on the basis of insufficient anti- lines (39). tumor activity (48). The combination of bortezomib-sorafenib is being in- A phase I study combining dasatinib with bortezomib is vestigated in two phase I trials. A study in advanced solid being conducted in patients with relapsed and/or refracto- tumor patients (NCT00303797) assessed sorafenib and ry MM (NCT00560352). Dasatinib, a multitargeted inhib- twice weekly bortezomib. Full doses of either agent could itor of c-abl, src family proteins, EphA2, and btk, is not be administered; an MTD of sorafenib 200 mg twice approved for the treatment of chronic myelogenous leuke- daily, and bortezomib 1 mg/m2 was identified. DLT in- mia (49). Preclinical studies of this combination in mye- cluded abdominal pain with hyperamylasemia and vomit- loma cell lines indicate there is synergistic antitumor ing. One patient with renal cancer had a PR, and four activity (50), and a phase I trial in MM (NCT00560352) patients were reported to have stable disease (40). Admin- is ongoing. istration of bortezomib on a weekly schedule in combina- Perifosine (KRX-0401) is an orally bioavailable signal tion with sorafenib in patients with relapsed or refractory transduction modulator with multiple effects, including MM is being assessed in a second trial (NCT00536575). inhibition of Akt. The combination of perifosine and bor- Sunitinib is another oral multikinase inhibitor with a tezomib has been assessed in myeloma and prostate cell wide spectrum of inhibitory activity [including VEGFR, line models (51–53). Perifosine is being investigated in PDGFR, fibroblast growth factor receptor (FGFR), c-kit, combination with bortezomib ± dexamethasone in a FLT3, and others], which has been approved for the treat- phase I–II study in patients with MM, all of whom are re- ment of renal cell carcinoma and gastrointestinal stromal lapsed or refractory to previous bortezomib therapy tumor (41). Bortezomib and sunitinib are being evaluated (NCT00401011). Results from this study indicate that in a phase I solid tumor patient study (NCT00720148), perifosine-bortezomib (±dexamethasone) is highly active and are being administered in a 6-week cycle with 4 weeks and well tolerated; overall response for 57 evaluable pa- of drug administration followed by 2 weeks of rest. tients was 40%, including 4% who achieved a CR (54).

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Table 1. Ongoing clinical trials program of bortezomib in combination with novel targeted agents

Class and/or agent Study and tumor types

HDACi Vorinostat • Phase I dose-escalation study in metastatic or unresectable solid tumors • Phase I dose-escalation study in relapsed or refractory MM • Phase I dose-escalation study in surgically resectable stage IB-IIIA NSCLC • Phase I dose-escalation study in advanced MM • Phase II study in progressive, recurrent glioblastoma • Phase II study in MCL and diffuse large B-cell lymphomas • Phase II study in NSCLC • Phase II study in relapsed and/or refractory MM • Phase III study in relapsed and/or refractory MM Belinostat • Phase I dose-escalation study in advanced solid tumors or lymphomas Panobinostat • Phase I dose-escalation study in relapsed MM Romidepsin • Phase I–II study in relapsed and/or refractory MM • Phase II study in relapsed and/or refractory MM with prior bortezomib therapy Kinase inhibitor Alvocidib • Phase I dose-escalation study in recurrent or refractory indolent B-cell neoplasms PD0332991 (CDK4/6 inhibitor) • Phase I–II study in relapsed and/or refractory MM Sorafenib • Phase I dose-escalation study in advanced solid tumors and MM or chronic lymphocytic leukemia • Phase I–II study in relapsed and/or refractory MM Sunitinib • Phase I dose-escalation study in chemorefractory advanced solid tumors Temsirolimus • Phase I–II study in relapsed and/or refractory MM Everolimus • Phase I dose-escalation study in relapsed and/or refractory MCL, other indolent non-Hodgkin's lymphoma Erlotinib • Phase II study in relapsed and/or refractory metastatic NSCLC Cetuximab • Phase I dose-escalation study in advanced solid tumors Dasatinib • Phase I study in relapsed and/or refractory MM Perifosine • Phase I–II study in relapsed and/or refractory MM (patients with prior progression on bortezomib treatment) Farnesyl transferase inhibitor Tipifarnib • Phase I dose-escalation study in advanced acute leukemias or chronic myelogenous leukemia in blast phase • Phase I–II study in newly diagnosed acute myeloid lymphoma ineligible for cytotoxic chemotherapy or in first relapse • Phase l dose-escalation study in relapsed and/or refractory MM HSP90 chaperone inhibitor Tanespimycin • Phase I dose-escalation study in advanced solid tumors or lymphoma • Phase I dose-escalation study in relapsed and/or refractory hematologic malignancies • Phase III study in MM after first relapse • Phase II–III study in relapsed and/or refractory MM (at least three prior therapies) AUY-922 • Phase I–II study in relapsed and/or refractory MM (one prior therapy) Other targets Pan-Bcl-2 family • Phase I–II study in MCL inhibitor obatoclax • Phase I–II study in relapsed and/or refractory MM • Phase I dose-escalation study in aggressive relapsed and/or recurrent non-Hodgkin's lymphoma DNA methyltransferase inhibitor • Phase I dose-escalation study in relapsed and/or refractory acute myeloid leukemia and azacytidine myelodysplastic syndromes Monoclonal antibodies

