Robert Kurman MD.
Richard Roden, Ph.D.
Brigitte M. Ronnett, M.D.
le-ming Shih, Ph.D.
Tzyy-Choou Wu, M.D., M.P.H., Ph.D.
|Research at Johns Hopkins|
Richard Roden, Ph.D.|
Our goal is to reduce the morbidity and mortality associated with ovarian cancer by developing a screening test for earlier detection of the disease when current therapies are most effective. Ovarian cancer is particularly insidious because symptoms of early stage disease are vague or absent. It is also an aggressive cancer and thus women generally present with large, disseminated tumors at diagnosis. Standard therapies have poor efficacy against disseminated disease, but a high cure rate for cancer that is detected early when confined to the ovary. Although early diagnosis is so critical, there is currently no test that is appropriate for routine screening of women. We favor development of an antibody-based blood test because it is likely to be simple, rapid, inexpensive, and applicable to population screening even in under-served or rural areas. It is known that tumors produce proteins or other molecules that can differ in nature and/or quantity from those produced by healthy tissues. Such molecules released by tumors into the bloodstream are of potential diagnostic value and are known as 'biomarkers', for example, PSA is a well-established serum biomarker for prostate cancer.
Currently available blood tests for ovarian cancer measure biomarkers such as CA125 that are not detectable in many patients with early stage ovarian cancers and are produced in healthy individuals or those with other benign conditions. As such they are not applicable to routine screening for early diagnosis of ovarian cancer. Therefore, development of a test for ovarian cancer requires identification of new serum biomarkers released into the bloodstream by the majority of early stage tumors but are absent, or at significantly lower levels in the blood of healthy individuals. Our approach to develop better screening tests involves exploitation of the patients own immune system.
The generation of mutant molecules and aberrant production of other molecules (e.g. molecules normally present only in fetal or testicular cells) is associated with the development of cancers, including ovarian cancer. The immune system can recognize such molecular changes in cancer cells as "foreign", and therefore patients often generate antibody against their cancer. We find that patients with ovarian cancer are able to generate an antibody response against their cancer. Therefore, we propose to use the cancer patient's own anti-tumor antibodies to identify proteins specific to early-stage ovarian cancer, and produce these proteins in bacteria. Being both immunogenic and cancer-specific, those molecules identified by patient's antibodies represent promising components for a cancer vaccine. Since these cancer-specific molecules may be involved in the development of disease, their identification may provide valuable insight into the mechanisms of tumor development.
Interestingly, only individuals with ovarian cancer should produce antibody to these tumor-specific molecules. Therefore detection of such tumor-specific antibodies in patient blood has strong potential for a diagnostic test. Having made the cancer-specific proteins in bacteria, antibodies to these proteins can be detected in the blood of patients using a simple, inexpensive and non-invasive test (ELISA). This could readily be applied on a large scale, even in rural areas by sending samples to a central laboratory, as seen for the prostate-specific antigen test used for older men. Therefore, having exploited the patient's immune system to identify cancer-specific molecules, we propose to test ovarian cancer patients and healthy women for antibodies to these cancer-specific molecules. We will examine the potential of such tests to screen women for early stage ovarian cancer.
Brigitte M. Ronnett, M.D.|
My research interests are focused on clinicopathologic studies in gynecologic pathology. The major theme of recent and ongoing studies has been investigating primary and metastatic mucinous neoplasms involving the ovaries utilizing both traditional clinicopathologic methods and immunohistochemical and molecular techniques. Specific projects have focused on the following issues:|
studies have provided morphologic, immunohistochemical, and molecular
genetic evidence to support the concept that PMP is derived from
appendiceal, not ovarian, mucinous tumors. Ongoing studies are
investigating the immunohistochemical distinction of metastatic mucinous
carcinomas in the ovaries from primary ovarian mucinous tumors.
