Drug-Like Compounds Hold Promise for Treatment-Resistant Prostate Cancer

Treatment seeks to reverse chemotherapy resistance caused by P-glycoprotein.

Treatment seeks to reverse chemotherapy resistance caused by P-glycoprotein.

Researchers at Southern Methodist University (SMU) recently discovered 3 new drug-like compounds that have the potential to offer better odds of survival to patients with prostate cancer. The compounds can be modified and developed into medicines that target a protein responsible for chemotherapy resistance in cancers.

Cancer chemotherapy resistance is caused by P-glycoprotein (P-gp), and there are currently no medications that reverse chemotherapy resistance caused by P-gp. Tariquidar is one potential treatment that could achieve this result, however the drug remains in clinical trials and many other therapies tested in the past have proven unsuccessful.

“The problem when a person has cancer is that the treatment itself is composed of cellular toxins — the chemotherapeutics that prevent the cells from dividing. Usually upon the first chemo treatment the cancer responds well, and initially goes away. Ideally it doesn’t come back,” said lead author Pia D. Vogel, director of SMU’s Center for Drug Discovery, Design and Delivery. “Sometimes, however, the cancer returns. The reason often is that some of the cancer cells ‘learn,’ after the first rounds of chemotherapy, how to make a lot of this P-gp pump. The normal function of P-gp is to pump toxins from cells, so it has evolved to protect cells against a large variety of toxins, including almost all currently available chemotherapeutics. After initial exposure, the cells surviving the chemo make so much P-gp that it allows the cells to pump the chemotherapy drugs straight back out of the cells during subsequent rounds of treatment.”

As a result, P-gp cause the resistance to cancer treatments, as well as to the treatment of diseases like HIV/AIDS.

The new drug-like compounds discovered by Vogel and her co-authors offer hope that using a computer-generated P-gp model, developed to accurately mimic the physical, chemical, and biological functions of the protein in the human body, will speed up the drug discovery process and work in real life as well.

“These are not drugs yet. We still have to develop them before they can go in the clinic,” Vogel said. “But what we know now is that they’re not toxic — they have low toxicity to noncancerous cells, so that’s a pretty good predictor that they may be good candidates for drug development. But we need to do much more work.”

A pharmaceutical hit compound, like those discovered by Vogel and her team, is one that shows promise in being further developed as a therapeutic drug for patients with various diseases. In this case, the compounds were commercially available for testing. The timeline from drug discovery to development to clinical trials and approval can take a decade or more.

The SMU researchers scanned 15 million small drug-like compounds made publically available in digital form from the pharmacology database Zinc at the University of California, San Francisco to find the 3 hit compounds.

Using SMU’s ManeFrame high performance computer, researchers ran the compounds through a computer-generated model of P-gp. The model is the first of its kind to simulate the actual behavior of P-gp in the human body, including interactions with drug-like compounds while taking on different shapes.

The ultra-high throughput computational searched by ManeFrame yielded 300 possible compounds that showed promise in inhibiting P-gp. Researchers then tested 38 of those compounds and found 4 that possessed this function.

Each of the 4 compounds was then tested in the lab to see how it would affect a line of prostate cancer cells relatively sensitive to the chemotherapeutic Paclitaxel, commonly used to treat prostate cancer patients. It was also tested on companion cell lines that were already drug-resistant as if the patient had already gone through treatment with Paclitaxel.

Three of the 4 compounds were able to push back the sensitivity of the resistant cancer line to the level of the non-resistant one.

“So the compounds re-sensitized the cancer cell lines to a really high degree, just as if the cancer was seeing the chemotherapy for the first time,” Vogel said.

It will take some time for researchers to develop a drug that can effectively treat those with prostate cancer who are treatment-resistant, but the discovery of this compound holds much promise for the future.