Editors' ChoiceCancer

XiAP-ping Castration-Resistant Prostate Cancer

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Science Translational Medicine  03 Jul 2013:
Vol. 5, Issue 192, pp. 192ec111
DOI: 10.1126/scitranslmed.3006880

The first-line treatment for prostate cancer is androgen-deprivation therapy, which starves prostate cancer cells of testosterone. Although this treatment is initially successful, new genetic alterations usually drive the reappearance of cancer, but in an androgen-insensitive form—castration-resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms by which CRPC develops could enable clinicians to identify which patients are most likely to eventually fail androgen-deprivation therapy and to target these mechanisms earlier to prevent disease progression. In a new study by Lunardi et al., the authors show that that genetic alterations that underlie prostate cancer initiation and progression also underlie the development of CRPC. Drugs targeting these pathways can treat androgen-resistant prostate cancer.

The authors used three genetic mouse models of prostate cancer: mice with conditional loss of the tumor suppressor Pten alone or together with Zbtb7a or Tp53, all of which are known drivers of prostate cancer. These mice develop de novo prostate cancer, which after castration evolves to CRPC (Pten null) or is initially castration-resistant (double null), mimicking aspects of the disease course of humans with prostate cancer. Indeed, in banked samples of human prostate cancer, tumors from patients with poorer responses (that is, despite androgen deprivation) exhibited down-regulation or loss of PTEN and ZBTB7A.

To identify the mechanisms by which these genetic events lead to CRPC, Lunardi et al. profiled mRNA expression with microarrays in prostate tumors from their mice lacking Pten or with Pten + Zbtb7a double null mutations. Xaf1 was strongly down-regulated in the double-null tumors, which inhibited apoptosis because XAF1 opposes the proapoptotic protein XIAP. The authors further demonstrate that the mouse tumors lacking both Pten and Zbtb7a showed increased amounts of Srd5a1, an enzyme that catalyzes the production of a more potent version of testosterone. To take these findings back to humans, the authors treated human prostate cancer cells or their double-null mice with combinations of agents targeting XIAP and SRD5A1. Simultaneous treatment with inhibitors of both enzymes, along with androgen-deprivation therapy, was able to reverse CRPC in these mice.

Not only have the authors identified new genetic biomarkers for tumors that may develop into CRPC, they have also demonstrated that targeting these genetic pathways may overcome CRPC. The next step is a clinical trial with a drug combination that targets both XIAP and SRD5A1.

A. Lunardi et al., A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nature 45, 747–755 (2013). [Abstract]

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