mTOR Inhibitor Treatment of Pancreatic Cancer in a Patient With Peutz-Jeghers Syndrome

15146 The rapamycin derived mTOR inhibitor RAD001 (everolimus) is cytotoxic to a number of cell lines. Because survivin, an important mediator of apoptosis and cell survival, is one of the targets down-regulated by RAD001, we tested the ability of a combination of RAD001 and siRNA mediated inhibition of survivin to enhance the cytotoxic effects. We have used four pancreatic cancer cell lines, MiaPaCa-2, BxPC-3, AsPC-1 and Panc-1. We found that the cytotoxic effect was enhanced in all cell lines after treatment with RAD001 and survivin siRNA. An efficient way of treatment was the initial down-regulation of survivin with RAD001 and a subsequent incubation with survivin siRNA. We conclude, that the transformation efficiency of siRNA, still a limiting factor in using this method, is more sufficiently combining both ways to down-regulate survivin. Our data indicate that a combination of mTOR inhibitors like RAD001 and survivin-targeted down-regulation with siRNA may improve the efficacy of therapy in pancreatic cancer. No significant financial relationships to disclose.

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Activity of a novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 to enhance antitumor activities of gemcitabine and EMAP II in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.255 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 255-255

Author(s):

N. Awasthi ◽

P. L. Yen ◽

M. A. Schwarz ◽

R. Schwarz

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Antitumor Activity ◽

Combination Therapy ◽

Mtor Inhibitor ◽

Single Agent ◽

Percent Inhibition ◽

Animal Survival

255 Background: Gemcitabine (Gem, G) has limited benefits as single agent or in combination for pancreatic ductal adenocarcinomas (PDACs). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in diverse human cancers including PDAC. NVP-BEZ235 (BEZ, B) is a novel dual PI3K/mTOR inhibitor that has been shown to have antitumor activity in multiple tumor types. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances Gem and docetaxel activity in PDAC. We tested the combination benefits of BEZ and Gem in addition to EMAP in experimental PDAC. Methods: In vitro cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo animal survival experiments were performed in NOD-SCID PDAC xenografts. Results: Cultured cells of PDAC (AsPC-1), endothelial (HUVECs), and fibroblast origin (WI-38) all expressed AKT and mTOR protein. BEZ inhibited in vitro cell proliferation of AsPC-1 and HUVECs cells, with some additive effects in combination with Gem or EMAP, after 72 hours of incubation. In AsPC-1, treatment of BEZ (100 nM), Gem (100 nM) and EMAP (1 μM) caused 34, -7, -16, 62, 51, 3, and 59 percent inhibition in proliferation in the B, G, E, B+G, B+E, G+E and B+G+E groups. In HUVECs, percent inhibition in proliferation was 35, 33, 15, 55, 35, 31 and 53 in the B, G, E, B+G, B+E, G+E and B+G+E groups, respectively. Compared to controls (median survival: 16 days), an animal survival increase after BEZ and EMAP therapy alone (both 21 days) and Gem therapy alone (28 d) was observed. Further increases in survival occurred in combination therapy groups B+G (30 d, p=0.007), B+E (27 d, p=0.02), G+E (31 d, p=0.001) and B+G+E (33 d, p=0.004). Conclusions: Bez has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of Gem and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment. No significant financial relationships to disclose.

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Effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, on chemotherapy and antiangiogenic response in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.243 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 243-243 ◽

Cited By ~ 1

Author(s):

Katherine T. Ostapoff ◽

Niranjan Awasthi ◽

Peter L. Yen ◽

Changhua Zhang ◽

Margaret A. Schwarz ◽

...

