Selina Chen-Kiang, PhD, Professor of Pathology and Laboratory Medicine and of Microbiology and Immunology at Weill Cornell Medicine, was recently awarded a $2.5 million Mantle Cell Lymphoma Research Initiative Award from the Leukemia and Lymphoma Society for her cutting-edge research on blood cancer.
How did you get interested in your field of research?
After completing my PhD in human genetics at Columbia, I asked my thesis advisor, Sid Udenfriend, how to proceed with my scientific career. He said, “It depends if you want to be a team player or you want to be a virtuosa.” I replied, “I only live once, I want to be a virtuosa.” So, his advice was to think of something new to do and just be fearless. I was trained in protein chemistry and enzymology, but I realized biology was my real interest.
After a postdoc in Jim Darnell’s lab at the Rockefeller University studying how gene expression was controlled, I started my own lab at Memorial Sloan Kettering Cancer Center as a faculty member of Weill Cornell Medicine and reassessed my interests again. I realized that I was fascinated by the immune system; it is exquisitely controlled and I wanted to understand how it kept itself in balance, a concept known as homeostasis. When immune system homeostasis is lost and blood cells divide uncontrollably, you end up with leukemia, lymphoma or multiple myeloma.
Can you explain the fundamental biology you are exploring in your research?
I study how to use basic science knowledge about how the cell cycle controls cell division in normal cells to devise targeted therapeutics for blood cancers. A key step in regulating the cell cycle occurs in the first phase, which is called G1. This phase is characterized by a period of growth in preparation for DNA replication and subsequent division into two daughter cells. Because proceeding through the cell cycle too soon can have devastating consequences to the organism, there are mechanisms in place that integrate environmental signals to decide whether conditions are suitable for growth and division. If they are not, then depending on the circumstances, the cell may initiate a program to kill itself or remain paused at that step for days, weeks or even years. I’ve been exploring the effect of intentional induction of this pause early in G1 (prolonged early G1 cell cycle arrest) in blood cancers.
How is your work making a difference to patients with blood malignancies?
In 2000, we received one of the three inaugural $7.5 million Specialized Center of Research grants from the Leukemia and Lymphoma Society to investigate whether inducing prolonged early G1 cell cycle arrest could be the basis for treating blood cancers. It turned out that Pfizer had a drug candidate on its shelf called palbociclib (PD0332991) that could activate the pause and hold cells in early G1 until the compound was withdrawn. I suspected that intentionally holding the cells there for a prolonged period would be detrimental to their survival, and we showed this was the case in a model of multiple myeloma, the second most common blood cancer. This novel finding spurred renewed interest in this drug, and prompted the company to sponsor a phase 1 clinical trial with palbociclib.
Since then we have conducted five hypothesis-driven clinical trials with a growing number of collaborators looking at how palbociclib can be used in combination with other treatments to make them more effective, longer lasting and less toxic in treating blood cancers.
Where do things currently stand with palbociclib?
Since progression through G1 is one of the major determinants for the expansion of cells in many cancers, others looked at the effect of palbociclib, in combination with other drugs, to treat metastatic breast cancer. Palbociclib has turned out to be the first FDA-approved drug that selectively targets the cell cycle.
But, in all of these trials, there is a portion of the treatment population that doesn’t respond to therapy and we have continued to work on the mechanism by which their cancer cells get around the blocks we throw at them.
Have there been any recent advances in your research that are particularly encouraging?
We now have all the tools we need to analyze the patient’s response to treatment over time. We can collect malignant cells from a patient before, during and after treatment and analyze the differences in response to therapy in individual patients, and between responders and non-responders at the molecular level by cutting-edge DNA and RNA sequencing, among other analyses. These data are yielding the mechanisms underlying resistance to treatment, suggesting new therapeutics that should be more effective. It’s very exciting.
We’re really grateful that we just received the grant from the Leukemia and Lymphoma Society to study this problem in patients with mantle cell lymphoma, an aggressive disease with a median survival of four to five years. These studies allow us to apply our creativity and think deeply about the science, for the benefit of patients.
I am so grateful because there are many ideas that never come to fruition and this idea about the cell cycle’s role in immune system homeostasis and blood cancers did, both clinically and mechanistically.
Source: WCM Central