Spotlight on Young Faculty

Memorial Sloan-Kettering Cancer Center is one of the oldest institutions dedicated to cancer care, and it has developed a time-honored reputation for excellence. Yet many of the advances in patient care, research, and education are made by young staff members who are just beginning their careers. These three vignettes -- featuring chemist David Y. Gin, physician-scientist David B. Solit, and molecular biologist Xiaolan Zhao -- are part of a series highlighting the contributions of Memorial Sloan-Kettering's younger staff members.

	Faculty member David Gin (left), shown with graduate student Jeremy Wilmot, synthesizes complex molecules that have the potential to treat cancer.

Chemist David Y. Gin discovered an affinity for chemistry while working as a cook in his father's restaurant in rural British Columbia, Canada. "This was my first real experience with mixing together different ingredients to create new products," he said. "I enjoyed the process and the sense of discovery and reward it offered."

He decided to study chemistry at the University of British Columbia, and during his second year, his interests grew in the direction of organic chemistry. "I liked its simple logic, which was accompanied by significant room for creativity -- in ways that reminded me of cooking," he said. "By this, I mean that from a few, simple foundations, one has the power to master molecular architecture. To me, that was very empowering."

After graduating from college, he moved to the United States to get his PhD at the California Institute of Technology, where he focused on target-oriented organic synthesis. He worked to build complex molecules that required the invention of new chemical reactions to make them.

When he completed his PhD, he chose to continue in academics and was accepted to a postdoctoral position in the laboratory of Nobel laureate E.J. Corey at Harvard University. "Working with Professor Corey, I tunneled even deeper into the field of organic synthesis to further develop my 'chemical intuition,' " Dr. Gin said. "We worked on the synthesis of an extremely complex class of molecules, again having to invent new chemistry along the way. The particular molecule we worked on happened to be an extremely potent anticancer agent. So, while it was a very challenging synthesis -- involving more than 40 steps -- it was also a compound of genuine therapeutic value and is currently in advanced clinical trials."

Dr. Gin accepted a faculty position at the University of Illinois at Urbana-Champaign after completing his postdoctoral fellowship. He established a research program that focused on synthesizing organic molecules that had the potential to become therapeutic agents for human diseases.

"With this direction in mind, my work started with carbohydrate synthesis," he explained. Carbohydrates comprise a highly diverse class of complex biological molecules, and they play key roles in many bodily functions, including immune system response and the pathology of disease. "Studying carbohydrates provided me with an expansive landscape to apply new chemical reactions being developed in my lab," Dr. Gin added. "And many of the carbohydrate natural products we were making were intimately connected, in terms of biological and therapeutic applications, to some of the work going on in the Sloan-Kettering Institute laboratory of Samuel Danishefsky."

During his time in Illinois Dr. Gin developed the technology not only to synthesize carbohydrates and other classes of natural products but also to modify their structures, thus enhancing their potency. In August 2006, his interests and skills brought him to Sloan-Kettering Institute, where Dr. Danishefsky was focusing on synthesizing extremely complex organic molecules as a foundation for developing anticancer vaccines. "For me, it was inspiring to see that exploring the biological applications of chemistry at Sloan-Kettering Institute did not mean that one's innovations at the forefront of organic synthesis had to suffer in any way," Dr. Gin said.

As a Member of the Molecular Pharmacology and Chemistry Program within Sloan-Kettering Institute, Dr. Gin plans to continue working at the frontiers of chemical synthesis -- developing new reactions and strategies and applying them to the synthesis of complex molecules. He points out that molecular therapeutics do not need to be derived solely from small simple molecules, as most drugs today are. "More-complex molecules can also be of therapeutic utility, so long as they are sufficiently potent and selective in their action," he noted.

"To me, it is an exciting time in our research program to converge our chemistry expertise with those who can help to realize the full extent of its biological potential," he concluded. "It is an incredible prospect, and I can't think of a better place than Sloan-Kettering Institute for this melding of chemistry and biology to come to fruition."

	Physician-scientist David Solit (standing), shown with senior research technician Jose Lobo, is working to develop better drugs for several different types of cancer.

Choosing a career in medicine was an easy decision for David B. Solit. "My father and grandfather were physicians, and they both loved their jobs," he recalled. "I always loved science, and as far back as college, I knew that I wanted to pursue a career in medical research." But it was his aunt's battle with breast cancer, as well as the lack of effective treatments for patients with metastatic disease, that led to his decision to pursue a career in cancer research. "It was clear to me that the treatments available to patients with advanced cancer were inadequate," he added.

Armed with that drive, he came to Memorial Sloan-Kettering in 1998 for a fellowship in medical oncology, and he has been here ever since. After completing the clinical year of his fellowship, he entered the laboratory of medical oncologist Neal Rosen, where he initially focused on the role of the Hsp90 protein in promoting cancer development and progression. As part of Dr. Rosen's laboratory, Dr. Solit helped to develop inhibitors of this protein. He also served as the lead investigator of several clinical trials of Hsp90 inhibitors.

"We have made great strides in understanding the molecular changes that cause cancer," he explained. "This improved understanding of cancer biology has allowed us to identify new ways to target the disease. I'm fortunate to be here, because Memorial Sloan-Kettering has strong programs for translating these new laboratory discoveries to the clinic."

Dr. Solit is one of a small number of physicians who both take care of patients and head a laboratory program. His laboratory is part of the Human Oncology and Pathogenesis Program, which was created in 2005 to strengthen the interplay between laboratory and clinical research at Memorial Sloan-Kettering. The goal of his laboratory is to develop cancer therapies that target pathways responsible for cancer development and its continued growth. It is hoped that these targeted therapies will be more effective and less toxic than traditional cancer treatments.

