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Journal of Clinical Oncology, Vol 23, No 3 (January 20), 2005: pp. 630-639 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.11.030
Proteasome Inhibition As a Novel Therapeutic Target in Human CancerFrom the Division of Hematology, Mayo Clinic, Rochester, MN; and Dana-Farber Cancer Institute, Boston, MA Address reprint requests to S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: rajks{at}mayo.edu
The 26S proteasome is a large intracellular adenosine 5'-triphosphate–dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.
The multicatalytic ubiquitin-proteasome pathway is responsible for the degradation of eukaryotic cellular proteins.1-4 This adenosine 5'-triphosphate–dependent process is vital for normal cell cycling, function, and survival, making proteasome inhibition a novel therapeutic target in cancer. Bortezomib is the first inhibitor of the ubiquitin-proteasome pathway to enter clinical studies.1,5,6 In a recent, large, multicenter, phase II, clinical trial, approximately one third of patients with advanced multiple myeloma (MM) had a significant response to therapy with bortezomib.7 On the basis of these findings, on May 13, 2003, the US Food and Drug Administration granted accelerated approval to this drug for the treatment of patients with MM who had relapsed after at least two prior treatment regimens and had evidence of resistance to their last treatment.8 The promising preclinical and clinical activity exhibited by bortezomib in MM and other malignancies has confirmed the proteasome as a relevant and important target in the treatment of cancer.
The orderly degradation of cellular proteins by the ubiquitin-proteasome pathway is critical for signal transduction, transcriptional regulation, response to stress, and control of receptor function.9-12 This pathway controls the activation of nuclear factor-kappa B (NF-  B; a major transcription factor) by regulating degradation of the NF-B inhibitor (I-B).13,14 The proteasome also plays a major role in antigen presentation.15 In cancer, dysregulation of this catalytic process may contribute to tumor progression, drug resistance, and altered immune surveillance.16 Thus, any inhibition of the proteasome system creates an imbalance of various regulatory proteins, triggering cell cycle arrest at G1-S and G2-M phases of the cell cycle and apoptotic pathways within the cell. The first step in the ubiquitin-proteasome pathway is the addition of polyubiquitinated tails to proteins destined for destruction (Fig 1). Ubiquitin is a small protein capable of forming multimeric chains.17 C-terminal glycine residues of ubiquitin molecules attach covalently to specific lysine moieties on the protein targeted for degradation.18 The selection of proteins for degradation is determined primarily at this stage and involves three enzymes, ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin ligase.11 This is a highly regulated process, and specific proteins can be targeted for degradation by controlling the affinity of the ubiquitin to a given substrate.18
The second step in the catalytic process is identification of these ubiquitinated proteins by the intracellular proteasome complex. The final step is degradation of identified proteins in the central portion of the proteasome complex.
The 26S proteasome (1,500 to 2,000 kd) consists of a core 20S catalytic complex (approximately 700 kd) and a 19S regulatory complex (Fig 1).1,9,12,18-21 It consists of two outer and two inner rings that are stacked to form a cylindrical structure with three compartments.22,23 Each outer ring has seven alpha-subunits (  1 to 7), whereas each inner ring contains seven beta-subunits (ß1 to ß7). The 20S proteasome complex has chymotryptic, tryptic, and peptidylglutamyl-like activities.18-20 It is conformationally flexible with active catalytic sites located on the inner surface of the cylinder where protein substrates bind.24,25 Seemüller et al26 found that deletion or mutation (to alanine) of the amino-terminal threonine residue on the 20S proteasome results in the inactivation of the enzyme, indicating that the active catalytic site is mediated by a threonine residue.
