Clinical update: proteasome inhibitors in solid tumors

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Abstract

The proteasome plays a critical role in regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib (VELCADE™; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Preclinical research has shown that through the prevention of IκB degradation, bortezomib may block chemotherapy-induced NF-κB activation and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilization of p21 and p27, as well as transcription factor p53. In preclinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and demonstrated anti-angiogenic properties. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/syngeristic role in overcoming resistance to conventional chemotherapy. Preliminary data from early clinical trials suggest that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities. Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials.

Introduction

The ubiquitin-proteasome pathway plays an important role in regulating the cell cycle, neoplastic growth, and metastasis. A number of key regulatory proteins are temporally degraded during the cell cycle by the ubiquitin-proteasome pathway, and the ordered degradation of these proteins is required for the cell to progress through the cell cycle and to undergo mitosis [1], [2].

One of the targets of ubiquitin-proteasome mediated degradation is the tumor suppressor p53, which acts as a negative regulator of cell growth (3). This suppressor is required for the transcription of a number of genes involved in cell-cycle control and DNA synthesis (ie, E2F, p21CIP1/WAF1), and also plays an important function in apoptosis induced by cellular damage including ionizing radiation.Cyclins and the cyclin-dependent kinase inhibitors p21 and p27KIP1 are another set of growth regulatory proteins that are regulated by proteasome-dependent proteolysis. Both p21 and p27 can induce G1 cell-cycle arrest by inhibiting the cyclin D-, E- and A-dependent kinases.

Furthermore, the ubiquitin-proteasome pathway is required for transcriptional regulation. Nuclear factor-κB (NF-κB) is a key transcription factor whose activation is regulated by proteasome-mediated degradation of the inhibitor protein IκB. Cell adhesion molecules (CAM) such as E-selectin, ICAM-1, and VCAM-1 are regulated by NF-κB and are involved in tumor metastasis and angiogenesis in vivo. During metastasis, these molecules direct the adhesion and extravasation of tumor cells from the vasculature to distant tissue sites within the body. As such, tumor cell metastasis will also be limited by the downregulation of NF-κB-dependent expression of cell adhesion molecules (4). Moreover, NF-κB is also required in a number of cell types to maintain cell viability as an anti-apoptotic controlling factor. Inhibiting NF-κB activation by stabilizing the IκB protein makes cells more sensitive to environmental stress and cytotoxic agents, ultimately leading to apoptosis.

It becomes clear that inhibitors of the proteasome can act through multiple mechanisms to arrest tumor growth, tumor spread, and angiogenesis. The combination of these mechanisms offers a potential new approach to treating cancer and laboratory findings support this hypothesis.

Bortezomib (VELCADE™; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. In laboratory studies, bortezomib has shown activity as a single agent and has exhibited additive effects when combined with standard chemotherapeutic agents (Table 1). The following data outline the preclinical rationale for bortezomib’s application to solid tumor treatment and provide a review of the current status of bortezomib in solid tumor clinical trials.

Section snippets

Preclinical rationale for proteasome inhibitors in solid tumors

Bortezomib appears to be a unique and selective inhibitor of proteasomal cellular protein degradation. In an NCI 60-cell line panel, bortezomib induced cytotoxicity with an average 50% growth inhibition at low concentrations (7 nM). An analysis employing the NCI COMPARE algorithm determined that bortezomib was unique compared with historical results of 60,000 other compounds. In addition, in an in vitro study of mice implanted with the PC-3 prostate tumor xenografts, weekly IV administration of

Phase I trials of bortezomib in solid tumors

There are currently 12 NCI CTEP- (9 open, 3 closed), 5 industry-sponsored, and one investigator initiated phase I trials researching the effect of bortezomib on advanced solid tumors (T, T). At the time of this writing, data from one published paper and several conference reports are available. Aghajanian et al. (11) conducted a phase I trial to evaluate toxicity and pharmacodynamics of bortezomib in patients with advanced solid tumor. Patients (N=43) were enrolled with a variety of tumor

Phase II trials of bortezomib in solid tumors

There are currently 7 single agent phase II trials underway assessing bortezomib in the treatment of solid tumors (Table 4). Tumor types include ovarian, breast, renal cell, sarcoma, and lung. The trials are currently accruing patients and preliminary data are not available. Three additional single agent phase II trials in renal cell cancer, neuroendocrine tumors and melanoma have closed, and data from these should be available soon. There are three active Phase II trials of bortezomib in

Protocols in development

In addition to the active trials listed in T, T, T, T, there are NCI/CTEP and Investigator Initiated Studies in development in solid tumors, both with bortezomib alone and in combination with a wide range of chemotherapeutic agents in cancers of the breast, colon, stomach and GE junction, liver, biliary system, bladder, lung, thyroid, ovary, prostate, and melanoma.

Conclusion

Taken together, it is clear that inhibitors of the proteasome can act through multiple mechanisms to arrest tumor growth, tumor spread and angiogenesis. The combination of these mechanisms offers a novel approach to treating cancer, with laboratory findings supporting this hypothesis. Indeed, tumor cells that bear multiple genetic defects, including impaired repair mechanisms and faulty cell cycle checkpoint controls, are sensitive to the growth inhibitory actions of proteasome inhibitors both

Acknowledgements

Supported by Grants UO1 CA62505-09, NO1-CM-17101.

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