- redefining pseudomyxoma peritonei (PMP)
as a pathologic entity,
- clarifying the relationship between ovarian
mucinous tumors and PMP,
- establishing diagnostic criteria for primary
ovarian mucinous tumors, and
- distinguishing metastatic mucinous
carcinomas in the ovary from primary ovarian mucinous tumors.
My other major area of effort has been resident teaching. I conduct a
weekly teaching session at a multiheaded microscope for residents on the
gynecologic pathology rotation. Thematic topics are covered in each
session using cases from the surgical pathology and consult files. I
received the 1999 Anatomic Pathology Teaching Award from the housestaff for
this activity. My teaching efforts also include participation in numerous
continuing medical education courses.
Ie-ming Shih, M.D., Ph.D. |
Our laboratory focuses on the studies to |
(a) understand the molecular changes leading to the development of ovarian carcinoma; and
Specifically, we will determine the molecular genetic alterations during the progression of ovarian serous carcinomas with molecular and morphologic correlations. For this aim, we will employ an array of new technologies to achieve our goals. Besides the conventional cell and molecular biology methods, we will employ digital karyotyping, digital PCR analysis, serial analysis for gene expression, somatic cell knockout, nanobiotechnology, mathematical and computer simulation. Further studies will focus on specific molecular or genetic alterations (i.e., new oncogenes or tumor suppressors) to determine their biological functions in the development of cancer and to assess their clinical significance. Engineered mouse model will also be used to assess the functional roles of newly identified genes. Finally, we will develop the body fluid-based assays to analyze molecular and genetic tumor markers we identified for molecular cancer diagnostics. The successful development of molecular diagnostic approaches may hopefully provide a simple and cost effective tool to detect and follow ovarian carcinomas, which would greatly facilitate clinical management of this deadly disease.
(b) develop molecular diagnostic tools for early cancer detection including ovarian cancer and other types of cancer.
Tzyy-Choou Wu, M.D., M.P.H., Ph.D.|
The ideal cancer treatment should be able to eradicate systemic tumors at multiple sites in the body while having the specificity to discriminate between neoplastic and non-neoplastic cells. In this regard, antigen-specific cancer immunotherapy and anti-angiogenesis represent two attractive approaches for cancer treatment. We have recently developed a DNA vaccine encoding calreticulin (CRT) linked to a model tumor antigen and demonstrated that it generated significant antigen-specific immunological effects and anti-angiogenesis. Thus, the major objective of this proposal is to create a therapeutic DNA vaccine using calreticulin (CRT) linked to a model ovarian cancer-specific antigen, mesothelin, to control ovarian cancer through the combination of immunotherapy and anti-angiogenesis. To test this ovarian cancer vaccine strategy, we will use a newly created preclinical mouse ovarian cancer model that expresses ovarian cancer antigens (such as mesothelin) and generates ascites in mice, simulating human ovarian cancer. In the next few years, we plan to:
With continued identification of highly immunogenic antigens that are consistently expressed in ovarian cancers but absent from or at low levels in normal tissue, we can validate their expression in our preclinical model and use this information for the development of antigen-specific ovarian cancer vaccines. These preclinical data will serve as stepping stones for future clinical trials in patients with ovarian cancers.
- Generate and characterize DNA vaccines encoding chimeric CRT/mesothelin ;
- Characterize the ability of DNA vaccines encoding chimeric CRT/mesothelin to induce mesothelin-specific humoral and T cell-mediated immune responses in vaccinated mice;
- Compare mesothelin-specific anti-tumor effects and anti-angiogenesis generated by DNA vaccines encoding chimeric CRT/mesothelin using mesothelin-expressing murine tumor models;
- Evaluate the mechanisms of the enhanced mesothelin-specific CD8+ T cell activity and antitumor effects generated by linkage with the CRT molecules.
Robert J. Kurman, M.D.|
Dr. Kurman's research has included work on germ cell tumors, gonadal stromal tumors and in the last ten years epithelial tumors, with particular interest in borderline tumors.