Current Investigators  :  Interview with Dr. Wong
Dr. Kwong K. Wong

Dr. Kwong K. Wong of the M.D. Anderson Cancer Center was the recipient of the 2010 HERA Award for research on the cause, early detection, treatment, and/or understanding “low-grade” ovarian cancer. Dr. Wong has published more than 60 peer-reviewed articles and 10 book chapters. He has been dedicated to ovarian cancer research using a molecular approach for years.  He cloned and sequenced the first tumor suppressor gene shown to be involved in ovarian cancer, DOC-2, in 1993.  More recently, he identified several serum markers for the potential early detection of ovarian cancer.

Dr. Wong’s research has also recently focused on “low-grade” ovarian cancers.  Although patients with these ovarian cancers at late stage have better prognoses than those with “high-grade” cancers, these tumors are the most resistant to chemotherapy and difficult to treat.  The primary goal of Dr. Wong’s proposed research is to decipher how insulin-like growth factor-1 (IGF-1) stimulates the growth of low-grade ovarian cancers and to determine which genes are involved.  Another goal is to develop a mouse model with low-grade ovarian cancer, and treat these mice with drugs that block IGF1 with the hopes that such treatments reduce tumor growth.  This work may lead to the identification of new drug therapies that can be used to block IGF1-induced growth of low-grade ovarian cancer in women.  Read more about Dr. Wong’s research findings.

Although the competition for this $100,000 award was formidable, HERA’s scientific review panel unanimously identified Dr. Wong’s research as the most innovative and promising of the 13 applications received in January 2010.  This research uses modern genomic approaches to uncover the mechanisms that make this disease so devastating and will also help determine what can be done to treat it.  Learn more in Dr. Wong’s interview below.

Q: What is low-grade ovarian cancer relative to other ovarian cancer?

KKW: Ovarian cancers can be divided into several types—the 4 major ones are serous, endometrioid, clear cell, and mucinous—depending on how the tumor cells look under a microscope. Serous ovarian cancer is the most common type. Serous ovarian cancer is further divided into low-grade and high-grade subtypes using a widely accepted system developed at M. D. Anderson Cancer Center. Only about 8% of serous ovarian cancers or about 1100 cancers diagnosed each year in the United States are low-grade. Since 1944, M.D. Anderson Cancer Center has seen more than 400 patients with low-grade ovarian cancer.

Low-grade ovarian cancer has several features that distinguish it from high-grade ovarian cancer. One is that patients with low-grade disease survive longer than patients with high-grade disease. In addition, recent studies at M. D. Anderson Cancer Center indicate that low-grade ovarian cancer is relative resistant to current therapy and that patients with low-grade ovarian cancer are usually younger than patients with other types of ovarian cancer. Low-grade serous ovarian cancer is a unique disease, and most cases are believed to develop from an indolent borderline tumor of the ovary. On the other hand, the origin of high-grade ovarian cancer is still debatable. Some high-grade serous ovarian cancers may develop rapidly from the surface of the ovary, while others may develop from the ovary proximal surface of the fallopian tube.

Unfortunately, even though patients with low-grade disease have relatively longer survival times, most of them eventually die of ovarian cancer. Thus, it is critically important that we improve our understanding of how low-grade ovarian cancer develops and progresses. Identifying genes and proteins involved in the progression of this disease could allow researchers to develop new treatments designed to disrupt the function of those genes and proteins and thus disrupt the progression of low-grade ovarian cancer.

Q: What stimulated you to become interested in low-grade ovarian cancer?

KKW: My department Chair, Dr. David Gershenson, got me interested in low-grade ovarian cancer. Low-grade ovarian cancer is more resistant than other types of ovarian cancer to current therapy, and patients with low-grade ovarian cancer tend to be younger at diagnosis and eventually die of the disease. Thus, trying to understand how low-grade ovarian cancer develops is an important and meaningful research area. From a scientific perspective, the fact that low-grade ovarian cancer is known to develop from serous borderline tumors makes it easier to decipher the genes and proteins involved in the progression of borderline tumor to low-grade ovarian cancer. Hopefully, some interventions can be developed to halt this progression process. Moreover, the genetic differences between borderline tumor and low-grade ovarian tumor are apparently not as extensive as the differences between borderline tumor and high-grade ovarian tumor, and thus in our research we might be able to identify the early genetic changes that are part of the series of changes leading to ovarian cancer. These early genetic changes might be potential biomarkers for early detection.

Q: What is the primary goal of the proposed research?

KKW: By studying samples of low-grade serous ovarian cancer and their precursors, serous borderline tumors, we found that low-grade serous ovarian cancers had much higher levels of the protein insulin-like growth factor I (IGF1) than did serous borderline tumors. Furthermore, we found that treating low-grade ovarian cancer cells with IGF1 stimulated their growth. These findings indicated that IGF1 may be an important protein involved in the development of low-grade serous ovarian cancer. The primary goal of our proposed research is to decipher how IGF1 stimulates the growth of low-grade serous ovarian cancer—specifically, to determine which genes are involved. Another goal is to develop mice with low-grade serous ovarian cancer, treat these mice with drugs that block the effect of IGF1, and determine whether such treatment reduces tumor growth. We hope that this work will lead to the identification of new drug therapies that can be used to block IGF1-induced growth of low-grade serous ovarian cancer.

Q: What are the biggest challenges, or obstacles, in this kind of research?

KKW: The biggest challenges today in research on low-grade serous ovarian cancer are (1) the lack of a good animal model in which to study the disease and (2) because of the rarity of the disease, the relative small number of cell lines and tumor samples available for molecular and genetic analyses, an international consortium of researchers to work together on this disease might be a solution to these challenges. For my proposed study, the biggest challenge is that the low-grade cell line grows relatively slow in mouse and it might take several months or longer to test the effect of any drug that can block IGF1-induced growth of low-grade serous ovarian cancer.

Q: How do you envision translating this research into beneficial treatments for women with cancer?

KKW: Currently, several drugs that target the IGF1 pathways are being tested in early clinical trials for other types of solid tumors. Our work will allow us to decipher the role of IGF1 pathway in low-grade ovarian cancer, and these results will provide the rationale for clinical trials of IGF1-targeting drugs against ovarian cancer.

Q: Of the many papers you have published, of which you are most proud, or which have been seminal in your career thus far?

KKW: I have been very interested in genomic technologies. In 1993, when I was a postdoc in Dr. Michael McClelland’s Lab, I used a novel genomic technique (RNA fingerprinting by arbitrary primed PCR) and identified the first tumor suppressor gene in ovarian cancer, Dab2.  Later, after the microarray had come of age, I used microarray technology and identified 5 potential biomarkers for ovarian cancer. I published these results in 2001.  I believe that genomic technologies such as the Next Generation Sequencing technologies are going to revolutionize future investigation into the causes, early detection, and treatment of low-grade serous ovarian cancer.

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