Ubiquitin-tagged proteins are recognized by the 19S regulatory complex, where the ubiquitin tags are removed. ATPases with chaperone-like activity at the base of the 19S regulatory complex then unfold the protein substrates and feed them into the inner catalytic compartments of the 20S proteasome cylinder.17,27 The opening into the 20S catalytic chamber is small (approximately 1.3 nm), and significant unfolding of the substrate is required.25 A molecular gate (N-terminal tail of the
Several regulatory proteins, tumor suppressors, transcription factors, and oncogenes are degraded by the proteasome pathway (Table 1). Proteasome inhibition can cause cellular apoptosis by affecting the levels of various short-lived proteins, resulting in inhibition of NF- B activity, increased activity of p53 and Bax proteins, and accumulation of cyclin-dependent kinase inhibitors p27 and p21.5,18 Preclinical studies show that malignant, transformed, and proliferating cells are more susceptible to proteasome inhibition than normal cells.1,29-32
Numerous proteasome inhibitors have been developed and described.9,18,33,34 Imajoh-Ohmi et al35 showed that lactacystin, an irreversible inhibitor of the catalytic ß-subunit of the proteasome, induces apoptosis of human monoblastic U937 cells. Later, Shinohara et al36 showed that benzyloxycarbonyl (Z)-Leu-Leu-leucinal, a tripeptide aldehyde inhibitor of the proteasome, induces p53-dependent apoptosis in leukemic cells. Tanimoto et al,37 Drexler,30 and Orlowski et al29 also made similar observations with proteasome inhibition. These and other studies provided proof of principle that the proteasome is a valid target for anticancer therapy; however, the available inhibitors lacked specificity.9,18 Therefore, Adams et al5 designed and developed several boronic acid–derived compounds that inhibit the proteasome pathway in a highly specific manner. Most of these boronated proteasome inhibitors were active across a 60–tumor cell line panel from the National Cancer Institute, and the potency of proteasome inhibition was correlated with growth-inhibitory effects. On the basis of its potency and cytotoxicity, bortezomib was identified as the best candidate for further clinical testing.
Bortezomib (N-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid; previously known as PS-341 or MLN-341), a boronic acid dipeptide, is a unique and specific inhibitor of the proteasome pathway.5,7 Bortezomib inhibits the proteasome pathway rapidly and in a reversible manner by binding directly with the 20S proteasome complex and blocking its enzymatic activity. In animal models, bortezomib does not enter the brain, spinal cord, testes, or the eye, thus sparing these tissues from the adverse effects of proteasome inhibition. However, because proteasome inhibition was not seen in tumor tissues isolated from brain and testes, it is less likely that proteasome inhibitors will be useful in these tumor types, unless the blood-brain or blood-testes barrier has been disrupted by the malignancy.5 Preclinical studies show that the cytotoxic and growth inhibitory effects of bortezomib are correlated with proteasome inhibition, independent of p53 status, and non-overlapping with other chemotherapeutic agents.5 Its average 50% growth inhibition across the panel of 60 cell lines from the National Cancer Institute was 3.9 nm. Further testing found significant single-agent activity in several murine and human xenograft tumor models.3,38-43
On the basis of the promising preclinical studies described earlier, Orlowski et al44 conducted a phase I trial in which 27 patients with advanced refractory hematologic malignancies were treated with bortezomib. The maximum-tolerated dose was 1.04 mg/m2 given on days 1, 4, 8, 11, 15, 18, 22, and 25 followed by a 2-week rest period (6-week cycle). A key finding in this study was that responses were seen in nine assessable patients with MM treated on this study, including one patient with relapsed, refractory MM who achieved a complete response (CR). Two other responses were seen in the phase I trial; one was seen in a patient with mantle-cell lymphoma, and another occurred in a patient with follicular lymphoma. In another phase I trial, bortezomib was studied in 43 patients with advanced solid tumors.45 Main dose-limiting adverse effects were diarrhea and neuropathy. The dosing schedule was more similar to the one used in MM trials, with treatments given twice weekly for 2 weeks (on days 1, 4, 8, and 11) followed by 1 week of rest. The maximum-tolerated dose in this trial was 1.56 mg/m2.
In addition to the clinical efficacy demonstrated in the phase I setting, bortezomib showed striking activity against MM cells in several preclinical models. It directly inhibited proliferation of MM cells, induced apoptosis in cell lines and primary MM cells, and inhibited binding of MM cells to bone marrow stromal cells.46 Most importantly, the median inhibitory concentration in several cell lines and patient-derived MM cells was achieved at less than 10 nmol/L concentrations, levels that are clinically achievable. In contrast, the median inhibitory concentration for normal peripheral-blood mononuclear cells was  100 nmol/L, suggesting preferential cytotoxicity in MM cells. Dexamethasone enhanced the activity of bortezomib, and interleukin-6 (IL-6) failed to protect MM cells from apoptosis. Bortezomib induced irreversible apoptosis in both p53 wild-type and p53 mutant cells. It also sensitized MM cell lines and patient cells to other active agents, such as doxorubicin and melphalan.47,48 Bortezomib was then studied in a human plasmacytoma xenograft mouse model.49 Significant inhibition of growth, including some complete tumor regressions, were noted in bortezomib-treated mice. Overall survival was doubled in treated mice compared with controls, and therapy was associated with tumor cell apoptosis and decreased angiogenesis.49 These preclinical results, along with evidence of activity in phase I trials, provided the rationale for phase II clinical trials with bortezomib in MM.
