MEET THE INNOVATIVE RESEARCH GRANT RECIPIENTS

Last May you helped launch Stand Up To Cancer, a groundbreaking initiative funding translational cancer research with the aim of getting promising new therapies from the bench to the bedside – and doing it fast. (You can read more about translational research here.) Thanks to your incredible generosity and support, SU2C has raised over $100 million in the short twelve months since its launch. But this is only the beginning. We’re thrilled to announce that our Scientific Advisory Committee has selected its first round of Innovative Research Grant recipients, and we think you’ll find the science behind their projects as exciting and inspiring as we do.

An Emerging Tumor Suppressor Pathway to Human Cancer

Fernando D. Camargo, Ph.D., Children’s Hospital Boston

Hippo is a biochemical pathway that is thought to regulate organ growth. It works by preventing further cell division once organs have reached their proper size. Camargo and his group believe that Hippo signals are part of a powerful checkpoint that restricts increases in cell numbers and activates cell death. This checkpoint would allow an organ to “know its size” and stop growing at the appropriate time, and may also suppress the unchecked increases in the numbers of cells that characterize tumor growth.

Camargo’s studies will determine the existence of this checkpoint and its role in suppressing tumor growth by using a model system in which the Hippo signal can be turned off and on. They will also identify novel proteins and small molecules that regulate Hippo signaling and could be used to develop new therapies for cancer. Insight into the relatively unexplored relationship between Hippo signaling, organ growth and tumor suppression holds the promise of yielding an entirely novel set of therapeutic targets for the treatment of human cancer, particularly for pediatric tumors.

“How does your body know that the liver needs to be a certain size?” Hamargo said. “What we want to do is understand this powerful intrinsic mechanism that regulates symmetry and tissue size and test whether those same mechanisms also act naturally to prevent cancer growth.”

Modeling Ewing Tumor Initiation in Human Neural Crest Stem Cells

Elizabeth R. Lawlor, M.D., Ph.D., Children’s Hospital Los Angeles

Ewing sarcomas are highly aggressive tumors that primarily affect children and young adults. They are believed to arise from neural crest stem cells — rare cells that contribute to the formation of multiple tissues throughout the body. Ewing sarcomas contain an abnormal gene called EWS-FLI1. The precise way in which expression of EWS-FLI1 causes Ewing sarcoma remains to be determined, but it is known to involve disruption of normal gene expression. Lawlor believes that this disruption is due, at least in part, to changes in some of the epigenetic marks on the DNA (DNA methylation) that result in turning on the expression of genes that should be off and turning off the expression of genes that should be on.

This project will use an innovative model to generate neural crest stem cells in the laboratory. Lawlor will study the ways in which expression of EWS-FLI1 affects the epigenetic marks in these neural crest stem cells and how EWS-FLI1 initiates tumor formation. She will also determine whether the epigenetic alterations in Ewing sarcoma cells can be corrected by treatment with a new targeted drug that prevents DNA methylation. These studies will provide novel insights into normal neural crest cell biology and could facilitate the development of more effective, less toxic therapies, such as DNA methylation inhibitors, to specifically target this pediatric malignancy.

“We need to develop drugs that are going to be selective, killing the cancer cells and sparing the normaldeveloping tissue,” Lawlor said. “That way, when children are finished treatment, they’re not only free of cancer, but they can go back to school and know they’re going to live a normal, healthy life and not be affected in the long term by these terrible side effects.”

Cancer Cell Specific, Self-Delivering Pro-Drugs

Matthew Levy, Ph.D., Albert Einstein College of Medicine of Yeshiva University

Most drugs that kill rapidly dividing cancer cells also kill normal healthy cells. The ability to direct drugs specifically to cancer cells would avoid some of the undesirable side effects of cancer treatment. Levy proposes to tackle this challenge by developing a new type of all-in-one drug that will only be taken up by cancer cells — a drug capable of both finding and killing cancer cells. To do this, he will start with a type of molecule known as an aptamer, which can specifically bind to particular proteins found on cancer cells. These aptamers will be adapted for delivery of anti-cancer drugs resulting in “aptamer-guided pro-drugs” that specifically bind to cancer cells and kill them. A second part of the project involves identifying new aptamers that can selectively bind to different tumor types, thus, expanding the types of cancers that could be treated with this novel class of self‐guided drugs. Both efforts combine the power of cell targeting with drug delivery in one single synergistic molecule.