Temsirolimus Inhibits Malignant Pleural Mesothelioma Growth In Vitro and In Vivo: Synergism with Chemotherapy Mir Alireza Hoda, MD, Amir Mohamed, BSc,

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Temsirolimus Inhibits Malignant Pleural Mesothelioma Growth In Vitro and In Vivo: Synergism with Chemotherapy Mir Alireza Hoda, MD, Amir Mohamed, BSc, Bahil Ghanim, MD, Martin Filipits, PhD, Balazs Hegedus, PhD, Masaya Tamura, MD, Judit Berta, MSc, Bernd Kubista, MD, Balazs Dome, MD, PhD, Michael Grusch, PhD, Ulrike Setinek, MD, Michael Micksche, MD, Walter Klepetko, MD, Walter Berger, PhD Journal of Thoracic Oncology Volume 6, Issue 5, Pages 852-863 (May 2011) DOI: 10.1097/JTO.0b013e31820e1a25 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 mTOR phosphorylation in human MPM. A–C, 70 human paraffin-embedded MPM surgical specimens of different histology (A, epitheloid; B, biphasic; C, sarcomatoid) were immunostained for phosphorylated mTOR (brown) and counterstained with hematoxylin (nuclei in blue) and (D, E) evaluation was performed by H-score as described under Materials and Methods section. Hyperphosphorylation of mTOR was predominantly detected in tumors with epitheloid differentiation (mean staining score: 55 ± 30 [epitheloid] versus 2 ± 3 [sarcomatoid]; p < 0.0001; unpaired t test; D) and in early-stage epitheloid MPM (mean staining score: 66 ± 27 [early-stage epitheloid] versus 46 ± 31 [late-stage epitheloid]; p = 0.031; E). F, Phosphorylation of mTOR and several downstream effectors as indicated in the investigated MPM cell lines by immunoblot. mTOR, Mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Activity of temsirolimus against human MPM cell lines relating to cell viability, DNA synthesis, and spheroid formation. A, Temsirolimus (Tem) and cisplatin (Cis) dose-response curves as indicated were established in four unrelated MPM cell lines (upper panel) and the cisplatin-resistant MPM cell model P31 (lower panel). Viability after 72 hours continuous drug exposure were measured by MTT assay and normalized to the untreated controls (Cnt). B, Effects of 24 hours drug temsirolimus exposure on DNA synthesis determined by [3H]-thymidine incorporation assay are given normalized to untreated controls. DNA synthesis inhibition was significantly stronger in P31res1.2 as compared with P31 cells (p < 0.0001, two-way analysis of variance). C, Effects of temsirolimus exposure (100 ng/ml) on nonadherent spheroid formation of MPM cells was determined after 96 hours drug exposure. Representative photomicrographs of SPC111 cells are shown in the left panel. Impacts on spheroid size and sphere number are indicated in the right panels. In all cases, data are means of at least three independent experiments; bars, SD; *p < 0.05, ***p < 0.0005. MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Activity of temsirolimus (Tem) combined with cisplatin (Cis) against human MPM cell lines. A, MPM cell lines were continuously exposed for 72 hours to the indicated doses of temsirolimus combined with cisplatin. Subsequently, changes in viability were measured by MTT assay and data are given as combination indices (CI) calculated using CalcuSyn Software (see Materials and Methods section). B, Effects of long-term exposure to temsirolimus without and with cisplatin on colony formation of the indicated cell lines were established. Cell lines sensitive to cisplatin (SPC111 and P31res1.2) were treated with 1 μM and the more resistant ones (SPC212 and P31res1.2) with 2.5 μM cisplatin. Temsirolimus was used at 100 ng/ml. After 7 days of exposure, cells were stained with crystal violet, representative photomicrographs were taken (left), and colonies were counted. Data from three experiments are given normalized to controls (right). **p < 0.05, ***p < 0.0005, significantly different from nontreated cells. Significance levels immediately above the SD bars represent comparisons with the untreated control. C, MPM cells were cultured in the presence of cisplatin (5 μM) and temsirolimus (250 ng/ml) alone or in combination for 48 hours. Expression and phosphorylation state were analyzed by Western blotting for mTOR and its downstream mediators as indicated. mTOR, Mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Impact of temsirolimus combined with cisplatin on apoptosis induction and cell cycle progression. A, Apoptosis induction by a 48 hours exposure to temsirolimus (250 ng/ml) and cisplatin (5 μM) as a single agent and in combination were determined by fluorescence microscopic evaluation of Hoechst 33342-stained P31 and P31res1.2 cells. Representative photomicrographs were taken (upper panel) and the mean percentage of apoptotic cells of at least three independent experiments was determined; bars, SD; *p < 0.05, ***p < 0.0005 (lower panel). Insets show cleavage of the caspase substrate PARP detected by immunoblot. The four lanes correspond to the indicated experimental groups. B, Influence of temsirolimus and cisplatin treatment, both as a single agent and in combination at the indicated concentrations, on cell cycle progression in MPM cells was determined by FACS analyses after 48 hours continuous drug exposure. One representative experiment out of three delivering comparable results is shown. MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Temsirolimus inhibits MPM tumor growth in vivo. A and B, Intraperitoneal tumor growth was determined 38 days after engraftment. Tumor growth in a representative control (Cnt) and treated (Tem) animal (A) is opposed to quantification of the tumor weight in all animals (median tumor weight: 225 mg [control] versus 48 mg [temsirolimus]) (B). C, Overall survival of severe combined immunodeficiency mice is shown as Kaplan-Meier curves (mean overall survival for SPC111: 52 days [control] versus 62 days [temsirolimus]; p = 0.018; mean overall survival for P31: 45 days [control] versus 57 days [temsirolimus]; p = 0.002). D, Impact of temsirolimus treatment on activation of mTOR and downstream effectors in the MPM xenograft tissue (48 hours after the last treatment) was analyzed by Western blot. E, Impact of temsirolimus on tumor weight (left panel) (median tumor weight: 587 mg [control] versus 156 mg [temsirolimus]; p = 0.032) and amount of tumor necrosis (right panel) at tumor progression and necessity for experiment termination (median tumor necrotic area: 1% [control] versus 51% [temsirolimus]; p < 0.0001). mTOR, Mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Activity of temsirolimus combined with cisplatin against MPM in vivo. A, Representative temsirolimus (Tem)- or solvent-treated (Cnt) SPC111 MPM tumors are shown. H&E stainings at two different magnifications are opposed to immunostainings for Ki67 and phosphorylated mTOR using consecutive sections. B, TUNEL stainings (red nuclei) were performed on sections as detailed in (A) to indicate programmed cell death in MPM xenograft tissues. Blue, nuclear counter stain by DAPI. Arrow bars, 100 μm. C, Anticancer activity of temsirolimus and cisplatin as single agents or in combination was determined against the SPC111 xenograft and survival curves (left panel) (mean overall survival: 46 days [control] versus 60 days [temsirolimus] versus 71 days [cisplatin] versus 83 days [temsirolimus/cisplatin]; p < 0.0001) are opposed to tumor weight (right panel) (median tumor weight: 402 mg [control] versus 259 mg [cisplatin] versus 178 mg [temsirolimus] versus 123 mg [temsirolimus/cisplatin]) at the time when animals had to be killed due to tumor progression. mTOR, Mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2011 6, 852-863DOI: (10.1097/JTO.0b013e31820e1a25) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions