MYC Protein No Longer Appears Undruggable in Prostate Cancer, Preclinical Data Shows

Sarki Abdulkadir, MD, PhD

MYC has been considered an “undruggable” target in cancer for many years, but more recent research has demonstrated that this protein may be successfully targeting to inhibit the growth of cancer. This approach is particularly important in the treatment landscape of prostate cancer and was a hot topic of discussion during the 27th Annual Prostate Cancer Foundation (PCF) Scientific Retreat.

This cancer-causing protein has been thought to be undruggable because it is a disordered protein, which doesn’t have a fixed structure. This makes it challenging to develop a compound that could target any pocket in the protein, according to Sarki Abdulkadir, MD, PhD. It was also assumed that even if an inhibitor of MYC was developed and administered, patients would not be able to tolerate the drug considered MYC is expressed on normal tissues, in addition to the cancer cells.

However, because the cancer tumors tend to be attracted more towards the MYC protein, it is suspected that cancer cells will die when MYC is targeted while the normal cells are still able to function. Preclinical data are now suggestive that MYC-targeted compounds may be an effective treatment for patients with prostate cancer.

In an interview with Targeted Oncology, Abdulkadir, John T. Grayhack Professor of Urologic Research, vice chair for research, professor of urology and pathology, Northwestern University Feinberg School of Medicine, discussed the emerging role of the MYC protein as a target for the treatment of patients with prostate cancer.

TARGETED ONCOLOGY: Why is MYC a good target for prostate cancer?

Abdulkadir: The MYC protein is 1 of the earliest cancer-causing proteins to be discovered. It's a well-known oncogene. When it's at very high levels in many, many different tumor types, it is involved in causing cancer, and estimates indicate that over half of all human cancers of all types have an involvement of this protein, so it is very well known to play a role in the initiation and progression of cancer.

Specifically, in prostate cancer, it is involved not only in the development of the cancer but also when the cancer becomes resistant to many of the treatments that are available, this protein gets upregulated or becomes more active and helps the cancer cells to survive and keep growing and doing bad things. It's recognized as a key protein that could be a target that should be inhibited to inhibit prostate cancer.

TARGETED ONCOLOGY: Could you discuss some of promising things we've seen in research of MYC protein in the prostate cancer space?

Abdulkadir: This protein was known to be undruggable for many, many years, and people used to say this was an undruggable protein for the following reasons. One reason is that it doesn't have the fixed structure; it is what is called a disordered protein, so it's very hard, almost impossible, to find any place on the protein where you can design a compound, so there's no pocket that can be targeted.

For many years, people used to think that, even if you get an inhibitor, it's not going to be tolerated because this protein plays a role in normal tissue, in normal cells, so 2 things happen that changed that. One is a series of studies that have shown, in principle, you can inhibit this protein or you could remove it from an organism and reduce its levels and still not affect normal tissues that much. However, you have a severe effect on the tumor, so tumors need it more than the normal tissue. If you just reduce it activity, the tumors are not very happy, and they will die while the normal cells can still function, so we have a therapeutic window for its function. That's the first thing.

The second thing is that now we have new ways to inhibit this protein in different ways, some of which are indirect, some of which are direct, and at the retreat, we talked about some of the approaches that have been used to make compounds that seem to have activity against this protein in cell culture and in animal models. For many years, it's been kind of difficult to get to this stage. I think the excitement is that now we can see light at the very end of a long tunnel, so to speak, where now maybe we can now make this compound that will work in animals; then the next step will be carrying them forward to patients.

TARGETED ONCOLOGY: Could you provide an overview of these presentations at the PCF Scientific Retreat?

Abdulkadir: One presentation talked about the idea that I mentioned about oncogene addiction, like tumor cells like MYC much more than normal cells, and that gives us hope that we can tolerate MYC inhibitors whenever we get a drug, and also how MYC not only affects the tumor but the immune system. Immunotherapy is very big nowadays, and we know that you can activate the immune system to help clear tumors, so it looks like when you inhibit MYC, you may be exploiting the immune system of the organism to help clear the tumor as well.

The second talk focused on how MYC protein is degraded in the cell and how understanding how you degrade make provides avenues for how we can develop drugs to get rid of the MYC protein. Then we had another talk specifically on prostate cancer, where when cancer becomes resistant to treatment, MYC becomes more and more important that cancer depends on MYC and how now even in therapy-resistant cancers, maybe if we have a way to inhibit MYC, that should help.

I give the final talk, which is talking about a new approach that we have recently published, to overcome a big obstacle that has faced the field for several years, which is that for many years, people will find compounds that look like they may be MYC inhibitors, but either they are too weak, or they just don't work in animals; when you give it to an animal, the compound is metabolized or degraded, so it doesn't get to the tumor. We have devised a strategy where we can more quickly screen for compounds that would work in vivo in organisms, and that has led us to some leads and compounds that inhibit MYC, cause degradation as a bonus, cause degradation of the MYC protein, and also activate the immune response. These compounds look very interesting, and we are actively pursuing them.

TARGETED ONCOLOGY: What do you hope people took away from this session?

Abdulkadir: The main message is that we should not give up hope, especially on targets that are very well validated. We know they play a role. They have just so much evidence that MYC is 1 of these proteins with tons of data showing that it is really important, but initial attempts to generate inhibitors did not go so easily. I think the message is that we should not give up. We need to keep trying to see different approaches for how we can hit these targets because if we succeed, then the payoff is big. While this is still all in the preclinical space, I think it does generate hope. It's very important to support this kind of effort because that's what we will look forward to down the line, and I believe that's why the PCF wanted to highlight this area in this year's retreat.