It’s always been a question of pathways for Nadya Tarasova. The most recent pathway to gain her attention is the hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. Her work with co-authors Jarrett Remsberg and Sergey Tarasov on this particular pathway, and their discovery of the opportunity to target tumor cells at this new juncture, landed Nadya Tarasova an invitation to deliver a presentation at a Plenary Session on late-breaking, high-impact research at the Annual Meeting of the American Association of Cancer Research (AACR) in Los Angeles April 14–18 this year.
All pathways have a beginning, and to appreciate the many that Dr. Tarasova has taken, perhaps it's best to start with her first one. Born in Belarus to a father who was a renowned journalist and a mother who was a practicing cardiologist, her bent for science was both genetic and environmental. Her father had grown up far to the east, in Kazakhstan . When he died while Dr. Tarasova and her sister were still quite young, mother and daughters sought solace there, where much of the family still lived.
Tucked away in Kazakhstan with her mother and grandparents, Dr. Tarasova flourished in the open, inquiring intellectual environment of Almaty, the Kazakh capital. During the Stalinist purges, Kazakhstan had become a cultural center of the former Soviet Union, as intellectuals, banished by the repressive regime, took up residence there. The young Nadya, at just 14 years of age, competed in the All-Soviet Scientific Olympiad with students representing every republic in the USSR. She took third place in chemistry and fourth in physics, earning a slot at the prestigious national physics and mathematics boarding school of Russian Academy of Sciences in far-off Novosibirsk . She was one of just three girls in a class of 40—the elite of the next generation of scientists.
At 17, she gained entrance to the University of Moscow, where competition for admission is fierce. Many describe the university as the Harvard, Yale, and Princeton of the former Soviet Union. The entrance exam was pure math, the most basic of all sciences. Dr. Tarasova was quickly admitted, majored in chemistry, and, at age 21, received a master's degree, graduating first in her class of 325.
She also received one of the highest honors possible: the Lomonosov Scholarship, which provided a salary and enabled her to continue at the university. Inspired by her parents and their love of science, she received her doctorate in bioorganic chemistry in 1982, defending her thesis “Chemical modifications of proteases.” During Dr. Tarasova's time at the university, she met the young scientist, Sergey Tarasov, who would become her husband and more recently, her research collaborator.
Upon graduation, newly minted PhD in hand, Dr. Tarasova chose a two-year postdoctoral position at the University of Copenhagen, researching the biochemistry of enzymes in the laboratory of Professor Bent Foltman. So superb was her training with Foltman that she returned to Moscow , fully prepared to take charge of her own research group in enzyme biochemistry, establishing active collaborations with many practicing oncologists and oncology researchers in Moscow.
It was a heady and optimistic period for the country. Perestroika had begun, and the antiquated, somewhat feudal system of apportioning money for science from a central source was being replaced by a more familiar system: grant writing. The former system was unpredictable and young scientists were often at the mercy of their lab chiefs, who could dole out rubles based on opinion rather than scientific potential and accomplishment. The grant system made gaining funds a matter of merit, and was, for young researchers especially, much fairer. Dr. Tarasova was able to justify sufficient funding to support 11 in her group—three permanent employees and several graduate and undergraduate students. They remained active and productive, forging cooperative links for the next eight years.
In 1991, at the invitation of NCI-Frederick researcher Chris Michejda, PhD, Dr. Tarasova came to Frederick for what was to be a one-year sabbatical in the Molecular Aspects of Drug Design (MADD) Section, Structural Biophysics Laboratory. It became clear during Dr. Tarasova's sabbatical just how complementary her scientific goals were to those of the MADD staff.
At that time in Russia, inflation was making research funding scarcer and more precious by the day. The once-stable ruble was worth only one-twentieth of its earlier value, and scientists despaired of being able to keep their laboratories functioning. Learning of Dr. Tarasova's circumstances, Dr. Michejda was happy to make a place for her on his staff. During the early 1990s, many former Soviet researchers came to universities, pharmaceutical companies, and government laboratories in the U.S. NCI-Frederick was fortunate to gain not only Dr. Tarasova, but also several from her original group in Moscow. U.S. biomedical science has been all the richer for it.
