Sitting in his office on the fourth floor of Kline Biology Tower, Craig Crews, professor of molecular, cellular and developmental biology, explains his initial curiosity that led him to research at Yale. TNP-470, a small molecule of interest that seemed to prevent the growth of blood vasculature, had “been found in humans, but we had no idea how it worked — which surprised me. So in 1995 I began my Yale career examining that question.”
Crews’ natural inquisitiveness proved useful. In the 13 years since, work originating in his lab has played a crucial role in advancing understanding of angiogenesis — the development of blood vessels — as well as delivering what scientists working alongside Crews call key breakthroughs for use in the establishment of a related anti-cancer regimen.
But what is the link between blood vasculature and cancerous growth, and how does TNP-470 play in to it?
One of the first experiments Crews completed at Yale showed that when TNP-470 enters the human body, it selectively binds to and inhibits a protein called methionyl aminopeptidase 2, more commonly known as MetAP-2.
The blocking of MetAP-2 from its usual activities disrupts key signaling pathways for the communication among endothelial cells along an incipient blood vessel. These cells, which must “coordinate their polarities” relative to the neighbors in a highly ordered fashion, according to Crews, are thus left without the framework they need to grow correctly. The end result is deformation and the inability to form new arteries, capillaries and veins.
Most recently, Pasquale Cirone, a postdoctoral fellow in the Crews lab, has definitively linked this process of cell orientation with angiogenesis. This discovery allows the scientific community to formalize the experimentally proven link between TNP-470 and the inhibition of cancerous growth, he said, because blood-vessel development is vital for the sustained growth of a tumor.
Once cells are even just fractions of millimeters away from the nearest blood source, it is impossible for them to participate in carbon-oxygen exchange, and they cannot absorb nutrients. For a tumor to reach a size that would be considered dangerous, therefore, it needs a new supply of blood.
While all of this has been examined at a detailed level and is generally resolved as a scientific question, Cirone noted one last piece to the puzzle: how the inhibition of MetAP-2 actually works to prevent cell coordination in blood vessels. “For us,” he said, “completely understanding the MetAP-2 pathway is a Holy Grail of sorts.”
Cirone is not exaggerating. Once the particular mechanism that MetAP-2 utilizes is uncovered, scientists will have a nearly complete understanding of the entire cascade that TNP-470 incites to prevent new vasculature from sprouting up.
Moreover, such a discovery would provide critical insight into why only endothelial cells in blood vessels are targeted by TNP-470.
Although trials on cancerous growth in mice and other model organisms have been promising, some researchers voice a visceral reaction that scientists should be wary of putting it into a human body without fully knowing why it acts the way it does.
There could, potentially, be a large number of unexpected long- or short-term side effects if TNP-470 is used clinically without precisely understanding how it functions, Crews said. While working against blood-vessel development on one end, he surmised such trials might also put the user at risk of suffering from unforeseen, perhaps less immediately obvious problems.
Those concerns have not stopped Ofra Benny-Ratsaby of Children’s Hospital Boston from looking to drug development based on TNP-470.
One of the initial problems with using this molecule for cancer treatment is that the molecule crossed the proverbial blood-brain barrier, impairing neural function. While this problem was later overcome, the newly formulated compound had to be delivered intravenously at a clinic — which would not only be very costly, but inconvenient as well, Benny-Ratsaby said.
Benny-Ratsaby’s latest work, published early this summer, addresses these issues. After a long period of research, the Children’s researcher formulated a compound she named “Lodamin,” which inhibits vascular development like TNP-470, does not cross the blood brain barrier and can be administered orally.
Lodamin is both “very active” and “very potent,” she said. It is currently undergoing later stages of pre-clinical trials.
Still, Benny-Ratsaby admits, “There’s a lot of room for understanding the acting mechanism of the drug.”
Sustained research, like that being done by Crews and Cirone, might offer just the information needed to fill in this last gap.