PI3K/mTOR Signaling in Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural Pneumonectomy

Bitanihirwe, Byron K.Y.; Meerang, Mayura; Friess, Martina; Soltermann, Alex; Frischknecht, Lukas; Thies, Svenja; Felley‐Bosco, Emanuela; Tsao, Ming‐Sound; Allo, Ghassan; Perrot, Marc de; Seifert, Burkhardt; Moch, Holger; Stahel, Rolf A.; Weder, Walter; Opitz, Isabelle

doi:10.1097/jto.0000000000000055

Cited by 31 publications

(53 citation statements)

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“…Overall survival (OS) represents survival from the first cycle chemotherapy to last follow-up or time-point of death. 16 Median survival time was assessed by Kaplan-Meier curves, and the influence of ERCC1 and RRM1 expression was analyzed by log-rank test. To test the independence of different factors on survival, a stepwise Cox regression was performed including all prognostic factors being significant in the univariate analysis: gender, age (61 vs >61 years), pT (categoric variable: pT1 vs pT2, pT1 vs pT3, pT1 vs pT4), pN (pN0 vs pN1/2), nuclear RRM1 (prechemotherapy), and nuclear ERCC1 (prechemotherapy).…”

Section: Discussionmentioning

confidence: 99%

“…Age at diagnosis 61 y (59): 20 (17)(18)(19)(20)(21)(22)(23)(24) >61 y (48): 23 (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) .06 61 y (59): 14 (10-18) >61 y (48): 15 (13)(14)(15)(16)(17) .008y…”

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“…Histotype pre-CTX* (19 missing) Epithelioid (55): 23 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) Nonepithelioid (33): 13 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) .003y…”

Section: Discussionunclassified

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Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery

Frischknecht

Meerang

Soltermann

et al. 2015

The Journal of Thoracic and Cardiovascular Surgery

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Section: Discussionmentioning

confidence: 99%

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Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery

Frischknecht

Meerang

Soltermann

et al. 2015

The Journal of Thoracic and Cardiovascular Surgery

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“…Alternatively combination strategy inhibiting both PI3K and mTOR may prove to be more successful in treating mesothelioma. 15 …”

Section: Discussionmentioning

confidence: 99%

SWOG S0722: Phase II Study of mTOR Inhibitor Everolimus (RAD001) in Advanced Malignant Pleural Mesothelioma (MPM)

Moon

Garland

et al. 2015

Journal of Thoracic Oncology

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Introduction The PI3K/Akt/mTOR pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mTOR inhibitor, in patients with unresectable MPM. Methods MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression free survival (PFS) by RECIST 1.1. Results A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate (ORR) was 2% (95%CI: 0%–12%) by RECIST 1.1 and 0% (0%–10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17%–41%) by RECIST 1.1 and 27% (95%CI: 16%–39%) by modified RECIST. The median PFS was 2.8 months (95%CI: 1.8–3.4) by RECIST 1.1. The median overall survival (OS) was 6.3 months (95%CI: 4.0–8.0). There was no difference in PFS among patients who received 1 or 2 prior chemotherapy regimens (p= 0.74). There was no difference in OS between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3–4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%). Conclusion Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.

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“…Increasing evidence indicates that the Akt/mTOR pathway is frequently activated in MPM [30] and plays a key role in tumor aggressiveness and chemoresistance [15, 31, 32]. However, in MPM, the molecular mechanism(s) leading to activation of mTOR and its interaction with other biomarkers are largely unknown.…”

Section: Discussionmentioning

confidence: 99%

CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome

et al. 2014

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Malignant mesothelioma is a deadly tumor whose diagnosis and treatment remain very challenging. There is an urgent need to advance our understanding of mesothelioma biology and to identify new molecular markers for improving management of patients. CD157 is a membrane glycoprotein linked to ovarian cancer progression and mesenchymal differentiation. The common embryonic origin of ovarian epithelial cells and mesothelial cells and the evident similarities between ovarian and mesothelial cancer prompted us to investigate the biological role and clinical significance of CD157 in malignant pleural mesothelioma (MPM).CD157 mRNA and protein were detected in four of nine MPM cell lines of diverse histotype and in 85.2% of MPM surgical tissue samples (32/37 epithelioid; 37/44 biphasic). CD157 expression correlated with clinical aggressiveness in biphasic MPM. Indeed, high CD157 was a negative prognostic factor and an independent predictor of poor survival for patients with biphasic MPM by multivariate survival analysis (HR = 2.433, 95% CI 1.120-5.284; p = 0.025). In mesothelioma cell lines, CD157 gain (in CD157-negative cells) or knockdown (in CD157-positive cells) affected cell growth, migration, invasion and tumorigenicity, most notably in biphasic MPM cell lines. In these cells, CD157 expression was associated with increased activation of the mTOR signaling pathway, resulting in decreased platinum sensitivity. Moreover, a trend towards reduced survival was observed in patients with biphasic MPM receiving postoperative platinum-based chemotherapy. These findings indicate that CD157 is implicated in multiple aspects of MPM progression and suggest that CD157 expression could be used to stratify patients into different prognostic groups or to select patients that might benefit from particular chemotherapeutic approach.

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PI3K/mTOR Signaling in Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural Pneumonectomy

Abstract: These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.

Cited by 31 publications

References 44 publications

Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery

Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery

SWOG S0722: Phase II Study of mTOR Inhibitor Everolimus (RAD001) in Advanced Malignant Pleural Mesothelioma (MPM)

CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome

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