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National Cancer Institute U.S. National Institutes of Health www.cancer.gov
About DCEG

Philip E. Castle, Ph.D., M.P.H.

Investigator

Location: Executive Plaza South, Room 5004
Phone: 301-435-3976
Fax: 301-402-0916
E-mail: castlep@mail.nih.gov

 Philip E. Castle, Ph.D., M.P.H.

Biography

Dr. Castle received his Ph.D. in Biophysics from the Johns Hopkins University in 1995. Dr. Castle did a post-doctoral fellowship in Laboratory of Cellular and Developmental Biology, NIDDK, NIH on the molecular biology of the zona pellucida. In 1999, he joined the Cancer Prevention Fellowship at NCI and received his MPH from the Johns Hopkins Bloomberg School of Public Health in 2000. He did his Cancer Prevention Fellowship training with NCI's Hormonal and Reproductive Epidemiology Branch (2000-2003) and joined the branch as a principle investigator in 2003.

Research Interests

  • Natural history of HPV infection
  • Secondary determinants (cofactors) for HPV persistence and progression to precancer and cancer
  • Protein biomarkers (Proteomics) related to HPV persistence and progression to precancer and cancer
  • Host immune response to natural HPV infection
  • Screening and diagnostics for HPV infection and disease; development and validation of low cost strategies for resource-limited countries
  • HPV Vaccines

Natural History of HPV and Cervical Cancer

It is now recognized that infections by cancer-associated (oncogenic) HPV are the necessary but not sufficient cause of cervical cancer. However, oncogenic HPV infection is common sexually transmitted infection, with most sexually women being exposed in their lifetime, and most infections resolve or become undetectable within 2 years causing nothing more than mild pathologic abnormalities. Less commonly, oncogenic HPV infections persist and then can progress to cervical precancer and cancer.

We are interested in understanding why for some women HPV infections persist and progress to cervical precancer and cancer. To examine secondary etiologic factors (HPV cofactors) that may influence the outcome of infection, we are using data and biospecimens generated from our three large NCI cohorts, the Portland Kaiser Study, the Guanacaste Project, and ALTS. Specifically, we are examining what viral factors, exogenous exposures, and host factors influence HPV infections to either clear or persist with or without progression. As example of viral factors, it appears that HPV16 is more likely to both persist and progress than any other type, which may explain why it causes about 50% of all cervical cancers. Some non-oncogenic types may prefer vaginal epithelial cells, which are generally not susceptible to carcinogenesis, and thus in part may explain why they do not cause cervical cancer. As an example of exogenous factors, we are examining the role of smoking, including the underlying biologic mechanism, in the development of cervical cancer. To examine host factors, we are also examining whether chronic inflammation may contribute to the risk of progression. In addition, we are engaged in methodologic work to explore whether measurements at the cervix are more relevant to disease outcome compared to serologic measurements. Thus, we are validating the use of new multiplex protein measurements such as Recycling Immunoaffinity Chromatography for measuring immune profiles in blood and in cervical secretions and relating these profiles to HPV infection outcome.

To explore the relationships of viral persistence and progression to secondary etiologic factors, we are now considering the initiation of additional cohort studies. In particular, we are now interested in beginning larger cohort studies that would enable us to examine the gene-environment interactions and the outcomes of infection. We are also interested in special populations that have impaired immune function, e.g., transplant patients, to explore the relationships of immune response and HPV natural history.

Prevention Strategies: Screening

Since its introduction in the middle of the last century, cervical cytologic screening using Papanicoloau (Pap) smears has significantly reduced the incidence of cervical cancer in populations where programs have been successfully implemented. For example, in the U.S., these rates have been reduced by over 70%. It is now recognized that Pap smears detect human papillomavirus (HPV)-induced cytomorphologic changes (e.g., low-grade squamous intraepithelial lesions [LSIL] and high-grade squamous intraepithelial lesions [HSIL]) that typically precede the development of invasive cervical cancer by several years. Although Pap smear screening has reduce the incidence of cervical cancer to <15,000 cases and <5,000 related mortalities per year in the U.S., Pap smears are an insensitive method of detection for HPV infection and HPV-induced changes, and the success of the Pap smear programs can be attributed to annual screening resulting in repeated screening tests in timeframe of disease progression.

We have continued our validation and evaluations of new technologies for HPV detection for use in epidemiologic research as well as for primary prevention of cervical cancer. In particular, we have extensively evaluated the clinical performance of each generation of Hybrid Capture tests for HPV DNA detection made by Digene Corporation. The Hybrid Capture 2 test is now FDA-approved for use in screening and clinical management of equivocal Pap smears. However, new tests are now becoming available and we continue to actively evaluate these products for their use in cervical cancer and precancer detection.

