A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

Powles, Thomas; Wheater, Matthew; Din, Omar; Geldart, Thomas; Boleti, Ekaterini; Stockdale, Andrew; Sundar, Santhanam; Robinson, Angus; Ahmed, Imtiaz; Wimalasingham, Akhila; Burke, Wendy; Sarker, Shah-Jalal; Hussain, Syed A.; Ralph, Christy

doi:10.1016/j.eururo.2015.08.035

Cited by 85 publications

(60 citation statements)

References 9 publications

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“…This molecule has superior/consistent rodent pharmacokinetics, low turnover in human hepatocytes 18 and has been well-tolerated in phase I trials in solid tumor patients. 21,44 Thus we considered it appropriate to study AZD2014 in order to expand understanding of how novel ATP competitive dual mTOR inhibitors impact cellular and humoral alloimmunity (compared to rapalogs). In particular, based on previous rodent studies showing an important role for mTORC2 in B cell maturation, homeostasis and Ab production, we hypothesized that AZD2014 might have (unique) advantages over RAPA in terms of inhibitory effects on B cells, circulating DSA levels and Ab deposition in the graft,- variables that we did not examine in our AZD8055 study.…”

Section: Discussionmentioning

confidence: 99%

“…However, AZD2014 (Vistusertib), a related compound, with a more favorable pharmacokinetic profile, 18,19 has entered early-phase trials in advanced malignancy. 19–21 Here, we examined for the first time, the influence of AZD2014 (compared with RAPA) on immune cell populations, allograft rejection and underlying cellular and humoral immunity.…”

Section: Introductionmentioning

confidence: 99%

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Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

et al. 2017

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Background Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. Methods mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts. Results The novel TORKinib AZD2014 impaired DC differentiation and T cell proliferation in vitro and depressed immune cells and allospecific T cell responses in vivo. A 9-day course of AZD2014 (10 mg/kg ip twice daily) or rapamycin (RAPA; 1mg/kg ip daily) prolonged median heart allograft survival time significantly (25 days for AZD2014; 100 days for RAPA; 9.5 days for control). Like RAPA, AZD2014 suppressed graft mononuclear cell infiltration, increased regulatory T cell (Treg) to effector memory T cell (Tem) ratios and reduced T follicular helper (Tfh) and B cells 7 days posttransplant. By 21 days (10 days after drug withdrawal), however, Tfh and B cells and donor-specific IgG1 and IgG2c antibody titers were significantly lower in RAPA- compared with AZD2014-treated mice. Elevated Treg to Tem ratios were maintained after RAPA, but not AZD2014 withdrawal. Conclusions Immunomodulatory effects of AZD2014, unlike those of RAPA, were not sustained after drug withdrawal, possibly reflecting distinct pharmacokinetics or/and inhibitory effects of AZD2014 on mTORC2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

et al. 2017

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“…As with the other selective mTORC1/mTORC2 inhibitors, CC-233 was well-tolerated and demonstrated comparable toxicities with other members of the class (Shih et al, 2012; Goy et al, 2013; Varga et al, 2013; Bendell et al, 2015a). Currently, phase II studies were underway for MLN0128, AZD8055, and AZD2014 (Sun, 2013b; Powles et al, 2016). More recently, the results of a phase II trial of AZD2014 vs. everolimus in patient with VEGF-refractory metastatic clear cell renal cancer were reported (Powles et al, 2016).…”

Section: Mtor Inhibitors For Modulating Mtor Activity To Combat Cancementioning

confidence: 99%

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

et al. 2016

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The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.

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“…Preclinical studies have shown that mTOR inhibitors suppress homologous recombination-mediated DNA repair (HDR) and synergize with poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1-proficient triple-negative breast cancers (13). AZD2014 is a novel small molecule ATP-competitive dual inhibitor of both mTORC1 and mTORC2 kinase that is well-tolerated in preclinical studies and is currently in phase II clinical trials (14, 15). …”

Section: Introductionmentioning

confidence: 99%

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Hai

Liu

Bufe

et al. 2017

Clinical Cancer Research

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Purpose KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. Experimental Design We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment. Results We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1. Conclusions These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers.

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A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

Cited by 85 publications

References 9 publications

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

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