New Enzyme Inhibitor Shows Modest Effect Against Relapsed Lymphoma

Dr. Jatin J. Shah, MD Associate Professor, Department of Lymphoma/Myeloma Assistant Professor, Lymphoma/Myeloma Division of Cancer Medicine The University of Texas, MD Anderson Cancer Center Houston, TX

Dr. Shah

MedicalResearch.com Interview with:
Dr. Jatin J. Shah, MD
Associate Professor, Department of Lymphoma/Myeloma
Assistant Professor, Lymphoma/Myeloma
Division of Cancer Medicine
The University of Texas, MD Anderson Cancer Center
Houston, TX 

Medical Research: What is the background for this study? What are the main findings?

Dr. Shah: The ubiquitin-proteasome system (UPS) is one of the key regulatory systems in our body’s cells. It controls the destruction of the majority of cellular proteins, which can be involved in making cells grow, expand, or die, among other functions. Defects in the UPS can result in a number of diseases, including cancer, for example by destroying too quickly the proteins that cause cells to die. The UPS has already been shown to be a rational target for cancer therapy: the approved drugs bortezomib and carfilzomib inhibit the proteasome itself, thus causing cancer cells to die. However, by completely blocking the proteasome, which is at the ‘end’ of the UPS, these drugs block the destruction of 100% of proteins, and can cause side effects. By contrast, blocking the NEDD8-activating enzyme (NAE) stops the cellular processes that are responsible for only approximately 20% of proteins being degraded by the UPS – including proteins of relevance to cancer development. Previous studies of pevonedistat in animals have shown that inhibiting NAE alters the ability of a cancer cell to repair its DNA after it is damaged; this leads to the death of cancer cells.

The man finding is this was the first reported study of pevonedistat in patients with multiple myeloma or lymphoma. It demonstrated that pevonedistat hits its target in cancer cells, exerted anticipated pharmacodynamic effects, and has modest activity as a single-agent in heavily pretreated patients with relapsed/refractory lymphoma.

Medical Research: What should clinicians and patients take away from your report?

Dr. Shah: Our study shows that pevonedistat causes NAE inhibition and the expected downstream effects, and demonstrates the validity of NAE inhibition as a therapeutic target for cancer therapy. The modest antitumor activity of single-agent pevonedistat in relapsed/refractory lymphoma suggests the possibility of future research in this indication. Based on our findings of limited activity in multiple myeloma, additional testing in this disease may not be warranted without additional research to support enrollment of a specific patient population.

However, the limitations of the study include the small number of patients, the fact that the patients were heavily pretreated and had a poor prognosis, and that patients with a range of different lymphomas were enrolled limiting our ability to determine if there was a particular disease type in which pevonedistat was more effective.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Shah: Future research will include further analysis of pharmacodynamic data on pevonedistat from this and other trials may be conducted to increase our understanding of how pevonedistat works.

The modest antitumor activity observed with single-agent pevonedistat suggests that even greater activity may be observed when pevonedistat is given in combination with standard therapy. Preclinical data supports this from a mechanistic perspective based on synergistic activity. Indeed, it was recently reported at ASH 2014 that the combination of pevonedistat plus azacitidine increased antitumor activity in acute myelogenous leukemia compared with single-agent azacitidine.

Citation:

Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

Jatin J. Shah, Andrzej J. Jakubowiak, Owen A. O’Connor, Robert Z. Orlowski,R. Donald Harvey, Mitchell R. Smith, Daniel Lebovic, Catherine Diefenbach,Kevin Kelly, Zhaowei Hua, Allison J. Berger, George Mulligan, Hélène M. Faessel,Stephen Tirrell, Bruce J. Dezube, and Sagar Lonial

Clin Cancer Res Published OnlineFirst November 11, 2015; doi:10.1158/1078-0432.CCR-15-1237julia.gunther@aacr.org

Dr. Jatin J. Shah, MD (2015). New Enzyme Inhibitor Shows Modest Effect Against Relapsed Lymphoma 

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