Two hundred two patients with relapsed, refractory MM were treated in a recent phase II multicenter trial of bortezomib in MM.7 Patients were required to have measurable monoclonal protein levels and/or measurable disease and to be refractory to salvage chemotherapy, which was defined as progressive disease on treatment or disease progression within 60 days of completing therapy. Bortezomib was administered at a starting dose of 1.3 mg/m2 intravenous (IV) over 3 to 5 seconds twice weekly for 2 weeks on days 1, 4, 8, and 11, with dose reductions permitted for toxicity. Treatment was repeated every 21 days for a maximum of eight cycles. Dexamethasone was added for patients with progressive disease after two cycles or stable disease after four cycles. The dose of dexamethasone consisted of 20 mg on the day of and the day after each dose of bortezomib. One hundred ninety-three patients were assessable. Most patients (n = 178) had failed all of the known active classes of drugs for the treatment of MM, with a median number of six lines (range, two to 15 lines) of prior therapy. Of the assessable patients, 53 (27%) achieved a partial response to therapy defined by the European Group for Blood and Marrow Transplant criteria.50 In addition, 14 patients (7%) achieved a minor response to therapy. The responses included 4% of patients who achieved a CR, with negative immunofixation, and a further 6% of patients with near CRs who met criteria for CR but who had persistently positive immunofixation. The median survival time for all patients was 16 months, and the median time to progression was 7 months (as compared with a median time to progression of 3 months with last prior therapy). Responses were durable, with a median response duration of 12 months in patients who achieved a CR, partial response, or minor response to therapy. Responses were associated with improvements in hemoglobin, platelet counts, renal function, performance status, and quality-of-life measures.51 The most common adverse events were gastrointestinal side effects, cytopenias (especially thrombocytopenia), fatigue, and peripheral neuropathy. These results were especially compelling considering the heavily pretreated nature of the patients; specifically, prior stem-cell transplantation had been used in 64% of patients, and 83% had received previous thalidomide therapy. Older age (> 65 years), the presence of abnormal cytogenetics, and more than 50% plasma cell bone marrow involvement were associated with a lower response rate.7,52 In contrast, chromosome 13 deletion, prior thalidomide therapy, and prior transplantation did not effect response to bortezomib. A separate randomized phase II trial has also been conducted in patients who failed to respond or relapsed after front-line therapy for MM.53 This trial examined the following two doses of bortezomib in 54 patients: 1.0 mg/m2 (28 patients) versus 1.3 mg/m2 (26 patients) on days 1, 4, 8, and 11 every 21 days. Responses (CR, partial response, or minor response) were seen in 33% of patients at the dose level of 1.0 mg/m2 and 50% of patients at the dose level of 1.3 mg/m2, which seems to suggest a dose-response relationship, although a formal statistical comparison was not reported by the authors. Although both phase II trials required a maximum of eight cycles of therapy, responding patients were allowed to receive continued treatment on a third study (an extension protocol). Data from 57 patients treated in this extension study show that it is safe to give at least an additional five to six cycles of therapy, with a similar toxicity profile as in the first eight cycles.53
After completing conventional-dose therapy or stem-cell transplantation, patients with relapsed MM are typically treated with conventional-dose chemotherapy, high-dose corticosteroids, or thalidomide.54 For these patients, bortezomib is now an important additional option. Because none of the therapeutic approaches are curative, patients are typically treated sequentially with these options, and the choice of therapy at each relapse needs to be determined by the clinical situation and patient preference. Patients who do not respond to induction therapy for MM often benefit from autologous stem-cell transplantation because the dose-intensity of melphalan-based conditioning overcomes drug resistance.55,56 Bortezomib may prove valuable in reducing pretransplantation tumor burden in such patients and may facilitate achievement of a CR with transplantation, a key therapeutic goal in MM. Preliminary evidence indicates that, in combination with dexamethasone, bortezomib has impressive activity as pretransplantation therapy in MM, with response rates exceeding 75%.57 However, additional clinical trials are needed, and we do not recommend such use outside the context of an approved trial.
