How antiretroviral drugs could be used to treat cervical cancer
Cervical cancer (CC) represents one of the main causes of morbidity and mortality in women worldwide, particularly in human papillomavirus (HPV) and human immunodeficiency virus (HIV) doubly infected women. CNAIDS is committed to developing new treatments to block CC onset and progression.
Despite the introduction of mass prevention screening, invasive CC is the 4th most frequent cancer in women worldwide and the 2nd in Africa, representing an important cause of morbidity and mortality. The risk of CC development is greatly increased by the persistent infection of cervical epithelial cells with the high-risk oncogenic papillomavirus (HR-HPV), the causative agent of CC. Of note, a significant fraction of CC is caused by HR-HPV types not targeted by current HPV vaccines, and dysplastic cervical lesions (CIN) can progress to invasive CC despite surgical intervention. Therefore, CIN/CC therapy could greatly benefit from targeted pharmacological interventions.
CIN incidence and aggressiveness are particularly dramatic in HIV/HPV co-infected women. In HIV+ patients, however, new combined antiretroviral therapies (cART) have reduced the appearance of CIN lesions or their progression in CC.
CNAIDS is committed to investigating the activity of antiretroviral drugs belonging to the HIV protease inhibitor (HIV-PI) class, which exert direct anti-angiogenic and anti- tumoral effects against various tumors, in the prevention of CC onset and progression. To this purpose, in collaboration with the IRCCS Istituto di Candiolo - FPO, we used the "transgenic" mice model expressing the HPV E6/E7 onco-proteins, which develop CIN/CC lesions. In this model, CIN progression occurs by activating an "angiogenic switch" that leads to progression into invasive cancer, thus allowing the study of HIV-PI activity in cervical lesions. CNAIDS is also involved in studies using HR-HPV-infected CIN/CC cell cultures "in vitro". These studies will allow to evaluate HIV-PI activity on key parameters of CIN/CC cells, such as proliferation, survival, invasion of surrounding tissues and differentiation. Our in-vivo and in-vitro results indicate that HIV-PI inhibit the activity and expression of extracellular matrix metalloprotease (MMP)-9, an enzyme responsible for "remodeling" the non-cellular component present in all tissues (the extracellular matrix), which has a key role in CIN development and progression into CC.
This project will therefore help to clarify HIV-PI effects on CIN/CC development and progression independently of HIV infection, and to develop new therapies to prevent or treat tumors that arise in both HIV+ and seronegative patients.