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Pulse - Winter 2018 Invented at Drexel: Startup Creates Novel Therapy For Drug-Resistant Cancer

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 metastasized, the five-year survival rate is about 29 percent (American Cancer Society). In 2016, more than 26,000 American men died from prostate cancer; the vast majority of them had developed resistance to standard drug treatments.

Assistant Professor Felix Kim, PhD, scientific founder of Context Therapeutics

Assistant Professor Felix Kim, PhD, scientific founder of Context Therapeutics

Prostate cancer cells are dependent on a protein called the androgen receptor, the primary driver of tumor growth and disease progression. Since androgens such as testosterone are the fuel that enables the androgen receptor to drive prostate cancer, the standard therapies involve depriving the cancer cells of androgens and preventing androgens from binding the androgen receptor using drugs designed to directly bind to and block the protein.

Currently, there are few drugs used to treat advanced prostate cancer in men, and they ultimately provide limited benefits to the patient. Though the drugs are effective for a time, eventu-ally 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 androgen receptor–targeted drugs that are designed specifically to suppress the disease," says Felix Kim, PhD, assistant professor in the College of Medicine and scientific founder of Context Therapeutics, the biotech startup spun out of his academic lab at Drexel.

While conducting neuropharmacology research at Memorial Sloan Kettering Cancer Center in 2005, Kim began looking at a unique protein called Sigma1 (also known as the sigma-1 receptor), which was identified more than four decades ago as a potential target for treating pain. "I became interested in Sigma1 through a confluence of circumstances: had I not been in a neuropharmacology lab at the time, I likely would not have known of Sigma1; and if I had not been at a cancer research center, I likely would not have thought to investigate Sigma1 in the context of cancer," he says.

In late 2010, Kim brought his research program to Drexel. He and his team found that Sigma1 is enriched and abnormally expressed in prostate tumors and discovered new compounds that suppressed prostate tumor growth by inhibiting Sigma1 in laboratory experimental models. The data generated by his team over several years made a compelling argument that Sigma1 could be a novel drug target for treating prostate cancer. In 2015, he co-founded Context Therapeutics with a former venture capitalist, Martin Lehr, to finance this drug discovery program and to develop these promising compounds into a new therapeutic agent to treat patients with refractory prostate cancers.

As described in their February 2017 Cancer Research publication "Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer," Kim and his colleagues have developed a new series of compounds 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, this approach was effective in sup-pressing prostate cancer cells that had become resistant to standard-of-care drugs. Kim also shared his findings and provided a review of the Sigma field in the recently released book Sigma Proteins: Evolution of the Concept of Sigma Receptors (Springer Press, 2017), of which he is co-editor.

This discovery paves the way for Context Therapeutics to develop a new class of drugs that will target Sigma1 and stop the progression of tumors in men with lethal prostate cancers that are resistant to current treatments. Through partnerships with scientists and clinicians at the Sidney Kimmel Cancer Center at Thomas Jefferson University, Fred Hutchinson Cancer Research Center, University of Washing-ton, Memorial Sloan Kettering Cancer Center and the Centre Léon Bérard in France, Context has built a network of leading prostate cancer experts helping to advance their compound to the clinic.

Context Therapeutics is exploring other applications for the Sigma1 technology, which Kim describes as a platform technology. In August, the company announced that it was initiating collaboration with three research partners — Cedars-Sinai Medical Center, Fred Hutchinson Cancer Research Center and Fondation Synergie Lyon Cancer — to determine the role of Sigma1 in other disease models and to evaluate the activity of Context's proprietary Sigma1 modulators in state-of-the-art prostate cancer patient–derived tumor models and tumor biopsy explant models. (See

"This project is a cornerstone of a mechanism-focused cancer pharmacology research program in which we will precisely define how the Sigma1 system works in tumors in order to effectively exploit it as a drug target to treat a number of cancers," Kim says. "We are also investigating other potential uses for our technol-ogy. We think our Sigma platform could be used to discover and develop therapeutic agents for pain as well as certain inflammatory and neurodegenerative diseases."

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