Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer

Massard, Christophe; Nguyen, Kim; Castellano, Daniel; Bono, Johann S. de; Gravis, Gwénaëlle; Dirix, Luc; Machiels, Jean‐Pascal; Mita, Alain C.; Mellado, Begoña; Turri, Sabine; Maier, Joan; Csonka, Dénes; Chakravartty, Arunava; Fizazi, Karim

doi:10.1016/j.ejca.2017.01.024

Cited by 67 publications

(52 citation statements)

References 20 publications

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“…Indeed, preclinical models inhibiting both AR and the PI3K/Akt axis show promising results (Carver et al 2011;Toren et al 2015;Yadav et al 2016). However, clinical pilot studies on anti-androgens and PI3K/Akt/mTOR inhibitors show high proportions of severe adverse effects and high rates of treatment discontinuation, with no clear indication that the PI3K/Akt/mTOR inhibitors reached and inhibited their targets in PCa tissues (Armstrong et al 2017;Massard et al 2017;Wei et al 2017). Given the association of increased nuclear mTOR levels with disease evolution, specifically targeting the transcriptional function of mTOR could offer a novel therapeutic avenue for the management of poor-outcome PCa and perhaps other malignancies, with fewer side effects than global PI3K/ Akt/mTOR inhibition.…”

Section: Discussionmentioning

confidence: 99%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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Section: Discussionmentioning

confidence: 99%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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“…However, the clinical trials of BEZ235 were not satisfactory. A phase I study investigated maximum tolerated dose (MTD), recommended dose for expansion (RDE), safety and antitumor activity of BEZ235, in combination with abiraterone acetate [86]. In this study, dose escalation was stopped after 200 mg bid due to challenging safety and tolerability profile; the most common adverse events (AEs) were diarrhea (78%), nausea (61%) and stomatitis (39%).…”

Section: Dual Pi3k/mtor Inhibitors Nvp-bez235 (Dactolisib)mentioning

confidence: 99%

“…In patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor (VEGF) targeted therapies, buparlisib (80 mg/day) with bevacizumab (10 mg/kg every 2 weeks), was shown to be a tolerable regimen with preliminary activity [116]. In patients with castration-resistant prostate cancer, buparlisib did not demonstrate significant activity in a phase II trial, furthermore, the combination of buparlisib with abiraterone acetate was not recommended as a phase Ib study reported [86,117].…”

Section: Pf-04691502 and Pf-05212384 (Gedatolisib Pki-587)mentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

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“…BEZ235 showed promising in vitro antitumor activities (26,27), but on the basis of its poor water solubility, BEZ235 must be administered orally in a polyethylene glycol (PEG)-based formulation in humans (28,29). Furthermore, phase 1/2 clinical trials revealed that the orally administered BEZ235 has poor bioavailability, limited antitumor activities, and high gastrointestinal toxicity (28,29). Thus, BEZ235 was withdrawn from further trials (28,29), although several new formulations have recently been reported for topical delivery of BEZ235 (30,31).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, phase 1/2 clinical trials revealed that the orally administered BEZ235 has poor bioavailability, limited antitumor activities, and high gastrointestinal toxicity (28,29). Thus, BEZ235 was withdrawn from further trials (28,29), although several new formulations have recently been reported for topical delivery of BEZ235 (30,31).…”

Section: Introductionmentioning

confidence: 99%

Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

Wang

Park

2020

Sci. Adv.

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Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

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Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer

Cited by 67 publications

References 20 publications

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

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