Karen K. Smith-McCune, MD, PhD
Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, UCSF
John A. Kerner Chair in Gynecologic Oncology, UCSF
My research program is focused on improving our understanding of the pathophysiologic mechanisms governing human papillomavirus (HPV)-induced cervical neoplasia and on translating these findings into the clinical arena. Pressing public health issues arising from problems with the current cervical cancer screening test, the Pap smear, motivate my goal to define new biomarkers and devise a molecularly based test that will outperform the Pap test in sensitivity and specificity. Through my role as Director of the UCSF Dysplasia Clinic for the past 10 years, I have direct day-to-day involvement in the management of clinical issues deriving from HPV-induced disease and have attained national recognition as an expert in this area. By virtue of integration between my basic science research and my direct involvement with patient care, I am in a unique position to provide new insights into disease pathophysiology and translate these findings into new strategies for the diagnosis and therapy of this common condition. My progress towards this goal is outlined below.
Identification and characterization of the angiogenic switch during cervical carcinogenesis
I have demonstrated that premalignant cervical lesions exhibit striking neovascularization localized to the area immediately below the dysplastic epithelium. Compared to normal cervix, this neovascularization is characterized by increased vessel count, increased vessel apposition to the basal cell layer, and markedly increased expression of vascular endothelial growth factor (VEGF). I have also shown that histologically normal epithelium adjacent to cervical dysplasia exhibits enhanced angiogenesis and increased expression of VEGF compared to truly normal cervix. More recently, my lab has demonstrated that the angiopoietins (ang-1 and ang-2) are also significantly up-regulated in dysplastic cervix compared to normal (manuscript in preparation). Ongoing research on this project is testing the hypotheses that ang-1, ang-2 and VEGF protein and mRNA can be detected in exfoliated cervical cells and that increased levels will correlate with dysplasia. I plan to continue to characterize the mechanisms governing the regulation of angiogenesis in the human cervix and, in collaboration with Dr. Douglas Hanahan (UCSF), to explore common mechanisms between human disease and the K14-HPV16 transgenic mouse model of cervical carcinogenesis. Based on preclinical testing of anti-angiogenic agents in the mouse model, I plan to initiate a Phase I trial of topical angiogenic inhibitors in women with CIN II/III as a novel therapeutic approach.
Development of new biomarkers for cervical cancer screening
The goal of this project is to discover new biomarkers for cervical cancer screening, to refine the sensitivity and specificity of the current screening test, and to devise a molecular point-of-care screening test with better performance and accessibility than the current Pap test. HPV is present in over 90% of high-grade dysplasia and cervical cancers. My previous work demonstrated that in arrested cells, E7 binds predominantly to p130, a member of the retinoblastoma (Rb) gene family, rather than to Rb itself, implying that p130 inactivation might explain cell cycle re-entry induced by E7. My current work is focused on measurements of E7 transcripts and E7 transcriptional target genes as biomarkers for detecting cervical dysplasia, to test the hypothesis that expression of the HPV early region gene E7 might distinguish between normal samples (absent expression) and high-grade lesions (detectable E7 expression). My lab has developed techniques for measurement of HPV 16 and 18 E7 transcripts in clinical samples collected for cervical cancer screening using quantitative real-time RT-PCR (TaqMan®). We have shown that measurement of E7 expression is technically feasible in clinical samples collected for cervical cancer screening, and appears to have diagnostic significance (manuscript submitted).
Using transciptional profiling of RNA from Pap samples performed by my lab at Millennium Pharmaceuticals, Inc, we have recently discovered that a novel gene protein is up-regulated in CIN III and cancer samples. We are currently validating the possibility that PSG can improve the performance of the Pap test in women referred for abnormal cytology, and studying the functional significance of this gene in cervical carcinogenesis. In addition, Margaret takeda in the lab is continuing transcriptional profiling experiments to identify and validate a panel of markers capable of distinguishing normal and low grade lesions from precancers and cancer.
Mucosal immunity to HPV in women with cervical dysplasia and alterations in women with HIV infection
This study, the Ph.D. thesis project of Akiko Kobayashi in the lab, is designed to better understand the mucosal immune response to HPV in women with CIN. The clinical issue driving the research is the observation that immunosuppressed women have a higher prevalence of HPV-induced disease than do immunocompetent women. We have found that the local mucosal immune response is significantly different in dysplastic lesions from HIV-negative versus HIV-positive women. We are currently studying the functional properties of CD8+ T cells in dysplastic lesions, and have found nearly complete absence of interferon gamma (IFNG) production by T cells in lesions from HIV-positive women, compared to abundant IFNG production in T cells from HIV-negative women. Quantification of immune cell numbers indicate that in the HIV-positive group, the local immune response to dysplasia is characterized by a shift to a Th2 response compared with a Th1 response in HIV-negative lesions. The functional lesions in CD8+ Tcells from HIV-positive women are under investigation using ex vivo techniques, in collaboration with the Core Immunology Laboratory at San Francisco General Hospital.