A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel

Abstract

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.

Personalized Nanomedicine: A Revolution at the Nanoscale

“…The most used targeting moieties have been monoclonal antibodies (e.g., OX26 to target the transferrin receptor, overexpressed in blood–brain barrier cells [55]), since they target specific molecules expressed by a single type of cells. Other type of tunable nanosystems that could be useful for personalized therapies are viruses and bacteriophages [3], such as the currently extended oncolytic virotherapy (e.g., the design of novel treatments to fight against pancreatic adenocarcinoma by taking advantage of adenoviral vectors [56]), since they can be genetically modified to express or suppress a gene of interest [38]. It is also important to keep in mind that to achieve the personalization of a therapy, the use of gene material as the active principle is recommended as compared with pharmacological therapies with drugs.…”

Clinical efficacy of nab-paclitaxel in patients with metastatic pancreatic cancer

“… 18 These data indicate that nab-paclitaxel plus Gem has a manageable safety profile and is an effective first-line option in patients in Western Europe with MPC. 21 – 23 …”

Retargeting adenoviruses for therapeutic applications and vaccines

“…Another innovative approach has been to insert albumin binding peptide into the hexon of Ad5 to shield it from neutralizing antibodies [246,247]. This approach allows the virus to cloak itself in albumin in the blood and may have utility to evade antibodies as well as other problematic factors in the blood.…”