Rekha Rao, PhD
The function of the ATPase p97, or valosin-containing protein, is essential in restoration of protein homeostasis in cancer cells. When working alongside the ubiquitin proteasome system, p97 can also promote the degradation of misfolded proteins.
at the 2017 AACR Annual Meeting, lead author Rekha Rao, PhD, assistant professor at University of Kansas Medical Center, discussed targeting p97 in MCL.
OncLive: Please provide an overview of your study.
: Most B cells are sensitive to agents that induce ER stress. So, we thought that targeting MCL, which is a B-cell lymphoma, with new agents that can induce ER stress may desensitize them. One example is bortezomib (Velcade), which has been used in MCL, the problem is that the patients relapse and then become boreztomib resistant, so we need new targets that induce ER stress in the mantle cells.
We did combination studies to look at apoptosis and the p97 inhibitor CB-5083, developed by Cleave Biosciences, which is currently in phase I clinical trial for relapsed/refractory multiple myeloma and solid tumors. We have combined these 2 in vitro, and are currently testing it in mice, to see if the combination works. This will be ready for an early phase clinical trial very soon.
Are there any next steps with this target?
We are finding that this p97 inhibition can also work in other B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL). We think that this could have a broader range of application other than just MCL. We are currently doing lab studies to confirm these in DLBCL and of course, as we all know, the problem in DLBCL is relapse. So, we are mainly targeting those patients with p97 in which the disease has relapsed. This will be a very good target for relapsed/refractory non-Hodgkin B-cell lymphoma—that is the direction we are taking this research.
What is the impact of this research on the field?
I think the takeaway from this is that there is hope. Even though we have very good drugs coming out in MCL, there is a need to develop novel therapies because somehow the cancer cells tend to develop resistance to whatever therapy we use. Therefore, I think targeting the B cell with an agent that induces ER stress—and an agent that is different from boreztomib—I think that it really exciting. This will have huge implications for patients who have no choices left for therapy.
Looking ahead, what challenges still exist in this treatment landscape?
The challenge is that, down the road, mantle cells can still develop resistance to p97 inhibitors, but we have a bunch of compounds that are slightly different from the compound that is currently in clinic. So, the future is to develop newer analogs of p97 inhibitors that can probably still work in patients who develop resistance to existing p97 inhibitors. P97 inhibition targets several different cellular processes, all of which can result in radiotoxic stress. It is not just ER or the cytosolic misfolded proteins, but p97 can impact ribosome-associated degradation and mitochondria-associated degradation—so it has huge implications. I think this will be very good for developing novel compounds out of this parent compound that we have.
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