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HOXA9, HOXA10, and HOXA11 as molecular markers and therapeutic targets in ovarian cancer
Posted August 16, 2005
Honami Naora, Ph.D.
MD Anderson, University of Texas

Ovarian cancer, the most lethal of all gynecological cancers, is thought to arise from cells of the surface epithelium of the ovary. The three major subtypes of epithelial ovarian cancer - serous, endometrioid and mucinous- are distinguished by their distinct patterns of histologic differentiation; however, the molecular mechanisms giving rise to these distinct subtypes are not yet understood. Dr. Honami Naora, recipient of a fiscal year 2003 Ovarian Cancer Research Program Idea Development Award, has investigated the role of a family of homeobox-containing (HOX) genes in regulating the histologic differentiation of ovarian tumors. HOX genes are transcription factors that play a critical role during normal embryonic development, but their aberrant expression in adult tissue can significantly contribute to tumorigenesis. Dr. Naora and colleagues at the University of Texas M. D. Anderson Cancer Center have implanted cell lines derived from mouse ovarian surface epithelium into immunocompromised mice to evaluate the role of various HOX genes on tumor formation. They have identified three HOX genes (HOXA9, HOXA10, and HOXA11) that control the development of each of the three major histological subtypes of epithelial ovarian cancer. These three HOX genes are not expressed in normal ovarian tissues, and may thus provide molecular markers that could improve the diagnosis of ovarian cancer and serve as therapeutic targets for drugs designed to treat the specific subtypes of epithelial cancer.

Publications:

Cheng W, Liu J, Yoshida H, et al. 2005. Lineage infidelity of epithelial ovarian cancer is controlled by HOX genes that specify regional identity in the reproductive tract. Nature Medicine 11:531-537.

Patent Pending: HOXA9, HOXA10, and HOXA11 as molecular markers and therapeutics targets in ovarian cancer.

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Mutant Endostatin: Promising Antiangiogenic Therapeutic Agent for Ovarian Cancer
Posted April 29, 2005
Dr. Sundaram Ramakrishnan, University of Minnesota

Dr. Ramakrishnan, an Ovarian Cancer Research Program-supported investigator at the University of Minnesota, has been studying the role of angiogenesis in the etiology and prevention of ovarian cancer. Angiogenesis, the formation of new blood vessels, is a fundamental process in the growth of normal and cancerous tissues. Dr. Ramakrishnan and his team are developing an exciting therapeutic approach aimed at preventing angiogenesis in ovarian cancer by enhancing the biological activity and therapeutic efficacy of human endostatin, an important antiangiogenic protein. Dr. Ramakrishan and his team created a mutant endostatin, called P125A-endostatin, by genetically engineering a single amino acid substitution (a substitution of the amino acid proline with alanine) with further modifications to increase the bioavailability of P125A-endostatin. When delivered in a mouse model of ovarian cancer, the genetically engineered endostatin showed improved antiangiogenic biological activity compared to the native protein. Dr. Ramakrishnan's preclinical studies will help support human clinical trials using the mutant endostatin to inhibit the growth of ovarian cancer. Thus, mutant endostatin may prove to be a valuable antiangiogenic therapeutic agent for the treatment of ovarian cancer.

Publications:

Subramanian IV, Ghebre R, and Ramakrishnan S. 2005. Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice. Gene Ther 12:30-38.

Yokoyama Y, and Ramakrishnan S. 2004. Improved biological activity of a mutant endostatin containing a single amino-acid substitution. Br J Cancer 90:1627-1635.

Yokoyama Y, Ramakrishnan S. 2004. Addition of integrin binding sequence to a mutant human endostatin improves inhibition of tumor growth. Int J Cancer. 10;111(6):839-48.

Patent: Genetic Modification of Endostatin. (6,825,167).

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Anti-Angiogenic Role of Dendritic Cells in Ovarian Cancer
Posted April 19, 2005
Weiping Zou, Ph.D., Tulane University Health Science Center, New Orleans, Louisiana

Dr Weiping Zou of the Tulane University Health Science Center is a recipient of a fiscal year 2002 Ovarian Cancer Research Program Idea Development Award to study the potential angiogenic role of immune cells, particularly dendritic cells (DCs), in the ovarian tumor. Tumor angiogenesis, the generation of new blood vessels, is essential for the tumor growth and nourishment. DCs, antigen-presenting cells, which play an important role in the immune system have not been studied for their role in tumor angiogenesis. The ultimate goal of this research is to determine the specific DC subsets that might differentially affect tumor angiogenesis. Dr. Zou's team isolated the two principal human DC subtypes, plasmcytoid cells (PDCs) and myeloid cells (MDCs), from peripheral blood mononuclear cells and ovarian tumor ascites and prepared two different subsets of Matrigel plugs bearing tumor-associated PDCs and MDCs cells. They tested these Matrigel plugs in healthy non-obese diabetic-severe combined immunodeficient mice and discovered that tumor-associated PDCs induced angiogenesis through production of tumor necrosis factor-alpha and interleukin-8. In contrast, MDCs suppressed angiogenesis in vivo through production of interleukin-12. Dr Zou's research demonstrates the novel role of DCs in tumor neo-angiogenesis. Furthermore, these results appear promising, as blocking PDC-mediated neovascularization in tumors may be a novel strategy to treat human ovarian cancer.

