Dr. Daniel James George is a Professor of Medicine and Professor in Surgery at Duke University.
Prostatepedia spoke with him recently about a clinical trial he is running for men with neuroendocrine prostate cancer.
What is neuroendocrine prostate cancer?
Dr. George: For a long time, people have known about neuroendocrine prostate cancer, which is a different biology of prostate cancer. The testosterone pathway drives most prostate cancers, as well as the androgen receptor or the testosterone receptor. That biology accounts for probably over 90% of initially presenting prostate cancers. A downstream protein that’s coded for and turned on from the androgen receptor is prostate-specific antigen (PSA). We have a blood test for PSA that measures this biology to some extent.
Also, for a long time, we’ve known about the activity of the androgen receptor in prostate cancer through the PSA and its kinetics—its ups, downs, and whatnot. We have thought of neuroendocrine prostate cancer as a rare form of prostate cancer that— instead of growing out of the basal cell of the prostate and into a luminal cell, which secretes PSA—grows out of a cell in the prostate environment called a neuroendocrine cell. It’s called that because it’s derived embryologically from the same types of cells derived from our endocrine system into neurons.
The neuroendocrine cell has characteristics very different from other prostate cancers. It doesn’t have the androgen receptor, it can secrete different types of proteins like CEA or chromogranin, and it grows irrespective of our effects on testosterone. It can spread to soft tissues like the liver, lung, and other areas in a pattern that differs from the spread in more common prostate cancers. It’s got an aggressive clinical course. It spreads quickly and can kill people in a matter of months.
More recently, we have come to understand that prostate cancer evolves in patients over time to have more and more neuroendocrine features. Some of our more novel ways of blocking the testosterone pathway with drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) have stressed this system so much that we’re seeing a greater percentage of patients evolve into or select for a neuroendocrine phenotype. This is becoming a more prevalent problem as patients live longer and as we use more of these hormone therapies.
How is the trial designed? What will you do and what should patients expect?
Dr. George: This project started when we were looking at how to block the testosterone receptor downstream.
Drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) are fantastic at blocking the androgen receptor by binding to a certain part of the receptor called the ligand-binding domain. Over time, this can get overexpressed to such a level that these drugs can inhibit it or result in a splice variant. A splice variant means that the DNA gets expressed only partially so that a shortened or truncated form of the receptor is made that doesn’t have the ligand binding domain and is therefore completely resistant to those drug therapies. That’s becoming more and more prevalent.
We looked to see if we could block some biology downstream. We found that when the androgen receptor is activated in these hormone resistant models, the copper transporter and other genes involved in copper metabolism were highly expressed. So, we tested drugs that would bind up copper, but it didn’t work well. It only worked at very toxic levels.
Then we decided to turn this around. Instead of blocking copper, we fed the cancer copper. We allowed the cancer cells to accumulate a bunch of copper, and then we screened for drugs that would kill the copper-laden cells particularly in this setting. We found several drugs in the dicarbamate family. First and foremost is a drug called disulfiram, also commonly known as Antabuse. This is a drug that is used to block alcohol dehydrogenase, making alcohol toxic in alcoholics. However, in tumors, we found that when disulfiram binds copper, it becomes lethal to cancers.
We’ve taken this to clinic, and under an investigational new drug authorization from the FDA, we’re going to load tumors with intravenous copper, image with a copper PET scan, and then treat patients with oral CX-02 (disulfiram) and additional oral copper. This strategy gets interesting for neuroendocrine tumors is because the copper transporter is also essential for platinum transport. Copper and platinum are both cations (positively charged ions), and platinum chemotherapies like carboplatin and cisplatin are very effective in neuroendocrine tumors for a period of time. For those cells to be sensitive to platinum, the platinum must get inside the cells, so we know they must also express the copper transporter.
We think targeting this copper transport mechanism may represent a second and novel way to target neuroendocrine prostate cancer.