Phase 2 Trial of Single-agent Everolimus in Chemotherapy-naive Patients with Castration-resistant Prostate Cancer (SAKK 08/08)

Templeton, Arnoud J.; Dutoit, Valérie; Cathomas, Richard; Rothermundt, Christian; Bärtschi, Daniela; Dröge, Cornelia; Gautschi, Oliver; Borner, Markus; Fechter, E.; Stenner, Frank; Winterhalder, Ralph; Müller, Beat; Schiess, Ralph; Wild, Peter J.; Rüschoff, Jan H.; Thalmann, George N.; Dietrich, Pierre‐Yves; Aebersold, Ruedi; Klingbiel, Dirk; Gillessen, Silke

doi:10.1016/j.eururo.2013.03.040

Cited by 116 publications

(84 citation statements)

References 24 publications

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“…One previous study did not find any modulation of T regs after rapalog treatment but T regs were monitored only once at 1 month after the beginning of treatment (34). However, an increase of T regs was also reported in prostate cancer patients treated with everolimus (35). Thus, like in organ transplantation, mTOR inhibition increases T regs number and their suppressive functions in cancer patients (12,36).…”

Section: Discussionmentioning

confidence: 95%

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

et al. 2016

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The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP 3 þ Helios þ Ki67 þ regulatory CD4 T cells (T regs ). In these patients, rapalogs strongly enhanced the suppressive functions of T regs , mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes þ CD8 þ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the T regs /antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased T regs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced T regs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed T regs , was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies.

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Section: Discussionmentioning

confidence: 95%

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

et al. 2016

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“…Finally, a cross-talk between NF-jB and AR indicates the role of the NF-jB signaling pathway in CR progression [68]. Phase II clinical trials of mTOR inhibitors (ridaforolimus, temsirolimus and everolimus), targeting the PI3K pathway in CRPC have not been overwhelming [69][70][71]. Nevertheless, combinatory trials of PI3K and AR inhibition have shown more promising results but may encounter some toxicity issues [72].…”

Section: Outlaw Pathwaymentioning

confidence: 94%

The hallmarks of castration-resistant prostate cancers

Katsogiannou

Ziouziou

Karaki

et al. 2015

Cancer Treatment Reviews

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“…Everolimus demonstrated PSA response in 11% of patients with CRPC in a non-biomarker selected population [48]. The PSA response to everolimus was correlated with a PTEN deletion by FISH [48].…”

Section: The Pten/pi3k/akt/mtor Pathwaymentioning

confidence: 98%

Molecular landscape of prostate cancer: Implications for current clinical trials

Khemlina

Ikeda²,

Kurzrock³

2015

Cancer Treatment Reviews

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Castration-resistant prostate cancer (CRPC) is a lethal disease, and improvement with androgen-deprivation therapy has plateaued. Next-generation sequencing studies have led to significant advances in our understanding of genomic alterations in prostate cancer. The most common genomic aberrations in this malignancy are the transcription factor fusion of TMPRSS2-ETS, and mutations in TP53, AR, RB1 and PTEN/PIK3CA. Some of these alterations are actionable by drugs available in the clinic. In addition, it was recently shown that aberrations in DNA repair genes, such as BRCA2 and ATM, are present in both somatic and germline form in a significant minority of prostate cancer; these abnormalities can be targeted by drugs such as platinums and PARP inhibitors. In the era of tumour profiling, targeting molecular alterations may provide an opportunity for new therapeutic approaches. Although there are promising new agents to attack a variety of genomic signal abnormalities, biomarker-matched therapy (other than for androgens) have been utilised in only 2.0% of clinical trials (September 2011 through September 2014; https://clinicaltrials.gov) for prostate cancer. Enhanced efforts to define subsets of patients with prostate cancer based on their molecular anomalies, and match them with cognate therapies, warrant investigation.

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Phase 2 Trial of Single-agent Everolimus in Chemotherapy-naive Patients with Castration-resistant Prostate Cancer (SAKK 08/08)

Cited by 116 publications

References 24 publications

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

The hallmarks of castration-resistant prostate cancers

Molecular landscape of prostate cancer: Implications for current clinical trials

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