Clinical update: proteasome inhibitors in hematologic malignancies

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Abstract

The proteasome inhibitor bortezomib (VELCADE™; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid. In cell culture and xenograft models, bortezomib showed potent activity, enhanced the sensitivity of cancer cells to traditional chemotherapeutics, and appeared to overcome drug resistance. In vitro, bortzomib downregulated the NF-κB pathway. NF-κB is a transcription factor that enhances the production of growth factors (e.g., IL-6), cell-adhesion molecules, and anti-apoptotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis. Phase II trials have been conducted in patients with relapsed and refractory multiple myeloma (SUMMIT trial, 202 patients) or relapsed myeloma (CREST trial, n=54) using a 1.3 mg/m2 dose given twice weekly for 2 weeks (days 1, 4, 8, 11; rest days 12–21). Both trials showed responses (including complete responses) with manageable toxicities, forming the basis for an ongoing phase III trial comparing response to bortezomib versus high-dose dexamethasone.

Introduction

The proteasome is a multicatalytic enzyme complex that degrades numerous types of proteins (reviewed by Adams in this issue), many of which are regulatory proteins that control the cell cycle or play a role in survival pathways. The coordinated expression and degradation of these proteins are essential for normal cellular function. Consequently, the proteasome plays a central role in up- or down-regulation of growth signaling pathways by removing key signals via protein degradation. Inhibition of the proteasome is therefore a promising approach for the treatment of cancer, a disease characterized by defects in growth signaling pathways that promote the hyperproliferation of aberrant cells.

The proteasome inhibitor, bortezomib (VELCADE™; formerly PS-341, LDP-341, MLN341), is a novel dipeptide boronic acid small molecule that has shown antitumor activity in preclinical studies and is the first such agent to have progressed to clinical trials. A phase III trial in patients with multiple myeloma (MM) is ongoing and several trials in patients with other hematologic malignancies or solid tumors are in progress. Here, we briefly review the preclinical rationale for bortezomib and the clinical trial status of bortezomib in patients with hematologic malignancies, with a focus on MM.

Section snippets

Preclinical rationale for proteasome inhibitors in hematologic malignancies

In cell culture and in xenografted tumors, bortezomib had potent activity, enhanced the sensitivity of cancer cells to traditional tumoricidal chemotherapeutics [1], [2], [3], [4] and appeared to overcome drug resistance (5). This activity is at least in part mediated by the activity of bortezomib against the NF-κB pathway. The NF-κB pathway is constitutively active in some cancer cells and is associated with proliferation, cell survival, and protection from chemotherapy-induced apoptosis (

Phase I: trial of bortezomib in patients with hematologic malignancies

Orlowski et al. conducted a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and phamacodynamics (PD) of bortezomib in patients with refractory hematologic malignancies (19) (Table 1). Patients (N=27) were enrolled at 0.40 mg/m2 (n=3), 1.04 mg/m2 (n=12), 1.20 mg/m2 (n=7), or 1.38 mg/m2 (n=5). Bortezomib was administered twice weekly for 4 weeks followed by a 2-week rest. Participants received a total of 293 doses of bortezomib, including 24 complete cycles.

Phase II: trials of bortezomib in patients with multiple myeloma

The safety and efficacy of bortezomib have been assessed in two phase II trials of patients with relapsed and refractory MM. Patients in Study 025 (SUMMIT) were relapsed and refractory to their most recent therapy; those in Study 024 (CREST) were relapsed or refractory after front-line therapy. Patients in Study 025 thus had more advanced disease.

This study enrolled patients in two cohorts: the first cohort filled rapidly (N=78), and, at the request of the investigators, enrollment continued to

Future directions

A phase III study comparing response to bortezomib versus high-dose dexamethasone is in progress. The multicenter Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial will be conducted at more than 60 centers in the United States, Canada, and Europe. Over 600 patients with relapsed or refractory MM will be enrolled and randomized to either bortezomib or dexamethasone treatment arms. Response will be assessed by prolongation of time-to-disease progression and selected

Conclusions

The NF-κB signaling pathway appears to be a promising target for the treatment of hematologic malignancies. Activation of NF-κB is an important step in transformation and can provide protection from cytotoxic treatments, while inhibition of this pathway with proteasome inhibitors results in apoptosis or sensitizes cancer cells to cytotoxic drugs. Phase I trials demonstrated responses in several hematologic malignancies, including MM; other phase I trials showed that this agent was relatively

References (25)

  • T. Hideshima et al.

    The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells

    Cancer Res.

    (2001)
  • M.H. Ma et al.

    Proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma cells to chemotherapeutic agents and overcomes chemoresistance through inhibition of the NF-κB pathway

    Blood

    (2001)
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