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Table 1. Ongoing clinical trials program of bortezomib in combination with novel targeted agents (Cont'd)

Class and/or agent Study and tumor types

Elotuzumab (anti-CS1) • Phase I–II study in relapsed and/or refractory MM Mapatumumab (anti-TRAIL-R1) • Phase II study in relapsed and/or refractory MM CNTO-328 (anti-IL6) • Phase II study in relapsed and/or refractory MM Bevacizumab (anti-VEGF) • Phase I dose-escalation study in solid tumors, lymphoma, myeloma • Phase II study in recurrent glioma or gliosarcoma • Phase I–II study in advanced or recurrent renal cell cancer • Phase II study in relapsed and/or refractory MM Rituximab (anti-CD20) • Phase II study in newly diagnosed Waldenstrom's macroglobulinemia • Phase II study in relapsed and/or refractory indolent and MCL • Phase II study in relapsed and/or refractory mantle cell and follicular non-Hodgkin's lymphoma Trastuzumab (anti-HER2) • Phase I dose-escalation study in HER2-expressing breast cancer

Other kinase inhibitors that have been investigated with Several ongoing early-phase clinical trials are investigat- bortezomib in preclinical studies include: BIRB796/dora- ing bortezomib-tipifarnib combination therapy in hemato- mapimod, a p38 MAPK inhibitor; BIBF 1000, a receptor logic malignancies. A phase I trial of bortezomib-tipifarnib kinase inhibitor of PDGF, basic FGF, and VEGF; enzastaur- in relapsed acute leukemia blast phase chronic myeloge- in, a protein kinase Cβ inhibitor; SCIO-469, a p38α MAPK nous leukemia (NCT00383474) established an MTD at full inhibitor; and LSN2322600, another p38 MAPK inhibitor doses of both agents (tipifarnib 600 mg twice daily and (Supplementary Table S3). bortezomib 1.3 mg/m2). Two patients achieved a CR and four had stable disease (61). Another phase I–II study in Farnesyltransferase inhibitors AML (NCT00510939) is evaluating this combination and Farnesyltransferase inhibitors (FTI) inhibit the activa- correlating clinical outcomes with results of a pretreatment tion of Ras, and many other target proteins that are sub- two gene expression signature for tipifarnib sensitivity strates of the farnesyltransferase enzyme, and regulate (62, 63). A phase I trial is being conducted in patients with signal transduction, tumor cell proliferation, and cell relapsed and/or refractory MM, and two patients have growth. Tipifarnib (R115777, Zarnestra) is an orally bio- evidence of response at doses below the MTD (64). available FTI with documented clinical activity in acute myeloid leukemia and myelodysplastic syndrome (55). Heat-shock protein 90 chaperone inhibitors In preclinical studies with bortezomib, tipifarnib, and an- Heat-shock protein 90 (HSP90), an abundant cellular other FTI, lonafarnib demonstrated additive and/or syner- protein, is a chaperone that stabilizes various client pro- gistic activity in head and neck squamous cell carcinoma teins (e.g., Flt3, Akt, c-Raf, Bcr-Abl, and c-Src), which are cells (56), as well as several hematologic malignancies in- key intermediates in cancer survival and proliferative path- cluding MM, AML, and MCL models (57–59). Increased ways (65). Several HSP90 inhibitors have been developed, apoptosis in MM cell lines and primary patient cells com- including the natural product benzoquinone ansamycin pared with either agent alone (58) was noted, as was a derivatives (e.g., tanespimycin, alvespimycin, retaspimy- sequence dependency with bortezomib followed by lona- cin, CNF1010), and other structurally unrelated synthetic farnib, which was critical for optimal induction of compounds (AUY922, an isoxazole derivative, SNX-5422, apoptosis (60). STA-9090, AT13387, PU-H71; ref. 66). Preclinical studies

Table 2. Histone deacetylase inhibitors combined with bortezomib in ongoing clinical trials

HDACi Class l and ll inhibitor Subclass or type Route of administration Stage of development or group of inhibitor

Vorinostat Hydroxamic acid Pan-HDACi Oral Approved for cutaneous T-cell lymphoma therapy Belinostat Hydroxamic acid Pan-HDACi Intravenous (oral) Phase II Panobinostat Hydroxamic acid Pan-HDACi Oral (intravenous) Phase II Romidepsin Cyclic depsipeptide Class l-selective HDACi Intravenous Phase II

