Editors' ChoiceCancer Signaling and Therapy

Of Mice and Men

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Science Translational Medicine  26 Jun 2013:
Vol. 5, Issue 191, pp. 191ec106
DOI: 10.1126/scitranslmed.3006773

Curing cancer is easy—in mice. However, successful translation of these findings to cancer patients has been far more limited and less successful. The mouse is an ideal model system to rigorously test single-variable experimental hypotheses. On the other hand, the inherent heterogeneity of human tumors results in genetic and biological complexity that makes the translation of these findings from mouse models challenging. Lunardi et al. used an innovative strategy to integrate the data gained from preclinical studies in disease-relevant transgenic mouse models of prostate cancer with information derived from the investigation of therapies (both conventional and experimental) in human patients.

Through a series of sophisticated genetic loss-of-function experiments in mouse models, this group examined the role of castration resistance in preventing tumor progression in prostate cancer. They found that although prostate cancer driven by phosphatase and tensin (PTEN) loss alone was responsive to castration, the coordinate loss of either Pten and Zbtb7a or Pten and Trp53 conferred castration resistance. Next, using a series of high-density tissue microarrays from radical prostatectomy human specimens and array-based comparative genomic hybridization, they were able to demonstrate that the coordinate loss of both Pten and Zbtb7a was a stronger indicator of castration-resistant prostate cancer in human tissues than loss of PTEN alone. Thus, using this integrated approach, this group was able to identify a potential new player in response to androgen-deprivation therapy. Furthermore, additional interrogation of the expression profiles from these mouse models revealed additional potential drivers of the castrate-resistant phenotype, specifically XAF1 and SRD5A1, and targeting these pathways with small-molecule inhibitors resulted in marked tumor regression in transgenic mouse models of the disease. The ability to translate these findings to the clinic remains to be determined, but perhaps by using an innovative coclinical trial platform, the discoveries of therapeutically active combination-based therapies can be translated from the bench to the mouse and ultimately to the real bedside—patients suffering from cancer.

A. Lunardi, et al., A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nat. Genet., 2 June 2013 (10.1038/ng.2650). [Abstract]

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