Valosin-containing protein – p97 – is crucial in restoring the homeostasis of cancer cells. When working alongside the ubiquitin proteasome system, it can also promoste the degradation of misfold proteins.
Additionally, p97 has been found to induce stress in the endoplasmic reticulum (ER) of cells. Cancers, specifically B-cell lymphomas, are sensitive to agents that induce ER stress—which led to researchers using p97 inhibitors in mantle cell lymphoma (MCL).
In a study evaluating the synergistic activity of p97 inhibitors with histone deacetylate 6 (HDAC6) inhibitors, it was hypothesized that inhibition of p97 function combined with HDAC6 inhibitors would induce phototoxic stress and/or apoptotic cell death in MCL.
In an interview with CURE at the 2017 AACR Annual Meeting, lead author Rekha Rao, Ph.D., assistant professor at University of Kansas Medical Center, discussed targeting p97 in MCL.
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 Velcade (bortezomib), which has been used in MCL, the problem is that the patients relapse and then become Velcade resistant, so we need new targets that induce ER stress in the mantle cells.
We tried p97, which is an ATPase that is involved in extracting misfolded proteins from the ER. When you inhibit p97 function, you can induce ER stress, which in turn, causes apoptosis in the mantle cell. That was the rational to choose p97 inhibitors, and we also have combined these with the HDAC6 inhibitors because HDAC-6 is another molecule that is required to remove these folded proteins from the cell. Either way — if you inhibit the p97 or the HDAC6 — we are going to get a buildup of polyubiquitinated proteins which are misfolded, and which get aggregated and cause proteotoxic stress.
We started out in cell lines. Now, we have tested a series of p97 inhibitors in cell lines and there is one HDAC6 inhibitor that is already in the clinic, ACY 1215, so we used that as a combination.
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 two 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 Velcade — 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.
The other thing I would like to try is a combination of Imbruvica (ibrutinib) with p97 inhibitors, which may hold promise for relapsed MCL patients. That is another area of interest which we have not started any studies on, but is probably in the future.
What attracts you to the combination of Imbruvica with p97 inhibitors?
Right now, Imbruvica is the wonder drug. It has worked beautifully in chronic lymphocytic leukemia and MCL. But, as time goes on, we are seeing that patients are developing resistance to Imbruvica, so there is a necessity to develop newer drugs that will work in the cohort of patients who develop resistance. So, this is me looking forward, because Imbruvica is working now, but five or 10 years down the road, you are going to want to have compounds in your pocket that you can take out and try.