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of bortezomib combined with geldanamycin, tanespimy- pressed on myeloma cells (80), and synergistically inhibits cin, and retaspimycin have been reported in solid tumor tumor growth with bortezomib in tumor models (81). and hematologic tumor models, and the combination Mapatumumab, a monoclonal antibody directed at the tu- seems to have synergistic antitumor activity (67–71), except mor necrosis factor-related apoptosis-inducing ligand bortezomib and AUY922, reportedly because of the potent (TRAIL)-R1 receptor (82), enhances apoptosis in TRAIL- low nanomolar efficacy of this HSP90 inhibitor in the MM 1R–expressing cell lines when combined with bortezomib model tested (72). Several mechanistic insights have been (83). Interleukin-6 (IL-6) is an important signaling inter- gained from these in vitro studies. Tanespimycin and borte- mediate in MM that is critical for the HSP response; combi- zomib treatment of MM cells results in enhanced intracel- nations of CNTO328, a chimeric antibody directed at IL-6, lular accumulation of ubiquitinated proteins because of and bortezomib have synergistic cytotoxic activity in IL-6– synergistic inhibition of the proteasome chymotryptic ac- dependent and IL-6–independent myeloma cell lines (84). tive site. HSP90 inhibitors and bortezomib also seem to Clinical trials evaluating the combination of bortezomib have complementary and distinct roles in undermining with these three antibodies in MM are ongoing (85). the unfolded protein response in cancer cells, resulting in VEGF clearly plays a critical role in the pathogenesis of a proapoptotic signal that culminates in cell death. solid tumors and myeloma (86), and preclinical studies of Bortezomib-tanespimycin combination therapy has G6.31, a VEGF-directed murine-human monoclonal anti- beenevaluatedinphaseItrialsinsolidtumorandMM body, in combination with bortezomib, produced a patients. Encouraging activity with manageable toxicities marked increase in antimyeloma activity (87). The bevaci- was shown in heavily pretreated patients with relapsed zumab-bortezomib regimen is being evaluated in early- and/or refractory MM, even in patients refractory to borte- phase glioma, renal cell cancer, NSCLC, and MM studies. zomib (73). These clinical results have led to initiation of Phase II studies of bortezomib-rituximab are being con- a phase III trial (TIME-1, NCT00546780) in MM patients ducted in Waldenstroms macroglobulinemia or indolent after first relapse comparing bortezomib-tanespimycin to NHL patients, on the basis primarily of clinical evidence bortezomib alone. A supportive phase II–III study of single agent activity; additive antitumor activity was (TIME-2) is a three-arm study of bortezomib and different seen with this combination only in a CLL model (88). A tanespimycin doses, which is accruing patients who have phase II study of bortezomib-trastuzumab in human epi- relapsed after at least three prior regimens that must have dermal growth factor receptor 2 (HER2)–positive breast included bortezomib and lenalidomide. cancer patients was initiated, on the basis of preclinical evidence indicating synergistic activity of the two agents in Pan-Bcl-2 family inhibitors breast cancer cell lines and bortezomib overcoming trastu- Obatoclax. The Bcl family of proteins, which mediates zumab resistance (89, 90). tumor cell survival and chemoresistance, is dysregulated Several studies are evaluating bortezomib in combina- in many malignancies and has emerged as an important tion with immunomodulatory drugs (IMiD), such as tha- therapeutic target. Obatoclax is a novel, small molecule lidomide or lenalidomide (91, 92). The rationale for these mimetic of proapoptotic BH3-only protein, which can combinations is provided by preclinical studies showing interact with the BH3-binding groove of Bcl-2 family that IMiDs potentiate the proapoptotic effect of bortezo- proteins (including Mcl-1), inhibit the interaction be- mib on MM cells through multiple mechanisms of action tween pro- and anti-apoptotic proteins, and induce ap- involving caspase-8 activation; MM cell sensitization to optosis (74). In addition, obatoclax induces an S-G2 cell Fas-mediated apoptosis; downregulation of the caspase- cycle block and initiates autophagy (75, 76). In preclin- 8 inhibitors, cellular inhibitor of apoptosis protein-2 ical studies, obatoclax and bortezomib had synergistic (cIAP-2) and FLICE inhibitory protein (FLIP); and down- antitumor activity against MCL and CLL cell lines, pur- regulation of NF-κB activity, among other anti-MM effects portedly through a combination of decreasing bortezo- (93). The efficacy of combining bortezomib and lenalido- mib-induced Mcl-1 and enhancing Noxa-mediated mide has been shown in a phase I study in patients with displacement of Bak from Mcl-1 (77, 78). Bortezomib relapsed and/or refractory MM, which reported the combi- is being investigated with obatoclax in three phase I nation to be well tolerated and to have promising activity or phase I–II studies in patients with relapsed and/or re- with durable responses (94). Bortezomib-lenalidomide fractory MCL (NCT00407303), MM (NCT00719901), combinations are subsequently under study in the phase and NHL (NCT00538187). Preliminary data from the II and III settings. MCL trial indicate that the combination is active (29% Other novel targeted agents are in development and have of patients achieved ≥PR) and has acceptable tolerability been investigated in combination with bortezomib in pre- in heavily pretreated patients (79). clinical studies. Supplementary Table S3 provides an overview of these agents and their mechanisms of action. Other novel targeted therapies Early-phase clinical trials combining bortezomib with Discussion monoclonal antibodies directed at a variety of targets are also ongoing. Elotuzumab is a humanized monoclonal The progress in clinical and translational research on bor- antibody that targets CS1, a cell surface glycoprotein ex- tezomib is providing increasing insights into the cellular