However, current methods of cervical cancer screening are not useful in developing countries because either the method is difficult to maintain at a high performance level, as is the case of cytology, or the test is unaffordable, as is the case with the current HPV DNA test. Thus, we are now working with public health organizations to encourage the development and validation of new, affordable tests or testing modalities (e.g. self-collected samples) suitable for resource limited regions of the world. Complementary to this effort, we are now working with the states and academic institutions in those states to reach underserved U.S. populations with these new screening methods to test efficacy and validate their use globally.

Prevention Strategies: Vaccines

A second active area of prevention research is the evaluation of vaccines that prevent or treat HPV infections. Proof of principle clinical trials have demonstrated that a virus-like particle (VLP) vaccine that targets HPV16, the HPV type that causes ~50% of cervical cancers worldwide, provides nearly 100% short-term protection against HPV16 infection. However, there is some evidence to suggest that there is 1-2 order of magnitude peri-ovulatory decrease in anti-HPV16 antibody concentration. We are now initiating a small experimental trial that will further explore the effects of menstrual cycle fluctuations and oral contraceptive use on genital tract immunity (anti-HPV16 and anti-HPV18 antibodies) after vaccination. Such a study is intended to be complementary to a 12,000-15,000 women vaccine trial led by Dr. Allan Hildesheim, and will also inform about mucosal immunity for prevention of other mucosal infections.

We are also exploring alternative, "mucosal" vaccine delivery systems, such as oral aerosols and ingestable vaccines, to the standard intramuscular vaccinations. Our aims are to increase genital tract immunity, where protection must be optimized for long-term protection, and to find methods of delivery that are more tolerable and applicable to global vaccination. A second effort is to develop an injectable "depositional" sustained-release delivery system that would permit a single vaccination and thus overcoming the difficulty of multiple vaccinations in transient populations.

Finally, we are working with several investigators on the development of second generation vaccines. One of the limitations of the current vaccine candidate despite its promise is that there is no evidence of cross-type protection. Thus, to truly protect against cervical cancer, the vaccination must be composed of ~13 VLP types. The feasibility of such a strategy is uncertain. Thus, alternative vaccinogens are being investigated to provide broader type (pan-HPV) protection. A second limitation is that there is no evidence that the VLP vaccine will "treat" preexisting infection. Thus, we will be evaluating new vaccines that generate vigorous T-cell responses to target epitopes expressed in epithelial cells at the basal layer, where the reservoir of infection resides

Keywords

Molecular epidemiology, HPV, cervical cancer, prevention, screening and diagnostics, vaccination, mucosal immune responses.

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Selected Publications

Collaborators

DCEG Collaborators

  • Abhijit Dasgupta, Ph.D., Ronnie Falk, M.S., Allan Hildesheim, Ph.D., Jose Jeronimo, M.D., Ruth Pfeiffer, Ph.D. Mark Schiffman, M.D., M.P.H., Mark Sherman, M.D., Rashmi Sinha, Ph.D., M.P.H., Sholom Wacholder, Ph.D.

Other NCI Collaborators

  • Carl Baker, M.D., Ph.D., Betty Conde, Ph.D., Doug Lowy, M.D., Ligia A. Pinto, Ph.D., Miriam Poirier, Ph.D., John Schiller, Ph.D., Diane Solomon, M.D., Denise Whitby, Ph.D.

Other Scientific Collaborators

  • Ronald Alvarez, M.D., University of Alabama
  • Raymond Apple, Ph.D., Roche Molecular Systems
  • M. Conchita Bratti, M.D., M.P.H., Proyecto Epidemiologico Guanacaste
  • Robert D. Burk, M.D., Albert Einstein College of Medicine
  • Robert P. Edwards, M.D., Ph.D., University of Louisville
  • Francisco A. Garcia, M.D., M.P.H., University of Arizona
  • Andrew G. Glass, M.D., Northwest Kaiser Permanente
  • Patti Gravitt, Ph.D., M.S., Johns Hopkins University
  • Rolando Herrero, M.D., Ph.D., Proyecto Epidemiologico Guanacaste
  • Sharon Hillier, Ph.D., University of Pittsburgh
  • E. Blair Holladay, Ph.D., Medical University of South Carolina
  • Walter Kinney, M.D., Northern California Kaiser Permanente
  • Janet Kornegay, Ph.D., Roche Molecular Systems
  • Attila Lorincz, Ph.D., Digene Corporation
  • Carolyn Y. Muller, M.D., University of Texas Southwestern
  • Groesbeck Parham, M.D., University of Alabama
  • Ed Partridge, M.D., University of Alabama
  • Richard B. Roden, Ph.D., Johns Hopkins University
  • Ana-Cecilia Rodriguez, M.D., M.P.H., Proyecto Epidemiologico Guanacaste
  • Brenda Rush, R.N., Northwest Kaiser Permanente
  • Isabel Scarinci, Ph.D., M.P.H., University of Alabama
  • David R. Scott, M.D., Northwest Kaiser Permanente
  • Raphael Viscidi, M.D., Johns Hopkins School of Medicine
  • Joan Walker, M.D., M.P.H., University of Oklahoma
  • Cosette Wheeler, Ph.D., University of New Mexico
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