Putting the Focus on p53 in Multiple Myeloma

Vijay G. Ramakrishnan, PhD

Research Associate

Hematology

Mayo Clinic

Rochester, MN

As with other types of cancer, the molecular drivers of multiple myeloma (MM) are of intense interest to researchers. In his laboratory at Mayo Clinic in Rochester, Minnesota, Shaji K. Kumar, MD, is working to understand the genomic intricacies of MM, particularly the role played by activity associated with the TP53 gene. He expects to publish the results of several such projects in 2013.

In a conversation with OncologyLive, a research associate in Kumar’s lab, Vijay G. Ramakrishnan, PhD, offered some details about those projects, which are funded by the National Institutes of Health, the Multiple Myeloma Research Foundation, and Mayo Clinic.

Q:

One of the lab’s research interests is identifying the reasons behind, and potential new treatments for, high-risk MM. Please discuss the team’s efforts to solve this problem.

A:

Of particular interest and focus is the impact of p53 deletion in myeloma, because it’s known that a significant proportion of patients with this deletion do poorly when compared with those who don’t have the deletion. To better understand this, we’re doing gene expression profiling on high-risk patients who have the deletion, and on those who don’t. The goal is to identify the genes that could be associated with p53 deletion. This would not only enable us to predict outcomes for specific patients, but would identify genes that would make likely targets for future treatments.

To get this information, we extract total RNA from patient cells and check the expression levels of all the expressed genes. This will present us with a global view of the genes of these two groups of patients and the genes associated with p53 deletion.

This is especially important because not all patients with the p53 deletion do poorly. Dr Kumar has already demonstrated that there are other compensatory mechanisms, like trisomies in the myeloma cells, which ameliorate the effect of a p53 deletion. So in those patients, the question is: Does this happen because specific genes are present abundantly, and does that somehow overcome the expected bad response?

Q:

Are you conducting any other investigations that focus on the p53 deletion?

A:

Yes, as part of the development of a novel drug, we are working in the lab to use molecules to upregulate p53, since it functions as a tumor suppressor. The drug we’re testing is an MDM2 inhibitor designed by a pharmaceutical company to kill cancer cells by increasing their levels of p53.

We’re conducting these experiments on established human MM cell lines and myeloma patient-derived plasma cells.

If not ultimately useful for the patient with a p53 deletion, we hope the drug might still help p53 wild-type patients.

Q:

Is your lab investigating any other drivers of MM?

A:

We’re analyzing the phenotypic differences between plasma cells from individuals with premalignant conditions and active MM disease. Such studies will help us to discover markers of prognostic relevance and help us to identify individuals with a high risk of progression to an active disease stage.

In addition, we are looking at the role of the tumor microenvironment in disease progression. It’s known that angiogenesis increases with disease progression. Specifically, we are trying to identify angiogenesis-related genes/proteins that are differentially expressed in patient plasma cells across disease stages. More recently, we have identified a few of these proteins that are of interest.

Now, we’ll start doing functional assays, in which we’ll be overexpressing and knocking down those proteins in the cell to see their effects on angiogenesis, tumor growth, and apoptosis. Such studies will help validate the role of angiogenesis in MM, the importance of the identified proteins in angiogenesis, and the benefits of inhibiting angiogenesis in patients with active disease.