Spotlight - Anne Chiang

Polycomb and Cancer

At the time, we thought that Polycomb was important in molecular memory because somehow it was able to regulate regions of DNA so that they are either "opened or closed for business" at different phases of development. Interestingly, there is a lot of current work being done looking at how Polycomb family proteins are dysregulated in cancer, including research underway in Steven Nimer's SKI Molecular Pharmacology and Chemistry Program lab. You can imagine that unregulated proliferation of cancer cells might occur if cells are confused about their identity and thus unresponsive to inhibitory signals in their environment. During my time at Harvard, we had hypothesized about the role Polycomb might play in cancer, and now these scientists are developing a real understanding.

Concurrent with my research work in grad school, I was involved with a number of extracurricular activities. I volunteered with a group called Women for Economic Justice, which was seeking to help small groups of immigrant women create co-operative businesses. It was something completely different from what I was doing in the lab, and that was just what I needed.

In thinking about what I wanted to do after completing my PhD, I started looking at the other MD/PhDs in the lab who were working on the clinical side, as well. They had this incredibly broad perspective fueled by a desire to find real clinical applications, the combination of which I found very attractive. Ultimately, I decided to study medicine, in order to apply my basic science training and insights to address clinical questions. Consequently, I enrolled in medical school at Weill Medical College of Cornell University.

Communication Skills Honed

With the aim of keeping the other half of my brain stimulated, I did an American Association for the Advancement of Science media internship at Good Morning America (GMA) during the summer before medical school. Working on GMA's science and medicine segments, it struck me how many people received their information about medicine and science from these three-minute clips on TV. As I had hoped, the internship helped me to develop some of my communication skills. So much in science and medicine is about communication -- writing grants, presenting papers, collaborating with colleagues in others disciplines, sharing information with patients -- that knowing how to communicate effectively is critical. 

During medical school and residency, I made it a point to keep involved to some degree in laboratory research. In medical school, I worked with Barbara Hempstead at Cornell, doing initial experiments looking at the role of BDNF (brain-derived neurotrophic factor) in angiogenesis. During my residency at Columbia University Medical Center, I worked briefly in the lab of Raphael Clynes, who was studying basic immunology. I was interested in looking at the use of tetramer technology to assess the immune response in patients who were receiving Herceptin®. (The HER-2 positive type of breast cancer is characterized by tumor cells that produce too much of a protein called HER-2. Herceptin® binds to and blocks the protein, consequently stopping or slowing tumor growth.)

Basic Science and Beyond

In the midst of this work, I took a year off to have twins and to work part-time as an internal medicine attending. In 2003, I came to Memorial Sloan-Kettering Cancer Center as a clinical fellow in Medical Oncology. When the time came to choose an area of research, I was able to join the lab of Joan Massagué, who is Chair of the Cancer Biology and Genetics Program in the Sloan-Kettering Institute and a Howard Hughes Medical Investigator.

Joan is a classic example of someone who has done fantastic basic science research in the role of the TGF-ß signaling pathway in cell regulation and disease. His research has evolved into studying its effects on metastasis and exploring basic mechanisms of metastasis, which obviously is a field with a great deal of clinical significance. At the time I joined Joan's lab, they had just identified the lung metastasis signature for breast cancer cells, and I was interested in trying to do the same for lung cancer cells, including ones derived from patient samples.   

Lung and Breast Cancer Metastasis Study

My project ended up being three-fold. The first focus involved injecting lung cancer cell lines into immunocompromised mice to see if they developed metastases. In fact, the mice did develop brain metastases. I was able to harvest and re-inject those brain-metastatic cells to find that they now exhibited a more aggressive tendency to spread and grow in the brain. Through gene-expression analysis, we have been able to develop a lung-to-brain metastasis signature, which we are trying to validate clinically.

The second focus was to take pleural fluid clinical samples from lung cancer patients, using those samples to try and extract more information than we might from cells that have been in culture for years.

And the third focus involved therapeutic intervention, specifically trying to find drugs that would target the genes identified in lung metastasis, hopefully in the process preventing cancer metastasis to the lung. We published a paper in the April 2007 issue of Nature in which we were able to target a subset of lung-metastatic through genetic and pharmacologic means. On a microscopic level, we were able to show that a combination of drugs could prevent breast cancer cells from exiting blood vessels to grow as micrometastases in the lung. Now, the challenge is to figure out how to design a clinical trial in breast cancer patients based upon this exciting research. This is pure translational work, which I find so satisfying.

MD/PhD: Managing Both Sides of the Equation

It is a constant juggling act to manage both the basic research and clinical sides of my work. To some extent, I think it is important to simply follow your interests -- just go where your interests take you and the rest will sort itself out later. I do not know the exact recipe for success. Still, there are certain personality requirements needed for this job. You have to be curious. You have to be imaginative enough to see new possibilities. And you need to be good at multitasking, i.e. having the ability to focus and follow through on a lot of different things all at the same time.

Fortunately, Memorial Sloan-Kettering is an extremely supportive environment for translational research work. It offers a tremendous treasure-trove of resources -- patients, clinical databases, tumor banks, core facilities, and, of course, the great people doing such cutting-edge work. While many institutions might say they are doing real translational work, it comes down to infrastructure, resources, and enthusiasm -- all of which we have in abundance here.

As a medical oncologist specializing in treating patients with gynecologic malignancies, I find myself crossing predefined borders with my research, taking what I have learned in terms of metastases in other tumor types and applying it to gynecologic malignancies. I believe that the future of oncology will focus more on basic disease processes (e.g. metastasis and angiogenesis), rather than a site-specific approach (e.g. breast versus ovarian cancer). How do cells travel from the primary site to metastatic sites? Is there a steady-state of tumor cells traveling in the circulation, hopping from one metastatic site to another to seed new camps? Are brain metastases which originate from lung vs. breast cancer cells similar in how they initiate and grow? How is the tumor vasculature different in primary and in metastatic sites? And, ultimately, how do we target these processes to halt the spread of cancer?

It will be challenging to tackle these questions in cancer research and to apply their answers to cancer care but infinitely rewarding.