Towards targeted virotherapy in gynecological cancer

ALEJANDRO NICOLA CANDIA ; ANA LAURA ALFANO ; CRISTIAN M. MALNERO ; ISMAEL R. BERMúDEZ; NICASIO CUNEO; MARIELA A. GANGEMI ; ALEJANDRO SODERINI ; VERóNICA M. LOPEZ; OSVALDO L PODHAJCER

Helsinski

Congreso; ESGCT and FSGT Collaborative Congress, Helsinki; 2015

European Society of Gene and Cell Therapy

Towards targetedvirotherapy in gynecological cancer  Worldwide more than 1 million women are diagnosed with agynecological cancer. Non-specific symptoms (ovary cancer) and disparities inaccessibility to health services (cervical cancer) explain the differences ingynecological cancer outcome globally. Most gynecological cancer types arecharacterized by an accompanying stroma that not only supports malignant cellsgrowth but is also largely responsible for the high resistance of the cancer toconventional and targeted therapies. We haverecently developed a stroma-targeted oncolytic adenovirus (AR-2011) whosereplication is driven by a triple chimeric promoter that drives a ÄRB E1A geneand was pseudotyped with a chimeric fiber 5/3. By using E4 gene levels we observed a large increase in lytic activity ofAR-2011 under hypoxia and in the presence of TNFa. We assessed thelytic capacity of AR-2011 on fresh explants of gynaecological cancers. AR-2011replicated in 5/8 cervical cancers, 3/4 uterine cancer and 3/4 ovariancarcinomas. AR-2011 lytic activity was also assessed in combination withchemotherapy. No viral lytic effect was observed already in explants from 2normal uterus, 2 normal cervix and 9 normal ovaries. In addition to the lyticeffect we are currently assessing biomarkers such as the expression levels ofthe receptor for the virus fiber (CD46 and desmoglein-2) and of the SPARC gene,and markers of an inflammatory and hypoxic environment. We propose that this approach combined wheneverpossible with in vivo assessment of virotherapy efficacy in patient derivedxenografts, might be very useful in helping guide personalized therapeuticdecisions in these devastating diseases.