While Dr. Tarasova's interest has always been science, her passion now is discovering novel therapies for cancer, understanding the roles of chemistry, and the interplay between myriad biological processes that can start and stop the cancer process. She sees drug discovery as having the essential roles of providing biological molecular tools and creating sensitive synthetic molecules to either block or promote a cellular function associated with cancer. The ultimate goal is to develop highly selective drugs that can be precisely targeted to a malignant cell. With such measures in the drug arsenal, physicians can offer their patients therapies with a minimum of toxicity and fewer of the brutal side effects traditionally associated with cancer treatments.
According to Dr. Tarasova, who takes the long view, when it comes to drug discovery, we are, perhaps, obsessed with small molecules. From an economic standpoint, the preference for small molecules is understandable; they are easier to manufacture and can be taken orally. The problem comes with targeting them to only one protein. Small molecules are powerful, having strong interactions, but they are frequently not selective. Thus, they carry that familiar drawback of affecting many more cells than the cancerous ones and causing severe side effects (e.g., immune dysfunction, fatigue, or a variety of gastrointestinal disturbances) that everyone wishes to avoid. Such side effects are not only unpleasant but are an additional and harmful burden to patients already fighting for their lives.
“Larger molecules,” explains Dr. Tarasova, “form multiple interactions, so they can be fine-tuned. Hormones such as insulin and other peptides or peptide imitators represent examples of these larger molecules.” The difficulty is that most cannot be taken orally. Unlike the small molecules, large molecules are neither stable in circulation nor do they penetrate tissues well—a significant problem in making drugs available where they are most needed—at tumor sites.
It's a problem that biochemists are not unfamiliar with, since the two—stability in circulation and binding ability—are often mutually exclusive. Unless it can bind to the desired site, the molecule is nothing more than a purposeless dodge'em car, bouncing off its intended docking stations.
Dr. Tarasova and her team have overcome the conundrum with two methods. First, they were able to coax the peptide into a morphing act that would make Houdini proud. The peptide can self-assemble and disassemble on a chemical cue, thus negotiating the twin hurdles of stability in circulation and binding at the target site. The results are encouraging: the peptide is effective in delaying lung metastases from breast cancer in mice. The peptide that naturally exists as a 10-nanometer-diameter nanoparticle, is a product of the successful collaboration among Dr. Tarasova's team and Drs. Zach Howard and Joost Oppenheim from the Laboratory of Molecular Immunoregulation.
And that brings us back to the most recent pathway in Dr. Tarasova's world, the one she recently described to the international research community at the AACR. Many mutations leading to tumor development occur along the hedgehog pathway. In collaboration with Dr. Michael Dean's group, Dr. Tarasova has developed a new and very effective way to overcome these mutations.
Dr. Tarasova and her team have shown that synthetic analogs of intracellular loops of smoothened peptides, a critical component of the pathway, inhibit cancer cell growth even in minute concentrations. Dr. Tarasova explains, “The hedgehog pathway is critical for cancer stem cell growth, and thus novel inhibitors carry a great hope of being able to eliminate tumors and offer a new type of cancer treatment.”
And that is one pathway we would all like to see mapped.
By Cheryl Parrott,
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National Cancer Institute at Frederick
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It’s always been a question of pathways for Nadya Tarasova. The most recent pathway to gain her attention is the hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. Her work with co-authors Jarrett Remsberg and Sergey Tarasov on this particular pathway, and their discovery of the opportunity to target tumor cells at this new juncture, landed Nadya Tarasova an invitation to deliver a presentation at a Plenary Session on late-breaking, high-impact research at the Annual Meeting of the American Association of Cancer Research (AACR) in Los Angeles April 14–18 this year.