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and molecular mechanisms underlying the antitumor effi- be well tolerated, and single agent concentrations of both cacy of this protean therapeutic agent. Important recent drugs are generally recommended for most, but not all, observations have included gene expression signatures as- phase II studies. Encouraging clinical responses have been sociated with sensitivity to bortezomib (95), impact of bor- noted in patients with solid tumors as well as MM pa- tezomib on cancer stem cell biology (96), and bortezomib's tients, and preliminary data also indicate a potential re- potent role as an inducer of the endoplasmic reticulum duction in toxicities with certain combinations, such as stress responses (22). In parallel, improved understanding the potential neuroprotective effect of tanespimycin with of the molecular pathways important in cancer cell biology bortezomib (73). has led to the development of an extraordinary number of Although trials of most combinations are still in early novel, targeted investigational agents, including the sec- stages, and conclusions about the overall effectiveness of ond-generation proteasome inhibitors carfilzomib (97), each doublet remain open, it is clear with the emergence marizomib (98), MLN9708 (99), and CEP18770 (100), of additional novel targeted agents and supportive preclin- which may expand the limited universe of proteasome- ical data that further assessment of this therapeutic strategy directed therapies and afford different clinical characteris- will be considered. Translational research conducted as tics from bortezomib. This convergence has led to the part of the ongoing trials may inform prioritization of spe- strategy of cotargeting signaling pathways or intermediates cific combinations. This approach may facilitate the devel- in the cancer cell by developing treatment regimens com- opment of combination regimens optimized for specific bining bortezomib and a targeted agent. tumor subtypes, thus providing the potential for tailored This review encompasses a diverse group of approxi- therapy in individual patients on the basis of certain mo- mately two dozen therapeutic agents currently being lecular and genetic characteristics of their disease. assessed with bortezomib in more than 40 ongoing early- phase clinical trials. Preclinical in vitro or in vivo data, using Disclosure of Potential Conflicts of Interest clinically achievable concentrations of drug, have shown evidence of synergistic antitumor efficacy, providing a No potential conflicts of interest were disclosed. Dr. Wright is a US government employee with no other source of financial support. supportive rationale for most of these doublet combinations. The majority of the studies are evaluating patients Acknowledgments with hematologic malignancies, primarily MM and lymphoma, on the basis of the proven activity of bortezomib The author would like to acknowledge the support of Millennium in MM and MCL. Phase III studies of two combinations, Pharmaceuticals, Inc. and assistance of Sarah Maloney and Jane Saunders bortezomib-vorinostat and bortezomib-tanespimycin, of FireKite have been initiated, and additional randomized studies Received 10/28/2009; revised 05/26/2010; accepted 05/26/2010; are planned. Most of the doublet combinations seem to published OnlineFirst 08/03/2010.

References 1. Bross PF, Kane R, Farrell AT, et al. Approval summary for bortezo- phalan and prednisone for initial treatment of multiple myeloma. mib for injection in the treatment of multiple myeloma. Clin Cancer N Engl J Med 2008;359:906–17. Res 2004;10:3954–64. 10. Duan J, Friedman J, Nottingham L, et al. Nuclear factor-kappaB 2. Dancey JE, Chen HX. Strategies for optimizing combinations of mo- p65 small interfering RNA or proteasome inhibitor bortezomib sen- lecularly targeted anticancer agents. Nat Rev Drug Discov 2006;5: sitizes head and neck squamous cell carcinomas to classic histone 649–59. deacetylase inhibitors and novel histone deacetylase inhibitor 3. Kane RC, Farrell AT, Sridhara R, et al. United States Food and Drug PXD101. Mol Cancer Ther 2007;6:37–50. Administration approval summary: bortezomib for the treatment of 11. Rasheed WK, Johnstone RW, Prince HM. Histone deacetylase in- progressive multiple myeloma after one prior therapy. Clin Cancer hibitors in cancer therapy. Expert Opin Investig Drugs 2007;16: Res 2006;12:2955–60. 659–78. 4. Kane RC, Dagher R, Farrell A, et al. Bortezomib for the treatment of 12. Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mantle cell lymphoma. Clin Cancer Res 2007;13:5291–4. mechanisms of cell death and promise in combination cancer ther- 5. Adams J, Kauffman M. Development of the proteasome inhibitor apy. Cancer Lett 2008;269:7–17. Velcade (Bortezomib). Cancer Invest 2004;22:304–11. 13. Yoshida M, Shimazu T, Matsuyama A. Protein deacetylases: en- 6. Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the zymes with functional diversity as novel therapeutic targets. Prog proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int Cell Cycle Res 2003;5:269–78. 2005;5:18. 14. Mann BS, Johnson JR, He K, et al. Vorinostat for treatment of cu- 7. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome taneous manifestations of advanced primary cutaneous T-cell lym- inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to phoma. Clin Cancer Res 2007;13:2318–22. conventional chemotherapeutic agents: therapeutic applications. 15. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and Blood 2003;101:2377–80. apoptosis in human multiple myeloma cells by the proteasome in- 8. Ning YM, He K, Dagher R, et al. Liposomal doxorubicin in combi- hibitor bortezomib and histone deacetylase inhibitors. Clin Cancer nation with bortezomib for relapsed or refractory multiple myeloma. Res 2004;10:3839–52. Oncology [Williston Park] 2007;21:1503–8. 16. Denlinger CE, Rundall BK, Jones DR. Proteasome inhibition sensitizes 9. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus mel- non-small cell lung cancer to histone deacetylase inhibitor-induced

