Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

Armstrong, Andrew J.; Halabi, Susan; Healy, Patrick; Alumkal, Joshi J.; Winters, Carolyn; Kephart, Julie J.G.; Bitting, Rhonda L.; Hobbs, Carey; Soleau, Colleen; Beer, Tomasz M.; Slottke, Rachel; Mundy, Kelly; Yu, Evan Y.; George, Daniel J.

doi:10.1016/j.ejca.2017.02.030

Cited by 84 publications

(52 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Yet, the drug response profiles clearly distinguished the two patients. For the uterine carcinosarcoma case, they identified the combination of the PIK3 inhibitor buparlisib (Armstrong et al , ) with the hypoxia signalling suppressor vorinostat (Zhang et al , ) as one of the top drug combinations. By contrast, for the endometrial adenocarcinoma case, a combination of buparlisib with the PARP and HDAC inhibitor olaparib (Yuan et al , ) was found as optimal treatment in both PDTO and PDTX models.…”

Section: Drug Screens and Personalized Medicine Using Pdtx And Pdto Mmentioning

confidence: 99%

Xenograft and organoid model systems in cancer research

et al. 2019

View full text Add to dashboard Cite

Patient‐derived tumour xenografts and tumour organoids have become important preclinical model systems for cancer research. Both models maintain key features from their parental tumours, such as genetic and phenotypic heterogeneity, which allows them to be used for a wide spectrum of applications. In contrast to patient‐derived xenografts, organoids can be established and expanded with high efficiency from primary patient material. On the other hand, xenografts retain tumour–stroma interactions, which are known to contribute to tumorigenesis. In this review, we discuss recent advances in patient‐derived tumour xenograft and tumour organoid model systems and compare their promises and challenges as preclinical models in cancer research.

show abstract

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

Cited by 84 publications

References 28 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

Xenograft and organoid model systems in cancer research

Contact Info

Product

Resources

About