Prostate Cancer: Translational and Emerging Therapies (Translational Medicine)

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Published online Sep Author information Article notes Copyright and License information Disclaimer. Correspondence should be addressed to S Prekovic: ln. Received Aug 24; Accepted Sep This work is licensed under a Creative Commons Attribution 4. Abstract The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. Keywords: enzalutamide, treatment resistance, biomarkers, androgen receptor, mutations, prostate cancer, mCRPC, androgen deprivation therapy, docetaxel. Introduction Ever since the discovery that prostate cancer PCa growth after androgen deprivation therapy ADT remains dependent on androgen receptor AR signaling, researchers have been looking for new effective ways to block the action of this hormone-dependent transcription factor Attard et al.

Open in a separate window. Figure 1. Figure 2. The pre-enzalutamide era Androgen deprivation therapy ADT has been the standard of care for patients with symptomatic metastatic PCa since the forties of the last century Merseburger et al. ADT, androgen-deprivation therapy; CI, confidence interval. Docetaxel resistance As described earlier, mCRPC patients treated with docetaxel-based chemotherapy have a modest OS benefit implying most patients will progress rather rapidly.

Enzalutamide as a second-line hormone therapy Preclinical development Ever since molecular profiling studies have revealed that many CRPC tumors remain AR driven, there has been great interest in identifying novel and potent strategies to better block the AR signaling axis Chen et al. Biomarkers for enzalutamide response The readout of PSA levels as a diagnostic biomarker was already introduced in the s, but has also been questioned since then, mainly due to its non-specificity as a marker for cancerous lesions Oesterling , Salman et al.

AR splice variants Alternatively spliced AR variants, especially AR-V7, have been reported to be implicated in resistance to AR-targeting drugs, including enzalutamide. Glucocorticoid receptor takeover The glucocorticoid receptor GR has been reported to be upregulated or re-expressed after AR blockade, indicating a complex cross-talk between AR and GR biology. Intratumoral production of androgens In addition, reactivation of the AR can occur via intratumoral production of androgens, enabling the prostate cancers to progress despite ongoing androgen deprivation Locke et al.

Other known resistance mechanisms Next to the aforementioned AR-related underpinnings of enzalutamide resistance, several additional mechanisms have been described to give rise to therapy resistance, but are not within the scope of this review. Figure 3. Table 2 Multiple large clinical trials of alternative therapies that improve survival of patients with mCRPC. Available therapeutic options in clinical practice For mCRPC patients responding to enzalutamide, there is no doubt that outcomes have improved significantly. Cabazitaxel Cabazitaxel is — like docetaxel — a taxane, which stabilizes microtubules and consequently impairs mitotic cell division Fig.

Figure 4. Abiraterone acetate Abiraterone acetate hereafter referred to as abiraterone is targeting the AR signaling axis by inhibiting cytochrome P 17A1 CYP17A1 — an enzyme involved in intracellular biosynthesis of androgens that enables prostate cancer cells to bypass androgen deprivation Fig.

Figure 5. Optimizing the sequence of therapies The introduction of the aforementioned novel effective therapies has added an additional dimension to the complex therapeutic landscape of mCRPC. Clinical and translational research exploring enzalutamide scheduling Since it is out of the scope of this review to discuss all ongoing clinical studies with enzalutamide co treatment, we have compiled a non-exhaustive list of clinical trials registered on clinicaltrials. Current consensus guidelines for enzalutamide treatment and therapy sequencing The St.

Novel therapeutic targets In addition to the clinically used enzalutamide alternatives described earlier, there are currently several treatment strategies in development. In the preclinical phase Besides targeting the AR itself, translational research has focused over the last couple of years on finding treatment options interfering with molecules that are associated with the AR signaling pathway and thus required for proper AR action.

Conclusion and future perspectives The introduction of enzalutamide as a second-line hormonal therapy for patients with mCRPC has led to significant improvements in the management of the disease. Supplementary Material Supporting Table 1: Click here to view. Supporting Table 2: Click here to view. Acknowledgements The authors would like to thank Thomas van den Broeck, Steven Joniau and Frank Claessens for their contributions and input on the initial draft of the manuscript.

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1. Introduction: Clinical Barriers and Emerging Clues

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Translational Horizons in the Tumor Microenvironment: Harnessing Breakthroughs and Targeting Cures

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Emerging Therapies in Castrate-Resistant Prostate Cancer

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Prostate 74 — Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Research 75 — Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer.

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Now, a new study co-led by Dr. Davide Ruggero of the University of California, San Francisco has identified a mechanism that may help cancer cells escape the effects of these drugs. Described this week in the journal Science Signaling, specific populations of prostate cancer cells are uniquely resistant to inhibitors of the PI3K pathway.

This alarming population of drug-resistant cells was found to harbor high levels of a protein known as 4EBP1, an important player in protein production. The authors found that high 4EBP1 levels decrease protein synthesis within cancer cells and make them immune to PI3K pathway inhibitors. When the researchers genetically manipulated these cells to reduce 4EBP1, protein production was restored and the tumor cells once again became sensitive to drug treatment.

This could be used to predict which prostate cancer patients might benefit most from this class of drugs and those who should not waste precious time with treatments that are likely to fail.

TRACO 2017: Prostate cancer and TGF beta

Using tumor samples from an ongoing clinical trial led by Dr. Hsieh points to these findings as substantiation of the clinical relevance of their discoveries in the laboratory in mouse models and cancer cell lines. According to Hsieh, "the next step is to understand how high levels of 4EBP1 and low protein-synthesis rates drive drug resistance," and to develop new treatment strategies that either increase protein production rates to drug-sensitive levels or suppress them to levels intolerable to cancers.

Their findings also add to a growing field of knowledge showing that how cancer cells make proteins -- the cells' building blocks -- matters for disease progression.

Until recently, the cancer research community has primarily viewed changes in DNA and RNA as the instigators of human malignancies, while protein production has been seen as a static and subservient process. However, this dogma is steadily changing to encompass a more complex dynamic in cell activities.