www.aacrjournals.org Clin Cancer Res; 16(16) August 15, 2010 4101

Wright

apoptosis through the generation of reactive oxygen species. 36. Huang X, Di Liberto M, Louie T, et al. Selective inhibition of CDK4 J Thorac Cardiovasc Surg 2004;128:740–8. and CDK6 primes chemoresistant myeloma cell for cytotoxic killing 17. Dai Y, Chen S, Kramer LB, et al. Interactions between bortezomib through induction of cell cycle-coupled mitochondrial dysfunction and romidepsin and belinostat in chronic lymphocytic leukemia and apoptosis [abstract]. Blood 2008;112:3678. cells. Clin Cancer Res 2008;14:549–58. 37. Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment 18. Heider U, Kaiser M, Zavrski I, et al. Synergistic interaction of the of advanced renal cell carcinoma. Clin Cancer Res 2006;12: histone deacetylase inhibitor SAHA with the proteasome inhibitor 7271–8. bortezomib in mantle cell lymphoma [abstract]. Blood 2006;108: 38. Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treat- 710–1a. ment of unresectable hepatocellular carcinoma. Oncologist 2009; 19. Yu C, Rahmani M, Conrad D, et al. The proteasome inhibitor borte- 14:95–100. zomib interacts synergistically with histone deacetylase inhibitors to 39. Yu C, Friday BB, Lai JP, et al. Cytotoxic synergy between the multi- induce apoptosis in Bcr/Abl+ cells sensitive and resistant to kinase inhibitor sorafenib and the proteasome inhibitor bortezomib STI571. Blood 2003;102:3765–74. in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal 20. Nawrocki ST, Carew JS, Pino MS, et al. Aggresome disruption: a kinase pathways. Mol Cancer Ther 2006;5:2378–87. novel strategy to enhance bortezomib-induced apoptosis in pan- 40. Kumar S, Marks RS, Richardson R, et al. A phase I study of the raf creatic cancer cells. Cancer Res 2006;66:3773–81. kinase/VEGF-R inhibitor sorafenib in combination with bortezomib 21. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition in patients with advanced malignancy [abstract]. J Clin Oncol 2008; of proteasome and aggresome function induces synergistic antitu- 26:2569. mor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005; 41. Goodman VL, Rock EP, Dagher R, et al. Approval summary: suniti- 102:8567–72. nib for the treatment of imatinib refractory or intolerant gastrointes- 22. Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors tinal stromal tumors and advanced renal cell carcinoma. Clin induce a terminal unfolded protein response in multiple myeloma Cancer Res 2007;13:1367–73. cells. Blood 2006;107:4907–16. 42. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon 23. Emanuele S, Lauricella M, Carlisi D, et al. SAHA induces apoptosis alfa, or both for advanced renal-cell carcinoma. N Engl J Med in hepatoma cells and synergistically interacts with the proteasome 2007;356:2271–81. inhibitor Bortezomib. Apoptosis 2007;12:1327–38. 43. Campbell R, Sanchez E, Steinberg J, et al. The mTOR inhibitor 24. Weber D, Badros A, Jagannath S, et al. Vorinostat plus bortezomib RAD001 (Everolimus) inhibits myeloma tumor growth in vivo and for the treatment of relapsed/refractory multiple myeloma: early enhances the anti-MM effects of bortezomib and arsenic trioxide clinical experience [abstract]. Blood 2008;112:871. [abstract]. Blood 2007:110. 25. Badros A, Burger AM, Philip S, et al. Phase I study of vorinostat in 44. Shanks JC, Fauble V, Lobocki CA, Terebelo H. Dual proteasome combination with bortezomib for relapsed and refractory multiple and mTOR inhibition promotes apoptosis in non-hodgkin lympho- myeloma. Clin Cancer Res 2009;15:5250–7. ma cell lines [abstract]. Blood 2008;112:5093. 26. Bryant O, Leong S, Camidge D, et al. A phase 1 study of belinostat 45. Ghobrial I, Munshi N, Schlossman R, et al. Phase I trial of CCI-779 (PXD101) in combination with bortezomib in patients with advanced (Temsirolimus) and weekly bortezomib in relapsed and/or refractory solid tumors and lymphomas [abstract]. AACR Meeting Abstracts, multiple myeloma [abstract]. Blood 2008;112:3696. Oct 2007. 2007, p. A149. 46. Cascone T, Morelli MP, Morgillo F, et al. Synergistic anti-proliferative 27. Siegel D, Sezer O, San-Miguel JF, et al. A phase IB, multicenter, and pro-apoptotic activity of combined therapy with bortezomib, a open-label, dose-escalation study of oral panobinostat (LBH589) proteasome inhibitor, with anti-epidermal growth factor receptor and I.V. bortezomib in patients with relapsed multiple myeloma (EGFR) drugs in human cancer cells. J Cell Physiol 2008;216: [abstract]. Blood 2008;112:2781. 698–707. 28. Prince M, Quach H, Neeson P, et al. Safety and efficacy of the com- 47. Piperdi B, Ling YH, Perez-Soler R. Schedule-dependent interaction bination of bortezomib with the deacetylase inhibitor romidepsin in between the proteosome inhibitor bortezomib and the EGFR-TK in- patients with relapsed or refractory multiple myeloma [abstract]. hibitor erlotinib in human non-small cell lung cancer cell lines. Blood 2007;110:1167. J Thorac Oncol 2007;2:715–21. 29. Lin TS, Heerema NA, Lozanski G, et al. Flavopiridol (Alvocidib) in- 48. Lynch TJ, Fenton D, Hirsh V, et al. A randomized phase 2 study of duces durable responses in relapsed chronic lymphocytic leukemia erlotinib alone and in combination with bortezomib in previously (CLL) patients with high-risk cytogenetic abnormalities [abstract]. treated advanced non-small cell lung cancer. J Thorac Oncol Blood 2008;112:46. 2009;4:1002–9. 30. Dai Y, Rahmani M, Pei XY, et al. Bortezomib and flavopiridol interact 49. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic my- synergistically to induce apoptosis in chronic myeloid leukemia eloid leukemia and Philadelphia chromosome-positive acute lym- cells resistant to imatinib mesylate through both Bcr/Abl-dependent phoblastic leukemia resistant to or intolerant of imatinib mesylate. and -independent mechanisms. Blood 2004;104:509–18. Clin Cancer Res 2008;14:352–9. 31. Dai Y, Rahmani M, Grant S. Proteasome inhibitors potentiate leuke- 50. Coluccia A, Cirulli T, Neri P, et al. Dasatinib inhibits multiple mic cell apoptosis induced by the cyclin-dependent kinase inhibitor myeloma growth by blocking PDGF-Rb and c-Src activity in flavopiridol through a SAPK/JNK- and NF-kappaB-dependent pro- patient-derived tumor and endothelial cells [abstract]. Blood cess. Oncogene 2003;22:7108–22. 2007;110:550. 32. Kapanen A, Tucker C, Chikh G, Bally M, Klasa R. Cell based assays 51. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive completed with the mantle cell lymphoma cell lines Z138 and NCEB- novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo 1 indicate that combinations of bortezomid and flavopiridol interact cytotoxicity in human multiple myeloma cells. Blood 2006;107: to achieve synergistic activity [abstract]. Blood 2005;106:678a. 4053–62. 33. Khong T, Sharkey J, Spencer A. Flavopiridol decreases the level of 52. Hideshima T, Catley L, Raje N, et al. Inhibition of Akt induces sig- p21 and induces apoptosis in human myeloma cell lines [abstract]. nificant downregulation of survivin and cytotoxicity in human multi- Blood 2005;106:381b. ple myeloma cells. Br J Haematol 2007;138:783–91. 34. Grant S, Sullivan D, Roodman D, et al. Phase I trial of bortezomib 53. Ayala G, Yan J, Li R, et al. Bortezomib-mediated inhibition of steroid (NSC 681239) and flavopiridol (NSC 649890) in patients with recur- receptor coactivator-3 degradation leads to activated Akt. Clin rent or refractory indolent B-cell neoplasms [abstract]. Blood 2008; Cancer Res 2008;14:7511–8. 112:1573. 54. Richardson P, Wolf J, Jakubowiak A, et al. Phase I/II results of a 35. Huang X, Bailey K, Di Liberto M, et al. Induction of sustained early multicenter trial of perifosine (KRX-0401) + bortezomib in patients G1 arrest by selective inhibition of CDK4 and CDK6 primes myelo- with relapsed or relapsed/refractory multiple myeloma who were ma cells for synergistic killing by proteasome inhibitors Carfilzomib previously relapsed from or refractory to bortezomib [abstract]. and PR-047 [abstract]. Blood 2008;112:3670. Blood 2008;112:870.

