Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer
TL;DR: Combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
About: This article is published in Cancer Cell.The article was published on 2011-05-17 and is currently open access. It has received 1083 citations till now. The article focuses on the topics: PHLPP & Prostate cancer.
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TL;DR: In this article, the androgen-receptor splice variant 7 (AR-V7) was found to be associated with resistance to enzalutamide and abiraterone.
Abstract: Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival. Resul...
2,221 citations
TL;DR: Using a 3D organoid system, this paper reported success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss.
1,101 citations
TL;DR: This Review highlights emerging mechanisms of acquired resistance to contemporary therapies targeting the AR pathway, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence.
Abstract: During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.
980 citations
TL;DR: This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents and describes predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance.
Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.
702 citations
TL;DR: The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.
Abstract: Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.
650 citations
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TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
Abstract: In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.
5,430 citations
Columbia University1, University of Michigan2, University of California, Davis3, Baylor College of Medicine4, University of Massachusetts Medical School5, Mayo Clinic6, University of Washington7, University of Arkansas for Medical Sciences8, University of California, San Francisco9, Cleveland Clinic10, University of Colorado Denver11
TL;DR: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.
Abstract: background Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormoneindependent prostate cancer. methods We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. results Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. conclusions The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.
3,554 citations
"Reciprocal Feedback Regulation of P..." refers background in this paper
...…by reciprocal negative feedback, such that inhibitio and survive when either single pathway is inhibited pharmaco with combined pathway inhibition in preclinical prostate tum patients. therapeutically efficacious; however, the median increase in survival was only 4 months (Petrylak et al., 2004)....
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...therapeutically efficacious; however, the median increase in survival was only 4 months (Petrylak et al., 2004)....
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TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.
3,310 citations
"Reciprocal Feedback Regulation of P..." refers background or methods in this paper
...Our preclinical data predict that single-agent PI3K pathway inhibitor therapy will most likely result in disease stabilization rather than tumor regression, particularly in PTEN null tumors that represent 40%of primary cancers and 70%ofmetastases (Taylor et al., 2010)....
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...Our preclinical data predict that single-agent PI3K pathway inhibitor therapy will most likely result in disease stabilization rather than tumor regression, particularly in PTEN null tumors that represent 40%of primary cancers and 70%ofmetastases (Taylor et al., 2010)....
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...Our human prostate cancer data set has been previously published (Taylor et al., 2010)....
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...Roughly 40% of primary and 70% of metastatic prostate cancers have genomic alterations in the PI3K-signaling pathway, mostly through loss of PTEN (El Sheikh et al., 2008; Reid et al., 2010; Taylor et al., 2010)....
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...Human CGH and mRNA Profiling Our human prostate cancer data set has been previously published (Taylor et al., 2010)....
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TL;DR: The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation, and reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
Abstract: Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
2,423 citations
"Reciprocal Feedback Regulation of P..." refers background in this paper
...One potential liability of mTORC1 inhibition is disruption of a negative feedback loop, resulting in hyperactivation of AKT and MAPK that can promote cell survival independent of mTORC1, thereby limiting therapeutic efficacy (Carracedo et al., 2008; O’Reilly et al., 2006; Sarbassov et al., 2005)....
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TL;DR: The potential of and challenges for the development of therapeutic agents that target this pathway in cancer are discussed and the potential and challenges in understanding of the PI3K pathway are highlighted.
Abstract: The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.
2,315 citations
"Reciprocal Feedback Regulation of P..." refers background in this paper
...The PI3K pathway plays a central role in tumorigenesis across a variety of malignancies (Courtney et al., 2010; Liu et al., 2009)....
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