Recent publications identify new targets for prostate cancer research

Date Posted: 
2018-03-08
Buttyan and Wang lab groups

Two recent publications led by our Centre’s PIs describe discoveries in the development of prostate cancer and progression to castration-resistant disease. This information provides new targets for the development of potential therapeutics.

Discovery of non-canonical activation of Hh signalling

Dr. Ralph Buttyan and his team have published a study describing a novel pathway for gene activation in prostate cancer which may be clinically relevant as a target for disease treatment. "Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3" was published in Oncogene.

The Hedgehog (Hh) signaling pathway is one of the major regulators of cell growth and differentiation during embryogenesis and early development. In adults, inappropriate activation of the Hh pathway is seen in a number of cancers including basal cell carcinomas,  medulloblastoma, and brain, gastrointestinal, lung, breast and prostate cancers. The glioma-associated oncogene homolog (Gli) transcription factors are critical mediators of the activated Hh pathway, and their expression may be elevated in some tumors independent of upstream Hh signaling.

Dr. Buttan and his research team have discovered a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors to Gli3. This is a novel pathway for non-canonical activation of Hh signaling in prostate cancer, and identifies a means for interference that may have clinical relevance for prostate (and potentially other) cancer patients.

This research was funded by Canadian Institutes of Health Research, Prostate Cancer Canada & Movember's Team Grant, the US Department of Defense, and the Terry Fox Research Institute's New Frontiers Program Project Grant.

Discovery of an early driver of neuroendocrine prostate cancer development

Dr. Yuzhuo Wang and his research team have developed a unique first-in-field, clinically relevant experimental neuroendocrine prostate cancer (NEPC) model that can be used to study the development of NEPC following androgen deprivation therapy. NEPC is a lethal, late manifestation of prostate cancer for which there is currently no effective treatment.

Using this model, they have recently discovered that a heterochromatin gene, called HP1α, plays a crucial role in the transition of prostate cancer into NEPC.  Their recent Cancer Research publication, “Heterochromatin protein 1α mediates development and aggressiveness of neuroendocrine prostate cancer”, reports an NEPC-specific heterochromatin gene signature that can be applied for precision diagnosis of the disease. Furthermore, HP1α appears to involve a novel mechanism in NEPC development and thus is a promising therapeutic target for both treatment and prevention of NEPC.

Funding for this work was provided by the Canadian Institutes of Health Research, Terry Fox Research Institute, BC Cancer Foundation, Urology Foundation, and Prostate Cancer Canada. In addition, salary support was provided as noted:  Prostate Cancer Canada-Movember Training award (for X. Ci), Mitacs Accelerate awards (for J. Hao and S. Qu), and CIHR Doctoral award (for S. Choi).

Discovery of a driver of castrate-resistant prostate cancer (CRPC)

Dr. Yuzhuou Wang and his research team have also created and used a model in a study aimed at identifying potential CRPC driver genes, in particular genes the elevated expression of which not only initiates but also sustains CRPC.

In their European Urology publication, "Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer", they report that out of eighty genes significantly upregulated at the CRPC stage, seven also showed elevated expression prior to CRPC development. Of these seven, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene; further work led to the conclusion that GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease.

This study was supported by funding from Canadian Institutes of Health Research, Terry Fox Research Institute, BC Cancer Foundation, Urology Foundation, Prostate Cancer Canada, Mitacs Accelerate, Prostate Cancer Canada-Movember, and China Scholarship Council.

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