Prostate cancer is the most common non-skin cancer among American men, according to the Centers for Disease Control and Prevention. Though many patients beat the disease, once the cancer has spread to distant organs — a process known as metastasis — the five-year survival rate is less than 30 percent. In 2016, more than 26,000 American men died from prostate cancer, the vast majority of whom developed resistance to standard drug treatment.
At all stages of the disease, prostate cancer cells are dependent on a protein called the androgen receptor (AR), the primary driver of tumor growth and disease progression. Since testosterone is the fuel that enables the androgen receptor to drive prostate cancer, current therapies involve suppressing the androgen receptor with targeted drugs that directly bind to and block the protein.
Currently, there are three main drugs used to treat advanced prostate cancer in men, but they ultimately provide limited benefits to patients. While the current medications are effective for a limited time, eventually the androgen receptors in prostate tumors reactivate and develop drug resistance.
“Prostate cancer is a highly adaptive and constantly evolving disease. Ironically, treatment resistance is driven, in part, by the AR-targeted drugs that are designed specifically to suppress the disease,” said Felix Kim, PhD, assistant professor in the College of Medicine and co-founder of Context Therapeutics.
Realizing a need to address this problem of drug resistance, Kim became interested in a unique protein called Sigma1 (also known as the sigma-1 receptor), which was identified over four decades ago as a potential target for treating pain. Kim and his research team found that Sigma1 is enriched and abnormally expressed in prostate tumors, making it a novel target for treating prostate cancer.
Kim likens the Sigma1 system to the cellular version of ride-share companies like Uber or Lyft, whose drivers sit idle until a rider sends an alert. Similarly, Sigma1 is found in every cell, but it remains inactive until promoted. Cellular stress, a hallmark of cancer, activates Sigma1 to pick up cancer-promoting client proteins and transfer them to sites of action. The androgen receptor is one such client protein of Sigma1.
As described in a recent paper published in Cancer Research, Kim and his colleagues have developed a new series of drugs that target Sigma1 to block the activity of the androgen receptor and essentially eliminate it from prostate cancer cells. By targeting Sigma1, rather than the androgen receptor directly, the researchers were able to knock out the receptor’s support system. Importantly, Kim said, this approach was effective in suppressing prostate cancer cells that had become resistant to all other drugs.
This discovery paves the way for Context Therapeutics — Kim’s startup that launched in 2015 — to develop a drug candidate that targets Sigma1 and stops the progression of tumors in men with lethal prostate cancers that are resistant to current treatments.