Regulation of Papillomavirus-Induced Immortalization by EGF-Receptor Inhibition

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DESCRIPTION (provided by applicant): Infection with a subset of human papillomaviruses (HPV) is the major risk factor for cervical cancer. The HPV E6 and E7 genes are selectively retained and expressed in most malignant tumors, and persistent infection with HPV and immortalization of cervical cells are important events in cervical carcinogenesis. The majority of HPV infections are eliminated by the host immune response. However, women with acquired immune deficiency syndrome (AIDS) develop persistent HPV infections that progress to cervical intraepithelial neoplasia or cancer. AIDS patients also respond poorly to conventional therapy and their disease is likely to recur. Thus, women with AIDS would benefit from chemoprevention or therapy targeted to molecular pathways that are important for cervical carcinogenesis. The epidermal growth factor receptor (EGF-R) is a relevant target. The EGF- R is over expressed in cervical dysplasias and carcinomas, and patients with high EGF-R levels in their tumor have a poor prognosis. Our preliminary results indicate that inhibition of the EGF-R blocks an important step in cervical carcinogenesis; immortalization of cervical cells by HPV-16. Our long term goal is to determine whether the EGF-R is an effective target for chemoprevention or therapy of cervical cancer in AIDS patients. The objectives of this proposal are to (1) confirm that EGF-R inhibition prevents immortalization of cervical cells by HPV-16, and (2) identify the mechanism by which immortalization is inhibited. We will examine these questions using cultures of human epithelial cells derived from the cervical transformation zone, the site where most cervical cancers originate. Experiments will use Erlotinib (Tarceva), a small molecule EGF-R tyrosine kinase inhibitor that has been approved for therapy of human cancer. Studies will determine whether Erlotinib prevents immortalization of normal cervical cells by HPV-16 or inhibits growth of cervical cancer cells. Experiments will also determine whether Erlotinib prevents immortalization by (1) increasing susceptibility of E6/E7-expressing cells to apoptosis, (2) stimulating premature senescence, or (3) decreasing expression of HPV-16 DNA. Our results will clarify how EGF-R inhibition targets a novel pathway that is potentially important for chemoprevention and therapy of cervical cancer. Women with AIDS are particularly susceptible to cervical cancer. They respond poorly to conventional therapy and their cancers are likely to recur. Our results describe a novel target for chemoprevention or chemotherapy of cervical cancer that is relevant to AIDS patients or immune suppressed individuals. This involves prevention of immortalization by papillomaviruses by inhibition of the epidermal growth factor receptor. Since drugs that inhibit this receptor have already been approved to treat lung and colorectal cancer, it is reasonable to test whether they also inhibit cervical carcinogenesis.