Blocking Two Key Signaling Pathways Reverses Prostate Cancer Drug Resistance

After studying a population of primitive, Docetaxel-resistant prostate cancer stem cells, cancer researchers have proposed a treatment regimen for advanced prostate cancer that blocks the Notch and Hedgehog molecular signaling pathways.

While acquired resistance to Docetaxel usually leads to death in hormone-refractory prostate cancer (HRPC), strategies that target Docetaxel-resistant cells have not been developed.

To change this situation investigators at Columbia University (New York, NY, USA) used in vitro and in vivo models to study the subpopulation of prostate cancer cells that survive Docetaxel exposure. Docetaxel is a synthetic derivative of the naturally occurring compound paclitaxel. Like paclitaxel, Docetaxel promotes the formation of microtubules that do not function properly. One of the roles of normal microtubules is to aid in cell duplication, and by disrupting this function, Docetaxel inhibits cell reproduction.

Results published in the September 11, 2012, issue of the journal Cancer Cell revealed that this subpopulation of prostate cancer cells lacked differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Cells from this subpopulation exhibited potent tumor-initiating capacity, which established a link between chemotherapy resistance and tumor progression.

Targeting Notch and Hedgehog signaling eliminated the Docetaxel-resistant stem cell subpopulation through inhibition of the survival molecules AKT (Protein Kinase B) and Bcl-2 ((B-cell lymphoma 2), suggesting a therapeutic strategy for abolishing Docetaxel resistance in HRPC.

"This is the first time these so-called cancer stem cells of prostate have been identified as the basis for drug resistance and tumor progression, indicating that they are cancer’s "Achilles Heel"," said senior author Dr. Carlos Cordon-Cardo, professor of pathology at Columbia University. "These findings are the culmination of more than six years of innovative research, which has led to the successful unveiling of cancer characteristics that are critical to understanding how the disease works and progresses."

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