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Robert Kurman MD.
Patrice Morin, Ph.D.
Richard Roden, Ph.D.
Brigitte M. Ronnett, M.D.
le-ming Shih, Ph.D.
Tzyy-Choou Wu, M.D., M.P.H., Ph.D.
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Research at Johns Hopkins
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Richard Roden, Ph.D.
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Honami Naora, PhD. Postdoctoral fellow
Yan-qin Yang, DDS. Research Technician
William Yutzy, BS. Research Technician
The investigators of Dr. Roden's and
Dr. Wu's laboratories.
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.
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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:
- 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.
Completed
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.
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.
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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
(b) develop molecular diagnostic tools for early cancer detection including ovarian cancer and other types of cancer.
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.
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Patrice Morin, Ph.D. |
The main focus of our laboratory is the molecular genetics of ovarian
cancer. More specifically, our interest can be divided in two parts:
- SAGE analysis of normal ovary and ovarian cancer. It is well documented
that, in the process of going from normal to malignant, cells reprogram
their gene expression. However, consistent changes that could be useful for
diagnosis and/or therapy have remained elusive for most tumor types,
including ovarian cancer. SAGE, one of the more powerful techniques
currently available for the quantitative study of gene expression, is being
used in our laboratory to analyze normal ovarian tissue, primary ovarian
tumors and ovarian cancer cell lines. We have identified hundreds of
transcripts differentially expressed during ovarian tumorigenesis.
Interestingly, several of these genes represent novel genes. We are
currently characterizing many of the differentially expressed transcripts
using a variety of techniques including immunohistochemistry, quantitative
(real-time) RT-PCR and functional assays. Some of these genes may become
targets of novel strategies for early detection and/or mechanism-based
therapy of ovarian cancer.
- Search for genetic alterations in ovarian cancer. Surprisingly little is
known about the molecular alterations in ovarian cancer. We have established
a panel of matched normal tissue and primary ovarian cancer specimens and
are using this panel, in conjunction with ovarian cancer cell lines, to
identify genes important in ovarian tumorigenesis. Techniques used include
representational difference analysis (RDA) and LOH studies. Of particular
interest are chromosomal regions on Xq, 11p and 6q, which are frequently
lost in ovarian cancers, suggesting the presence of tumor suppressor genes
important in ovarian tumorigenesis. We have recently suggested that GPC3, a
gene located at Xq26 and previously implicated in an overgrowth syndrome,
may be silenced during ovarian tumorigenesis.
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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:
- 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.
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.
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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.
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