Several clinical trials are currently ongoing with bortezomib in various hematologic and nonhematologic malignancies. Data reported from phase II trials of bortezomib thus far are listed in Table 2. 7,53,58-63 Preliminary results suggest promising activity in mantle-cell lymphoma and possibly low-grade follicular or small lymphocytic lymphomas.64
The antitumor effects of bortezomib are a result of cell cycle arrest and apoptosis resulting from the effects of proteasome inhibition (Table 1). The underlying mechanisms include NF- B inhibition, upregulation of various apoptotic pathways, and effects on the tumor microenvironment. These consequences of proteasome inhibition have been well studied in the context of MM, where it is now increasingly apparent that the malignant cell and its microenvironment are both important targets for therapy.65-67 New agents, like thalidomide and its analog CC-5013, are representative of this new therapeutic strategy in MM,68-71 and current data support a similar dual role for bortezomib (Fig 2). 47,72
NF- B InhibitionSeveral effects of bortezomib, including apoptosis, seem to be mediated through inhibition of NF- B.73 The Rel/NF-B family of proteins are inducible dimeric transcription factors that recognize and bind a common sequence motif in nuclear DNA.73-76 NF-B, the major transcription factor in this family, is a p50/RelA heterodimer (p50/p65) present in the cytoplasm of almost all cells.75,77 NF-B regulates cell growth and apoptosis, as well as expression of various cytokines, adhesion molecules, and their receptors.18 In the cytoplasm, NF-B is normally bound to its inhibitor, I-B.76 When cells are stimulated (by cytokines, stress, or chemotherapy), signaling cascades are triggered that lead to activation of I-B kinase, a heterodimeric protein kinase that catalyzes I-B phosphorylation (Fig 3). I-B kinase phosphorylates two serine residues in the amino-terminal regulatory domain of I-B.78 The phosphorylated sites on I-B are then recognized by E3RS(I-B/ß-TrCP), an SCF-type E3 ubiquitin ligase, leading to ubiquitination.74 I-B is then degraded by the proteasome pathway, releasing free active NF-B. When activated (ie, released from I-B inhibition), NF-B translocates to the nucleus and binds to promoter regions of several target genes, thereby triggering their transcription. This leads to increased expression of various cytokines and chemokines, adhesion molecules, and cyclin D that promote cell growth and survival.73
Proteasome inhibitors inhibit NF- B activity in cells by blocking the degradation of I-B.73,79,80 Inhibition of NF-B transcriptional activity plays a beneficial role in cancer by downregulating the expression of various growth, survival, and angiogenic factors. It leads to decreased levels of the proapoptotic proteins Bcl-2 and A1/Bfl-1, triggering cytochrome C release, caspase-9 activation, and apoptosis.47 Given the known role of NF-B in MM, NF-B inhibition is likely one of the main mechanisms by which bortezomib induces apoptosis and overcomes drug resistance.73
NF-
NF-
Although, as discussed earlier, NF-
Upregulation of Proapoptotic Pathways
Bortezomib activates the c-Jun N-terminal kinase (JNK) leading to Fas upregulation and caspase-8 and caspase-3 activation.47 This caspase-8–mediated apoptotic pathway is independent of the caspase-9–mediated pathway described earlier in relation to NF-
Other Effects Bortezomib also induces cytoprotective responses, such as upregulation of heat-shock proteins (eg, hsp90), and thus, inhibitors to these cytoprotective proteins can increase sensitivity or overcome resistance to bortezomib.47 Despite the data discussed earlier, the specific effects of proteasome inhibition in malignancy and the precise mechanism of action of bortezomib remain unclear and are subject to further investigation.
The pharmacokinetics and elimination pathways of bortezomib have not been fully characterized. After IV administration, more than 90% of the drug is rapidly cleared from the plasma within minutes.1 Bortezomib is metabolized by cytochrome P450 liver microenzymes (3A4, 2D6, 2C19, 2C9, and 1A2) into several inactive deboronated hydroxylated metabolites.86 Because of the rapid clearing of the drug from blood, a bioassay to estimate degree of proteasome inhibition was developed to assist with phase I and II clinical trials. Primate studies have identified that the target level of proteasome inhibition should not exceed 80%. With the recommended dosing, approximately 60% proteasome inhibition is achieved. The degree of proteasome inhibition is dose dependent and does not seem to be affected significantly by patient characteristics.1 Thus, monitoring of proteasome inhibition is not needed for routine clinical practice. There are no good data on drug interactions or pharmacokinetics in children.