Publications:

Curiel TJ, Cheng P, Mottram P, et al. 2004. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Research. 64:5535-5538.

Link:

Abstract: SDF-1, DC1/DC2, and tumor angiogenesis

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Novel Serum Biomarkers for the Detection of Ovarian Cancer
Posted March 29, 2005
Dr. Samuel Mok Ph.D., Brigham and Women's Hospital

Most women are diagnosed with ovarian cancer at late stages of the disease. The 5 year survival rate for women diagnosed with early-stage localized disease is almost three times higher than that for women diagnosed with distant metastases. A method of early-stage detection could save thousands of lives every year. Dr. Samuel Mok, a recipient of a fiscal year 1998 Ovarian Cancer Research Program Project Award, has been seeking new biomarkers to identify women with early-stage ovarian cancer. DNA microarray analysis shows that the epithelial cell adhesion molecule (Ep-CAM) is greatly over-expressed in ovarian cancers as compared to normal and benign ovarian epithelia. Ovarian tumors overexpressing Ep-CAM also produce corresponding levels of Ep-CAM autoantibodies, which can be measured easily in serum. Ep-Cam autoantibody expression is significantly higher in ovarian cancer patients than in patients with benign tumors or normal controls. Dr. Mok and colleagues also identified kallikrein 6 (hK6, also known as protease M) as being overexpressed in ovarian cancer. Using a monoclonal antibody to hK6, they demonstrated that hK6 is highly expressed in ovarian tumors of various stages and subtypes, but not in normal ovarian epithelial cells. High levels of hK6 expression are found in many early-stage and low-grade tumors, and elevated hK6 proteins are found in benign epithelia adjacent to borderline and invasive tissues, suggesting that overexpression of hK6 is an early event in ovarian cancer development. Taken together, these findings suggest that Ep-CAM and hK6 may prove to be valuable serum biomarkers when screening women for early signs of ovarian cancer.

Publications:

Kim JH, Herlyn D, Wong KK, et al. 2003. Identification of epithelial cell adhesion molecule autoantibody in patients with ovarian cancer. Clin Cancer Res. 9:4782-91.

Ni X, Zhang W, Huang KC, et al. 2004. Characterization of human kallikrein 6/protease M expression in ovarian cancer. Br J Cancer 91:725-731.

Link:

Abstract: Multidisciplinary Strategies in the Prevention and Early Detection of Ovarian Cancer

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Squalamine and Cisplatin: Potential Ovarian Cancer Therapeutic Agents
Posted February 11, 2005
Richard J. Pietras, M.D., Ph.D., University of California, Los Angeles

Squalamine, a naturally occurring antiangiogenic steroidal compound, is found in tissues of the dogfish shark. Squalamine works through the protein vascular endothelial growth factor (VEGF) signaling pathway to inhibit endothelial cell surface proliferation and new capillary formation (angiogenesis). Squalamine also interacts with many chemotherapeutic agents and has been shown to enhance their effectiveness. Richard Pietras, a scientist from the University of California, Los Angeles, is studying a potential angiogenic role of Squalamine alone and in combination with other chemotherapeutic drugs such as cisplatin and carboplatin. Through research funded by a fiscal year 2000 Ovarian Cancer Research Program Idea Development Award, Dr. Pietras has shown that Squalamine is antiangiogenic in ovarian cancer xenografts and is able to enhance the cytotoxic effects of cisplatin on ovarian cancer cells. Dr. Pietras's research also provides evidence that ovarian tumor growth can be slowed due to the decreases in microvessel formation with Squalamine treatment. Additionally, apoptosis (killing) of ovarian cancer cells was increased in xenograft nude mice due to increases in the cytotoxic effects of cisplatin in combination with Squalamine. Dr. Pietras's preclinical studies in xenograft nude mouse models and ovarian cancer cells helped promote the initiation of clinical-translational Phase II trials of Squlamine for the treatment of patients with ovarian cancer. Squalamine shows great promise for the treatment of women afflicted with ovarian cancer.

Publications:

Li D, Williams JI, and Pietras RJ. 2002. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene 21:2805-2814.

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