Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

Principal Investigator: KURMAN, ROBERT J
Institution Receiving Award: JOHNS HOPKINS UNIVERSITY
Program: OCRP
Proposal Number: OC010017
Award Number: DAMD17-02-1-0667
Funding Mechanism: Program Project - Overall Program
Partnering Awards:
Award Amount: $2,319,646.00


Ovarian cancer is the most lethal gynecologic malignancy. Approximately 23,000 women are diagnosed with ovarian cancer each year in the United States, and 14,000 women die of this disease annually. Although new chemotherapeutic agents have prolonged survival, the overall mortality of ovarian cancer has remained unchanged. This is because conventional therapy is only curative for early stage disease, and there is currently no effective screen to catch serous carcinoma at this stage. Therefore, the overall objective of our program is to identify biomarkers that define the molecular pathogenesis of serous carcinoma and thereby develop an early detection test and antigen-specific immunotherapy for this deadly disease. We hypothesize that there are biomarker molecules uniquely expressed by serous carcinoma and linked to pathogenesis. Furthermore, we hypothesize that such molecules are immunogenic in patients with serous carcinoma and serve as important candidates for development of both an early detection blood test and for antigen-specific cancer immunotherapy. Progress toward a test and cure for ovarian cancer has been hampered by our lack of understanding of its causes. Understanding the basic biology of ovarian cancer will move research beyond trial and error to rational design of new diagnostic tests and therapies. Although ovarian cancer is often viewed as a single disease, it is considerably more complex and represents a family of related but distinct tumors. However, serous carcinoma is responsible for the large majority of `ovarian cancer¿-related deaths and therefore is the focus of our program. At present, serous carcinoma is considered by most investigators to be a single entity. However, we believe that `serous carcinoma¿ comprises at least two distinctive types of tumors. The conventional type of serous carcinoma (CSC) grows rapidly and kills patients within 5 years despite aggressive treatment, and the second type, designated ¿micropapillary serous carcinoma (MPSC),¿ is low grade and indolent but fails to respond to conventional chemotherapy. Based on our files and a population-based study, MPSC represent 35' of all serous carcinomas. Understanding the molecular basis that distinguishes CSC and MPSC is important to rational development of early diagnostic tests and effective, specific therapy.

In order to accomplish our objective, we propose three complementary research projects, a Tissue and Blood Bank to provide specimens for study, and an Administration/Statistics Core to co-ordinate data analysis and promote synergy. In Project 1, Dr. Shih will identify the specific genetic changes and genes that are expressed by the two different types of tumors using powerful molecular biologic techniques (digital PCR, SAGE, and oligonucleotide-based microarray analysis) to provide biomarkers of disease pathways. The development of ovarian cancer is associated with the mutation and aberrant production of proteins that are recognized by the immune system as `foreign¿ and therefore result in the production of antibodies against their cancer. Molecules recognized by these antibodies are called tumor antigens, and in Project 2, Dr. Roden proposes to define their genetic sequence using a serologic analysis of recombinant tumor cDNA expression libraries (SEREX). Tumor-specific proteins relevant as biomarkers will be validated by immunohistochemistry in Projects 1 and 2. We have demonstrated that patients with serous carcinoma, but not healthy women, make antibodies that are specific for particular tumor antigens and readily detectable using a simple blood test called enzyme-linked immunosorbant assay (ELISA). Having identified tumor antigens of early stage serous carcinoma, Dr. Roden proposes exploration of the potential of the tumor antigen-specific antibody for diagnosis of early stage serous carcinoma. A natural extension of this study and Project 1 is to exploit advances in antigen presentation and immunotherapy to develop cancer-specific vaccines that target tumor antigens and biomarkers uniquely expressed by cancer cells. In Project 3, Dr. Wu proposes to develop specific vaccines first using a model ovarian cancer antigen, mesothelin, that is found in over 90' of serous carcinomas. Dr. Wu has developed novel strategies to generate antigen-specific immune responses that are therapeutic in model tumor systems and will be tested using the unique mesothelin-expressing mouse peritoneal/ovarian tumor model developed in our laboratory that resembles human ovarian serous carcinoma. In summary, this is an integrated multidisciplinary Project in which Projects 1 and 2 use molecular biologic and immunologic approaches to define biomarkers of serous carcinoma that are critical as probes for the etiology/pathogenesis of ovarian cancer, fundamental to the development of a blood test for early stage disease, and represent targets for cancer vaccines generated using the novel strategies of Project 3.