The most common (occurring with a frequency of at least 20%) toxicities attributable to bortezomib therapy are gastrointestinal side effects, transient thrombocytopenia, fatigue, fever, and peripheral neuropathy.7 Nausea, vomiting, and abdominal bloating may be a manifestation of autonomic neuropathy, but this has not been well studied. Most of these toxicities are of grade 1 to 2 severity. Less common side effects include rash (15%), headache (20%), and dizziness (10%). There are usually no infusion-related side effects, and routine premedication is not necessary. Prophylactic antiemetics are recommended if patients experience nausea or vomiting with therapy, and administration of normal saline to ensure adequate hydration may be helpful. Fever occurs in approximately 20% of patients and is typically low grade but occasionally can reach 39°C or higher. It usually occurs in the first cycle of therapy, approximately 12 hours after drug administration, and lasts 24 to 26 hours. Cytopenias (primarily leukopenia and thrombocytopenia) are common and are managed with supportive measures. Thrombocytopenia can be of grade 3 or higher in approximately 30% of patients and may necessitate dose reduction or transfusion. In most cases, it is transient and predictable (occurring usually after day 10), with recovery by day 1 of the next cycle. In some patients, the proportion of decrease in platelet count may be constant, leading to smaller absolute decrements as the platelet count drops with therapy. Peripheral neuropathy occurs in approximately 35% of patients and is more frequent in patients who have received prior neurotoxic therapy and in patients with pre-existing neuropathy.7,87 Neuropathy is mostly sensory and can be of grade 3 severity in approximately 10% of patients. Symptoms of neuropathy can be minimized by dose adjustments and are usually reversible with discontinuation of bortezomib. Postural hypotension (possibly dose dependent) occurs in approximately 10% of patients and is associated with dehydration, concomitant antihypertensive therapy, or autonomic dysfunction. IV saline at the time of bortezomib administration may be helpful for dehydration. The consequences of postural hypotension may be serious in patients with pre-existing low cardiac output states. There are no pharmacokinetic data on patients with renal or hepatic impairment.86 Patients with significant renal impairment (creatinine clearance, 10 to 30 mL/min) were included in MM trials, and it does not seem that efficacy, toxicity, or degree of proteasome inhibition is affected by renal failure.88 However, bortezomib is metabolized by hepatic cytochrome p450 enzymes, and caution is recommended when using the drug in patients with liver disease. The usual dose of bortezomib for the treatment of relapsed, refractory MM is 1.3 mg/m2 given twice weekly on days 1, 4, 8, and 11 every 21 days.7 Patients with adverse events at the standard dose of bortezomib can be dose reduced to 1 mg/m2 and 0.7 mg/m2.86
In preclinical studies, tumor resistance to conventional chemotherapy agents can be overcome by the addition of bortezomib, highlighting the importance of developing combination trials in MM and other malignancies.46,89 In the two phase II MM trials described earlier, dexamethasone was added to a total of 106 patients who failed to respond or had progressive disease with single-agent bortezomib therapy.7,90 Nineteen of these patients (18%) responded to addition of dexamethasone. This included some patients who were previously refractory to corticosteroids, suggesting at least an additive effect. When bortezomib is combined with melphalan in MM, initial reports have suggested promising activity, but the dose of both drugs needs to be lowered.91 Preliminary results suggest that the combination of bortezomib with pegylated doxorubicin also merits additional testing.92 In solid tumors, there is strong preclinical evidence that the activity of bortezomib is significantly higher when used in combination with chemotherapeutic agents such as gemcitabine, doxorubicin, irinotecan, docetaxel, and paclitaxel.89,93 Preliminary data from phase I trials indicate that the combination of bortezomib with other chemotherapy drugs is feasible and safe.93 Phase II clinical trials of bortezomib in combination with gemcitabine, docetaxel, irinotecan, and other cytotoxic agents are ongoing.
Bortezomib is the first proteasome inhibitor to enter clinical practice and is the first new anti-MM agent approved by the US Food and Drug Administration in several years. An international, multicenter, randomized trial comparing bortezomib versus pulsed dexamethasone in relapsed or refractory MM has just completed accrual. Ongoing studies are examining the role of bortezomib alone and in combination with other active agents in various malignancies. The success seen with bortezomib is remarkable because it has validated the proteasome as a novel and legitimate target in the treatment of cancer. We fully hope that other more improved inhibitors of this enzymatic system will be tested in clinical trials soon.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Kenneth C. Anderson, Millennium Pharmaceuticals, Celgene; Paul G. Richardson, Millennium Pharmaceuticals, Celgene; S. Vincent Rajkumar, Millennium Pharmaceuticals, Celgene.
Supported in part by grant Nos. CA85818, CA93842, CA100080, CA62242, CA50947, and CA78378 from the National Cancer Institute, Bethesda, MD. Also supported in part by the Multiple Myeloma Research Foundation (S.V.R. and K.C.A.), Goldman Philanthropic Partnerships (S.V.R.), the Leukemia and Lymphoma Society (S.V.R.), the Myeloma Research Fund (K.C.A. and T.H.), and the Doris Duke Distinguished Clinical Research Award (K.C.A.). The authors have received research support from Millennium Pharmaceuticals. K.C.A. and P.G.R. have received payments from Millennium Pharmaceuticals for lectures and serving on its advisory board. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.1 µmol/L concentrations.
