BioDrugs

, Volume 20, Issue 1, pp 13–23 | Cite as

Mechanistic Rationale and Clinical Evidence for the Efficacy of Proteasome Inhibitors against Indolent and Mantle Cell Lymphomas

  • Luca Paoluzzi
  • Owen A. O’Connor
Mechanisms and Targets

Abstract

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially ‘drugable’ targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies.

The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.

Notes

Acknowledgments

Dr L. Paoluzzi is supported by an American-Italian Cancer Foundation Fellowship. Dr O.A. O’s the recipient of the Leukemia and Lymphoma Society Scholar in Research Award and is on the Speakers’ Bureau for Millennium Pharmaceuticals. This work was supported under a NCI Phase II Grant (UOl CA 69913). Dr O’Connor would also like to thank Mortimer J. Lacher and the generous support from the Werner and Elaine Dannheisser Fund for Research on the Biology of Aging of the Lymphoma Foundation.

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Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Luca Paoluzzi
    • 1
    • 2
  • Owen A. O’Connor
    • 1
    • 3
  1. 1.Laboratory of Experimental Therapeutics for the Lymphoproliferative MalignanciesMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Division of Medical Oncology ARegina Elena Cancer InstituteRomeItaly
  3. 3.Department of Medicine, Division of Hematologie Malignancies, Lymphoma and Developmental Chemotherapy ServicesMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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