Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

Markman, Ben; Dienstmann, Rodrigo; Tabernero, Josep

doi:10.18632/oncotarget.188

Cited by 280 publications

(143 citation statements)

References 82 publications

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“…A positive feedback loop on the Akt pathway by rapalogs has been previously described in other cell types [21]. Based on this, we studied the impact of everolimus on Akt and ERK activation on three randomly selected tumors.…”

Section: Everolimus Decreased Meningioma Cell Viability But Activatementioning

confidence: 82%

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Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

et al. 2015

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Treatment for recurrent and aggressive meningiomas remains an unmet medical need in neuro-oncology, and chemotherapy exhibits limited clinical activity, if any. Merlin expression, encoded by the NF2 gene, is lost in a majority of meningiomas, and merlin is a negative regulator of mTORC1. The sst2 somatostatin receptor, targeted by octreotide, is highly expressed in meningiomas. To investigate new therapeutic strategies, we evaluated the activity of everolimus (mTOR inhibitor), BKM-120 and BEZ-235 (new Pi3K/Akt/mTOR inhibitors), octreotide and a combined treatment (octreotide plus everolimus), on cell proliferation, signaling pathways, and cell cycle proteins, respectively. The in vitro study was conducted on human meningioma primary cells extracted from fresh tumors, allowing the assessment of somatostatin analogs at the concentration levels used in patients. The results were correlated to WHO grades. Further, everolimus decreased cell viability of human meningiomas, but concomitantly, induced Akt activation, reducing the antiproliferative effect of the drug. The new Pi3K inhibitors were not more active than everolimus alone, limiting their clinical relevance. In contrast, a clear cooperative inhibitory effect of octreotide and everolimus was observed on cell proliferation in all tested meningiomas, including WHO grades II-III. Octreotide not only reversed everolimus-induced Akt phosphorylation but also displayed additive and complementary effects with everolimus on downstream proteins involved in translation (4EB-P1), and controlling cell cycle (p27Kip1 and cyclin D1). We have demonstrated a co-operative action between everolimus and octreotide on cell proliferation in human meningiomas, including aggressive ones, establishing the basis for a clinical trial.

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Section: Everolimus Decreased Meningioma Cell Viability But Activatementioning

confidence: 82%

“…On merlin-deficient schwannomas, everolimus was ineffective for the treatment of progressive tumors from 10 patients [29]. Consequently, for blocking this positive feedback, a concomitant inhibition of both Pi3K and mTOR or Pi3K alone has been attempted [21].…”

Section: Mtor Inhibitors Effect On Meningiomasmentioning

confidence: 99%

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

et al. 2015

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“…PIK3CA mutations have been detected in various frequencies (4-25 %) of GC [21,22], but a recent biomarker analysis in a prospective clinical trial showed low rate of the mutation [23]. & Constitutive activation of PI3K caused by activating PIK3CA mutations, reduced PTEN expression, or deregulated signaling can induce resistance to HER2 inhibition [24,25]. Collectively, PI3K inhibition warrants evaluation in EBV-positive GC.…”

Section: Ebv-infected Tumorsmentioning

confidence: 99%

Molecular Classification of Gastric Adenocarcinoma: Translating New Insights from The Cancer Genome Atlas Research Network

Sunakawa

Lenz

2015

Curr. Treat. Options in Oncol.

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Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein-Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies.

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“…Inhibitors of mTORC1 (rapamycin and its analogs, or "rapalogues") have shown activities in RCC patients. Two of such agents, temsirolimus (CCI-779) and everolimus (RAD001), were approved by USA FDA for treatment of advanced or recurrent RCC; however, their efficacy is thought to be limited by feedback loops and cross talk with other pathways, leading to the development of drug resistance [7].…”

mentioning

confidence: 99%

Cancer-associated fibroblasts promote renal cell carcinoma progression

Song

et al. 2015

Tumor Biol.

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The aim of this study was to determine the effect of cancer-associated fibroblasts (CAFs) on renal cell carcinoma (RCC) tumor proliferation, migration, and development of drug resistance, thus underlying their potential as therapeutic targets in RCC patients. CAFs were grown in primary cultures. The in vitro model of interaction of RCC cell lines with CAFs was established. The influence of CAFs on the proliferation and migration ability as well as sensitivity to everolimus of RCC cells was further analyzed. Furthermore, Western blotting analysis was performed to examine the mechanisms mediating the effect of CAFs on RCC cells. The results of the MTT assay showed that coculture with CAFs increased the proliferation activity of both 786-O and Caki-1 cells compared with serum-free medium controls. The migration ability of RCC cell lines was also significantly enhanced after coculture treatment compared with untreated control. The inhibition effect of everolimus on 786-O and Caki-1 cells abrogated in cocultures with CAFs. The sensitivity of both two cell lines to everolimus was dramatically decreased when cocultured with CAFs. RCC cells cocultured with CAFs resulted in the activation of both proliferation-related (Erks) and survival-related (Akt) pathways. These data indicate that CAFs have an important role in supporting and promoting RCC. The interaction of CAFs with RCC cell lines stimulates tumor cell proliferation and migration and induces resistance to everolimus in RCC cells, suggesting that target of the tumor microenvironment may be a novel targeted therapies for RCC.

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Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

Cited by 280 publications

References 82 publications

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas

Molecular Classification of Gastric Adenocarcinoma: Translating New Insights from The Cancer Genome Atlas Research Network

Cancer-associated fibroblasts promote renal cell carcinoma progression

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