4102 Clin Cancer Res; 16(16) August 15, 2010 Clinical Cancer Research

Bortezomib in Combination with Novel Targeted Agents

55. Karp JE, Lancet JE. Development of the farnesyltransferase inhibi- 74. Trudel S, Li ZH, Rauw J, et al. Preclinical studies of the pan-Bcl tor tipifarnib for therapy of hematologic malignancies. Future Oncol inhibitor obatoclax (GX015–070) in multiple myeloma. Blood 2007; 2005;1:719–31. 109:5430–8. 56. Klass CM, Chen G, Zhang X, Lonial S, Khuri FR, Shin DM. Antitumor 75. Hernandez-Ilizaliturri FJ, Khubchandani S, Olejniczak SH, Hosking effects of combined bortezomib and tipifarnib in head and neck P, Gruber EA, Czuczman M. The BH3-mimetic obatoclax (GX15– squamous cell carcinoma (HNSCC) cells [abstract]. J Clin Oncol 070) posses a dual-mechanism of action and induces both apopto- 2006;24:5581. sis and autophagy-dependent cell death of B cell non-hodgkin's 57. Yanamandra N, Colaco NM, Parquet NA, et al. Tipifarnib and bor- lymphoma (B-NHL) cells [abstract]. Blood 2008;112:605. tezomib are synergistic and overcome cell adhesion-mediated drug 76. Konopleva M, Watt J, Contractor R, et al. Mechanisms of antileu- resistance in multiple myeloma and acute myeloid leukemia. Clin kemic activity of the novel Bcl-2 homology domain-3 mimetic Cancer Res 2006;12:591–9. GX15–070 (obatoclax). Cancer Res 2008;68:3413–20. 58. Kaufman JL, David E, Torre C, Sinha R, Lonial S. Enhanced levels of 77. Perez-Galan P, Roue G, Villamor N, et al. The BH3-mimetic GX15– apoptosis by combination of farnesyl transferase inhibition (tipifar- 070 synergizes with Bortezomib in Mantle Cell Lymphoma by en- nib) and proteasome inhibition (bortezomib) in myeloma cell lines hancing Noxa-mediated activation of Bak. Blood 2007;109:4441–9. and primary myeloma cells and its mechanistic effects on Akt and 78. Perez-Galan P, Roue G, Lopez-Guerra M, et al. BCL-2 phosphory- caspase pathways [abstract]. Blood 2005;106:451a. lation modulates sensitivity to the BH3 mimetic GX15–070 (Obato- 59. Rolland D, Camara-Clayette V, Barbarat A, et al. Farnesyltransfer- clax) and reduces its synergistic interaction with bortezomib in ase inhibitor R115777 inhibits cell growth and induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 2008;22:1712–20. mantle cell lymphoma. Cancer Chemother Pharmacol 2008;61: 79. Goy A, Ford P, Feldman T, et al. A phase l trial of the pan bcl-2 855–63. family inhibitor obatoclax mesylate (GX15–070) in combination with 60. David E, Sun SY, Waller EK, et al. The combination of the Farnesyl bortezomib in patients with relapsed/refractory mantle cell lympho- transferase inhibitor (Lonafarnib) and the proteasome inhibitor (Bor- ma [abstract]. Blood 2007;110:2569. tezomib) induces synergistic apoptosis in human myeloma cells 80. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic that is associated with down-regulation of p-AKT. Blood 2005; antibody target for the treatment of multiple myeloma. Clin Cancer 106:4322–9. Res 2008;14:2775–84. 61. Lancet J, Winton E, Stuart R, et al. A phase l clinical-pharmacodynamic 81. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal study on the farnesyltransferase inhibitor tipifarnib in combination antibody HuLuc63 inhibits myeloma cell adhesion and induces with the proteasome inhibitor bortezomib in advanced acute leuke- antibody-dependent cellular cytotoxicity in the bone marrow milieu. mias [abstract]. Blood 2008;112:1945. Blood 2008;112:1329–37. 62. Paolini S, Ottaviani E, Lama B, et al. Phase I/II study of tipifarnib and 82. Tolcher AW, Mita M, Meropol NJ, et al. Phase I pharmacokinetic bortezomib in the treatment of poor risk adult acute myeloid leuke- and biologic correlative study of mapatumumab, a fully human mia [abstract]. Blood 2008;112:2982. monoclonal antibody with agonist activity to tumor necrosis factor- 63. Raponi M, Lancet JE, Fan H, et al. A 2-gene classifier for predicting related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007;25: response to the farnesyltransferase inhibitor tipifarnib in acute my- 1390–5. eloid leukemia. Blood 2008;111:2589–96. 