Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy

Drake, Charles G.; Sharma, Padmanee; Gerritsen, Winald R.

doi:10.1038/onc.2013.497

Cited by 44 publications

(32 citation statements)

References 85 publications

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“…However, the development of enzalutamide resistance is a newly encountered problem, which is mainly induced by AR dysfunction. Therapeutic strategies have been investigated in which enzalutamide is used in combination with other drugs 46. Several compounds were proved to enhance the anti-PCa effect of enzalutamide in vitro or in vivo , such as the RSK inhibitor SL0101,47 the 5α-reductase inhibitor dutasteride,48 and AZD5363,49 which targets the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells

Han¹,

Huang²,

Liu³

et al. 2017

Theranostics

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Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop. Thus, novel agents are urgently needed to treat this devastating disease. Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti-cancer activity in human prostate cancer cells. However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown. In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels. Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7. As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment. Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs. Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti-cancer effect of enzalutamide on CRPC xenografts with minimal side effects. Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs. Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC.

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Section: Discussionmentioning

confidence: 99%

Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells

Han¹,

Huang²,

Liu³

et al. 2017

Theranostics

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“…To more successfully combat prostate cancer, screening programs for early diagnosis and treatment of localized disease are important. In addition, some alternatives for docetaxel as first-line treatment for metastatic disease and options for those cases where docetaxel failed have become available (5). Nevertheless, once the disease has spread beyond the prostate, no curative treatments are currently available (6).…”

Section: Introductionmentioning

confidence: 99%

SYK Is a Candidate Kinase Target for the Treatment of Advanced Prostate Cancer

Ghotra

Horst

et al. 2015

Cancer Research

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Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin a2b1 and CD44 were diminished. RNAimediated silencing of a2b1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for a2b1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer. Cancer Res; 75(1); 230-40. Ó2014 AACR.

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“…This suggests that an AR-directed vaccine could synergize with radiation therapy. Other chemotherapy approaches, which may nonetheless have beneficial immunomodulatory effects (39), may lead to decreased AR expression (40). However, because combined chemohormonal therapy is being used earlier in the treatment course in patients with recurrent disease (41), evaluation of effects of these therapies on AR expression and potential combination with immunotherapeutic approaches warrants evaluation.…”

Section: Discussionmentioning

confidence: 99%

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells

Olson

Gamat

Seliski

et al. 2017

Cancer Immunology Research

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Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anti-cancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo. The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches.

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Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy

Cited by 44 publications

References 85 publications

Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells

Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells

SYK Is a Candidate Kinase Target for the Treatment of Advanced Prostate Cancer

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells

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