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Kolenko Receives Grant to Study Link Between Cholesterol and Androgen Deprivation Therapy Resistance in Prostate Cancer

February 25, 2020

Kolenko and colleagues plan to target cholesterol homeostasis using genetic and pharmacological approaches in order to reinstate or re-emphasize sensitivity of prostate cancer cells to anti-androgens like abiraterone and enzalutamide.Kolenko and colleagues plan to target cholesterol homeostasis using genetic and pharmacological approaches in order to reinstate or re-emphasize sensitivity of prostate cancer cells to anti-androgens like abiraterone and enzalutamide.

PHILADELPHIA (February 25, 2020) – Vladimir Kolenko, MD, PhD, a researcher at Fox Chase Cancer Center, has received a grant to study the role of cholesterol in resistance to the androgen receptor inhibitor enzalutamide and how to improve the effectiveness of enzalutamide by targeting cellular cholesterol stability in prostate cancer tumors.

Enzalutamide is one of the first Food and Drug Administration-approved second-generation androgen receptor inhibitors used for the treatment of both non-metastatic and metastatic castration-resistant prostate cancer, which keeps growing even when testosterone is reduced to very low levels.

Enzalutamide and abiraterone, another anti-androgen therapy, are among the most common drugs used for prostate cancer treatment, said Kolenko, an associate research professor in the Cancer Biology program at Fox Chase.

“These are drugs that are most commonly used to treat metastatic prostate cancer, but eventually tumors develop resistance. Partially, it can be because cholesterol—either LDL cholesterol or HDL cholesterol, it doesn’t matter which one—can activate pro-survival signaling pathways in prostate cancer cells that can simply bypass the therapeutic effect of anti-androgens,” said Kolenko.

Kolenko received the two-year $200,000 grant from the National Cancer Institute. During those two years, Kolenko and colleagues plan to target cholesterol homeostasis using genetic and pharmacological approaches in order to reinstate or re-emphasize sensitivity of prostate cancer cells to anti-androgens like abiraterone and enzalutamide.

“It’s well known that cholesterol can serve as a precursor for hormone synthesis. We propose a novel conceptual model that, in addition to serving as a precursor for androgen synthesis, lipoprotein-derived cholesterol may promote development of castration-resistant phenotype in prostate cancer cells via androgen-independent activation of Akt/mTOR signaling,” Kolenko said.

Akt/mTOR signaling plays a critical role in the progression of prostate cancer to castration-resistant growth and development of resistance to androgen deprivation therapy (ADT). “First, we plan to validate the role of cholesterol in ADT resistance, and second, we will try to reinstate sensitivity of tumor cells using several agents that can interact with cholesterol—either uptake or trafficking in tumor cells,” said Kolenko.

The new study, Kolenko added, could establish for the first time the role of different lipoproteins in prostate cancer progression to castration-resistant growth and ADT resistance. “We anticipate that the proposed studies will gain insights that suggest new therapeutic options for the treatment of prostate cancer,” he said.

      

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

 

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