A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel
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Ana Mato-Berciano1,2, Giulia Raimondi1,2, Maria Victoria Maliandi1,2, Ramon Alemany3, Lluis Montoliu2,4, Cristina Fillat1,2
1Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
3Institut Català d’Oncologia-IDIBELL. L’Hospitalet de Llobregat, Barcelona, Spain
4Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
Cristina Fillat, email: [email protected]
Keywords: pancreatic cancer, oncolytic adenovirus, cancer stem cells, gemcitabine, nab-paclitaxel
Received: February 08, 2016 Accepted: January 23, 2017 Published: February 07, 2017
Notch signaling pathway is an embryonic program that becomes reactivated in pancreatic cancer and contributes to cancer stem cell (CSC) maintenance. We explored the concept of oncolytic adenoviral activity in response to Notch activation signaling, in the context of a chimeric promoter with uPAR regulatory sequences, as a strategy to drive its activity in neoplastic and CSC. We explored the advantages of a chemo-virotherapy approach based on synergistic combinations. Regulatory sequences recognized by the transcriptional factor CSL upstream a minimal uPAR promoter were engineered in adenoviral vectors and in the oncolytic adenovirus AdNuPARmE1A. Viral response to Notch signaling, and viral potency in cell lines and pancreatic cancer stem cells (PCSC) was tested. Preclinical toxicity and antitumor efficacy in xenografts and Patient-derived xenografts (PDX) mouse models was evaluated, as unimodal or in combination with gemcitabine+nab-paclitaxel. Mechanistic studies were conducted to explore the synergism of combined therapies.
We demonstrate that CSL-binding site optimized-engineered sequences respond to Notch activation in AdNuPARmLuc and AdNuPARmE1A. AdNuPARmE1A showed strong lytic effects in pancreatic cancer cell lines and PCSC. AdNuPARmE1A displayed attenuated activity in normal tissues, but robust antitumor effects in xenograft and PDX models, leading to a reduced capacity of treated tumors to form tumorspheres. Chemo-virotherapy treatment enlarged therapeutic response in both tumor models. Synergistic effects of the combination resulted from viral sensitization of apoptotic cell death triggered by chemotherapy.
In summary we present a novel effective oncolytic adenovirus, AdNuPARmE1A that reduces PCSC and presents synergistic effects with gemcitabine and nab-paclitaxel, supporting further clinical development.
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