83. Smith MR, Jin F, Joshi I. Bortezomib sensitizes non-Hodgkin's lym- 64. Lonial S, Francis D, Karanes C, et al. A phase I clinical trial testing phoma cells to apoptosis induced by antibodies to tumor necrosis the combination of bortezomib and tipifarnib in relapsed/refractory factor related apoptosis-inducing ligand (TRAIL) receptors TRAIL- multiple myeloma [abstract]. Blood 2008;112:3706. R1 and TRAIL-R2. Clin Cancer Res 2007;13:5528s–34s. 65. Workman P, Burrows F, Neckers L, et al. Drugging the cancer chap- 84. Voorhees PM, Chen Q, Kuhn DJ, et al. Inhibition of interleukin-6 erone HSP90: Combinatorial therapeutic exploitation of oncogene signaling with CNTO 328 enhances the activity of bortezomib in addiction and tumor stress. Ann N Y Acad Sci 2007;1113:202–16. preclinical models of multiple myeloma. Clin Cancer Res 2007;13: 66. Li Y, Zhang T, Schwartz SJ, et al. New developments in Hsp90 in- 6469–78. hibitors as anti-cancer therapeutics: Mechanisms, clinical perspec- 85. Rossi J-F, Manges RF, Sutherland H, et al. Preliminary results of tive and more potential. Drug Resist Updat 2009;12:17–27. CNTO 328, an anti-interleukin-6 monoclonal antibody, in combina- 67. Davenport EL, Moore HE, Dunlop AS, et al. Heat shock protein in- tion with bortezomib in the treatment of relapsed or refractory mul- hibition is associated with activation of the unfolded protein re- tiple myeloma [abstract]. Blood 2008;112:867. sponse (UPR) pathway in myeloma plasma cells. Blood 2007;110: 86. Podar K, Anderson KC. Inhibition of VEGF signaling pathways in 2641–9. multiple myeloma and other malignancies. Cell Cycle 2007;6: 68. Mimnaugh EG, Xu W, Vos M, et al. Simultaneous inhibition of hsp 538–42. 90 and the proteasome promotes protein ubiquitination, causes en- 87. Campbell R, Sanchez E, Steinberg J, Share M, Wang J, Li M. An doplasmic reticulum-derived cytosolic vacuolization, and enhances anti-VEGF antibody, in combination with bortezomib, markedly in- antitumor activity. Mol Cancer Ther 2004;3:551–66. hibits tumor growth in SCID-hu models of human multiple myeloma 69. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma [abstract]. Blood 2007;110:4802. activity of heat shock protein-90 inhibition. Blood 2006;107: 88. Smolewski P, Duechler M, Linke A, et al. Additive cytotoxic effect of 1092–100. bortezomib in combination with anti-CD20 or anti-CD52 monoclo- 70. Roue G, Perez-Galan P, Lopez-Guerra M, Villamor N, Campo E, nal antibodies on chronic lymphocytic leukemia cells. Leuk Res Colomer D. The novel HSP90 inhibitor IPI-504 synergizes with bor- 2006;30:1521–9. tezomib in mantle cell lymphoma cells by targeting both NF-kappaB 89. Fujita T, Doihara H, Washio K, et al. Proteasome inhibitor bortezo- signaling and unfolded protein response and leading to increased mib increases PTEN expression and enhances trastuzumab- mitochondrial apoptosis [abstract]. Blood 2007;110:1601. induced growth inhibition in trastuzumab-resistant cells. Anticancer 71. Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino- Drugs 2006;17:455–62. 17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), 90. Cardoso F, Durbecq V, Laes JF, et al. Bortezomib (PS-341, Vel- an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci cade) increases the efficacy of trastuzumab (Herceptin) in HER-2- U S A 2006;103:17408–13. positive breast cancer cells in a synergistic manner. Mol Cancer 72. McMillin D, Negri J, Delmore J, et al. Activity of new heat shock pro- Ther 2006;5:3042–51. tein 90 inhibitor NVP-AUY922 against myeloma cells sensitive and 91. Jagannath S, Kyle RA, Palumbo A, Siegel DS, Cunningham S, resistant to conventional agents [abstract]. Blood 2007;110:1587. Berenson J. The current status and future of multiple myeloma 73. Richardson PG, Chanan-Khan A, Lonial S, et al. Tanespimycin (T) + in the clinic. Clin Lymphoma Myeloma Leuk 2010;10:28–43. bortezomib (BZ) in multiple myeloma (MM): Confirmation of the re- 92. Laubach JP, Mitsiades CS, Mahindra A, et al. Novel therapies in the commended dose using a novel formulation [abstract]. Blood 2007; treatment of multiple myeloma. J Natl Compr Canc Netw 2009;7: 110:1165. 947–60.