Of particular interest to Drs. Solit and Rosen is the RAS/RAF/MEK/ERK pathway, a cascade of signals that regulate cell growth, division, and survival in many types of human cancer. Indeed, some of the most aggressive tumors, such as melanoma and pancreatic and lung cancers, are often fueled by mutations in this pathway. "This is a critically important area of study," said Dr. Solit. "Cancer patients with mutations in this pathway are among those who fare the worst, and new treatments for these diseases are therefore urgently needed."

Drs. Solit and Rosen and their fellow investigators have made important advances in understanding the cancer-promoting role of the MEK protein, a component of this pathway. Last year, they reported in the journal Nature that tumor cells with mutations in a gene called BRAF (which is altered in approximately seven percent of cancers) are sensitive to drugs that inhibit the MEK protein, whereas tumor cells whose growth is driven by mutations of proteins that are further "upstream" of MEK in the signaling cascade are less sensitive to MEK inhibitors. [PubMed Abstract]

They were also able to identify several drugs that inhibit this pathway, which are now being assessed in cancer patients. One such drug, PD0325901, is being evaluated in early stage clinical trials at Memorial Sloan-Kettering in patients with melanoma and cancers of the breast, colon, and lung. Another MEK inhibitor, AZD6244, is being compared with the anticancer drug temozolomide in patients with advanced inoperable melanoma in an ongoing trial at Memorial Sloan-Kettering.

When not in the laboratory, Dr. Solit can be found caring for patients with prostate cancer (as a member of the Genitourinary Oncology Service) and those with breast cancer and melanoma being treated on his clinical trials. "Although I primarily care for patients with prostate cancer, discoveries coming out of my laboratory are often relevant to other types of cancer," he noted. "The environment at Memorial Sloan-Kettering is really unique in that it provides opportunities to collaborate with other clinicians, and to translate the work we are doing in the lab to the treatment of all types of cancer -- not only those in which I have clinical expertise."

What does David Solit want to be doing ten years from now? "I hope I can continue to conduct basic science research while still seeing patients. The contact I have with my patients motivates and focuses me," he noted. "Despite all the promising achievements that have been made in oncology, there's still a huge amount of work to be done. I'm proud to be a part of that effort."

	Faculty member Xiaolan Zhao studies the molecular mechanisms of chromosomes.

Molecular biologist Xiaolan Zhao grew up in a small city near the Great Wall in northern China. While studying at Peking University she began to appreciate the amazing world inside tiny cells, with all its intricate beauty and unexplored complexity.

For her undergraduate and masters research, she participated in several projects related to the biology of rice and viruses that cause diseases in rice. "The research itself was fascinating, but it was a great experience in other aspects, too," she said. "People in the lab worked closely together, exchanging ideas and sharing experiment tricks. I enjoyed the lab work and lab life so much that I thought of making it my career." With this in mind, she moved on to pursue a PhD in the Department of Genetics and Development at Columbia University.

"My initial plan for graduate study was to understand the cause of cancers," Dr. Zhao said. "I soon realized that an excellent approach to do so is to use model organisms, such as a fly, a worm, and yeast, because they not only contain the same or similar cellular programs as those altered in cancers but also offer supreme technical advantages over human cells." She joined the lab of Rodney Rothstein, whose lab studies the function of certain yeast genes that are comparable to human genes -- known as homologs.

Her thesis project was based on her discovery that the yeast homolog of the cancer-related genes ATM and ATR in humans had an essential function aside from their previously known role of helping to control the cycle by which cells divide. She found that the genes also remove an inhibitor from an enzyme that plays a key role in the synthesis of dNTP, the chemical units from which DNA molecules are constructed. The team also found the regulatory pathway and molecular mechanisms by which the genes regulate dNTP levels and the stability of the genome.

"This work was very satisfying," Dr. Zhao said, "not only because we revealed a new function of a protein important to a human disease but also because it showed me just how powerful yeast genetics can be. Because defects in genomic stability are the main causes of cancers and many other human diseases, the in-depth understanding of how cells maintain that stability by using model organisms is very important for battling human diseases."

Dr. Zhao's interests evolved into the dynamic and spatial organization of chromosomal activities in live cells, a less-explored field in genomic stability. It is extremely important that chromosomes carry out specific functions at the right place and the right time to ensure that genetic information is passed on correctly when cells divide. To study this, she joined the laboratory of Nobel laureate Günter Blobel at The Rockefeller University for her postdoctoral research.

She soon realized that one important regulatory mechanism in these processes is a protein modification called "sumoylation." SUMO is a special protein that can change the properties of many other proteins when it is linked to them. In addition, she identified a novel protein complex that contains a protein that controls the addition of SUMO to other proteins. "This complex is quite remarkable," she said, "as two of its parts are members of the family of proteins that can actively tether and fold chromosomes." In addition, it contains the particular SUMO enzyme that can change properties of other proteins.

In October 2005, Dr. Zhao joined the Molecular Biology Program in the Sloan-Kettering Institute. Her lab is now employing genetic, cell biological, and biochemical approaches to reveal the molecular mechanisms of how this new complex contributes to chromosomal replication, repair, and segregation. They are also identifying new players in the SUMO pathway.

"These two directions are closely related, and the understanding of one benefits the other," Dr. Zhao said. "As proteins under study are highly conserved in humans, molecular mechanisms uncovered in our studies will have important implications in the understanding of how human cells work. In addition, since both chromosomal stability and the SUMO pathway are involved in multiple human diseases, we hope that our research will eventually lead to better strategies to prevent and treat these diseases."