Keyword(s):

Pancreatic Cancer ◽

Combination Therapy ◽

Mtor Inhibitor ◽

Mammalian Target Of Rapamycin ◽

Animal Experiments ◽

Ductal Adenocarcinoma ◽

Clinical Benefits ◽

Induced Apoptosis

243 Background: The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathway dysregulation is a prominent feature of pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), a standard systemic treatment for PDAC, has limited clinical benefits. The present study investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Methods: Protein expression and cell proliferation were analyzed by Western blotting and WST-1 assay. Animal experiments were performed in murine xenografts. Results: BEZ235 inhibited phospho-AKT (Ser473) and phospho-mTOR (Ser2448) expression in PDAC (AsPC-1), endothelial (HUVECs) and fibroblast (WI-38) cells. NVP-BEZ235 also caused a significant dephosphorylation of downstream mTORC1 target proteins phospho-p70 S6K (Thr389) and phospho-4E-BP1 (Thr37/46). In vitro 72-hour proliferation of four PDAC cell lines was significantly inhibited by BEZ235. Additive effects on proliferation inhibition were observed in the BEZ235 and GEM combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with GEM and EMAP, induced apoptosis in AsPC-1, HUVECs and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. PDAC in vivo therapy demonstrated that compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and GEM monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235+GEM (30 days, p=0.007), BEZ235+EMAP (27 days, p=0.02), GEM+EMAP (31 days, p=0.001) and BEZ235+GEM +EMAP (33 days, p=0.004). Conclusions: BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that can be enhanced in combination with cytotoxic (GEM) and antiendothelial (EMAP) agents. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

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Combination of antiangiogenic therapy using the mTOR inhibitor RAD001 (everolimus) and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: Dose-finding study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.360 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 360-360

Author(s):

Mareile Joka ◽

Stefan Hubert Boeck ◽

Christian Hosius ◽

Laetitia Decroix ◽

Christoph May ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase I ◽

Low Dose ◽

Mtor Inhibitor ◽

Antiangiogenic Therapy ◽

Locally Advanced ◽

Study Drug ◽

Dose Finding ◽

Metastatic Pancreatic Cancer ◽

Low Dose Chemotherapy

360 Background: This was an open-label, multicenter two-arm combined phase I (dose finding, cohort 1-5)/II (dose expansion) study of continuous doses of RAD001 every 2nd day or every day in combination with escalating low dose gemcitabine in patients (pts) with locally advanced and/or metastatic pancreatic cancer. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). The secondary objectives were to characterize safety and tolerability and to evaluate preliminary efficacy (ORR). Methods: A total of 27 pts were enrolled in phase I. All of these were analyzed in the safety population and 23 pts in the MTD-determining population. In total, 21 pts completed the study. Results: The MTD was determined to be 500mg/m2/week gemcitabine and 5mg/d RAD001 (cohort 4, 7 pts treated). In total, 3 DLTs occured: hepatic toxicity and unknown DLT as worsed case assumption in cohort 5 and hepatic toxicity in cohort 4. Overall, 25 of 27 pts (92.59%) reported at least one AE. Thrombocytopenia was most frequent AE, followed by leukopenia and nausea. In the individual dose groups, thrombocytopenia was most common in cohorts 1, 2 and 5, leukopenia in cohort 3 and nausea in cohort 4. The majority of pts experienced AEs with suspected relation to study drug (81.48%), AEs leading to dose adjustments or temporary interruption (77.78%) or required concomitant medication (66.67%). A total of 11 pts (40.74%) experienced SAEs. Two pts died during the study (not related to study drug). 4 pts were dicontinued permanently due to 2 AEs and 2 SAEs. ORR was 13%. None of the pts reported complete response (CR), the progressive disease rate was 13%. The clinical benefit rate was 78.3%. Conclusions: The present study was prematurely terminated due to slow recruitment and the dose expansion phase (phase II) was not started. In phase I, the MTD was determined to be 500mg/m2/week Gemcitabine and 5mg/d RAD001. No new safety concerns were identified for combination of antiangiogenic therapy using the mTOR- inhibitor RAD001 (Everolimus) and low dose chemotherapy for locally advanced and/or metastatic pancreatic cancer.

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