www.aacrjournals.org Clin Cancer Res; 16(16) August 15, 2010 4103

Wright

93. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling 97. O'Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose esca- induced by immunomodulatory thalidomide analogs in human lation study of the safety and pharmacokinetics of the novel protea- multiple myeloma cells: therapeutic implications. Blood 2002;99: some inhibitor carfilzomib (PR-171) in patients with hematologic 4525–30. malignancies. Clin Cancer Res 2009;15:7085–91. 94. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, 98. Singh AV, Palladino MA, Lloyd GK, et al. Pharmacodynamic and dose-escalation trial of lenalidomide plus bortezomib for relapsed efficacy studies of the novel proteasome inhibitor NPI-0052 (mari- and relapsed/refractory multiple myeloma. J Clin Oncol 2009;27: zomib) in a human plasmacytoma xenograft murine model. Br J 5713–9. Haematol 2010;149:550–9. 95. Chng WJ, Kumar S, Vanwier S, et al. Molecular dissection of hyper- 99. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome diploid multiple myeloma by gene expression profiling. Cancer Res inhibitor MLN9708 in preclinical models of human cancer. Cancer 2007;67:2982–9. Res 2010;70:1970–80. 96. Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma 100. Piva R, Ruggeri B, Williams M, et al. CEP-18770: A novel, orally ac- progenitors, stem cell properties, and drug resistance. Cancer Res tive proteasome inhibitor with a tumor-selective pharmacologic 2008;68:190–7. profile competitive with bortezomib. Blood 2008;111:2765–75.

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

John J. Wright

Clin Cancer Res 2010;16:4094-4104. Published OnlineFirst August 3, 2010.

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