Study Identifies New Approach to Overcome Docetaxel Resistance in Patients with Advanced Prostate Cancer

The treatment landscape for patients with prostate cancer, especially individuals with advanced disease, has dramatically changed in recent years. However, aside from drug or hormonal therapies, other targets to treat prostate cancer are still necessary to prolong life and slow the progression of this potentially lethal disease. A new studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, found that inhibition of the sterol regulatory element of binding (SREB) can reinduce sensitivity to the drug docetaxel, commonly used to treat prostate and other cancers. These findings show promise to improve the efficacy of docetaxel-based chemotherapy in patients with prostate cancer.

Co-lead investigator Maximilian P. Brandt, MD, Department of Urology and Pediatric Urology, Mainz University Medical Center, Mainz, Germany, explains, "Prostate cancer is the most common cancer in men, and it remains a clinical challenge to find the right treatment for patients with metastatic disease. It is crucial to develop new therapeutic strategies and find new targets to optimize treatment. Knowing that every patient with metastatic prostate cancer who receives a first line of systemic treatment will eventually develop therapy resistance, e.g. against docetaxel or hormones, makes this research highly interesting and necessary."

Over the past decade, treatment options for patients with metastatic prostate cancer have dramatically increased with improved disease control by prolonging progression-free survival and overall survival. Docetaxel is one of the most established chemotherapy regimens for prostate cancer and remains a cornerstone in the treatment of patients with prostate cancer. Combining docetaxel with second-generation hormonal therapy is a novel treatment approach, with recent studies showing improved progression-free and overall survival. However, the efficacy of chemotherapy is restricted by the development of therapy resistance, which represents a significant limitation in clinical practice.

Investigators performed RNA sequencing in docetaxel-resistant prostate cancer cell models after treatment with a combination of docetaxel and mifepristone. This treatment significantly reduced cancer cell viability. RNA sequencing revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly down-regulated target. This is a central cellular regulator involved in docetaxel-resistant prostate cancer. Specific Inhibition of cholesterol and lipid biosynthesis reinduced sensitivity to docetaxel. Furthermore, researchers were able to show that SREBPs are increasingly expressed in metastatic prostate cancer, which they found in a specific tissue microarray from tumor tissue from advanced prostate cancer patients.

Co-lead investigator Martin Puhr, PhD, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria, notes, “Our results support the idea that SREBPs are essential regulators of cell survival and susceptibility to docetaxel in advanced and metastatic prostate cancer, affecting prostate cancer aggressiveness and docetaxel resistance. Our data provide further evidence that inhibiting cholesterol and lipid biosynthesis might provide a clinically meaningful rationale for increasing the efficacy of prostate cancer therapies and in specific, drug-resistant prostate cancer.”

Notes for editors

The article is “Inhibition of the Sterol Regulatory Element Binding Protein SREBF-1 Overcomes Docetaxel Resistance in Advanced Prostate Cancer,” by Maximilian P. Brandt, Olesya Vakhrusheva, Hubert Hackl, Tamas Daher, Katrin Tagscherer, Wilfried Roth, Igor Tsaur, Florian Handle, Andrea Eigentler, Zoran Culig, Christian Thomas, Holger H.H. Erb, Axel Haferkamp, Eva Jüngel, and Martin Puhr (https://doi.org/10.1016/j.ajpath.2024.07.019opens in new tab/window). It appears online in The American Journal of Pathology, volume 194, issue 11 (November 2024), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(24)00295-5/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact Maximilian P. Brandt, MD, at [email protected]opens in new tab/window.

The study was supported by the Anniversary Fund of the Oesterreichische Nationalbank (grant 18280), the Brigitte und Dr. Konstanze Wegener-Stiftung (grant 72), and Ferdinand-Eisenberger (grant BrM1/FE-18).

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.orgopens in new tab/window

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