Funding outcome

INTRODUCTION: The two most common childhood solid cancers are Neuroblastoma, a cancer affecting nerve cells and Wilms tumor, a kidney cancer. More than 50% of children diagnosed with advanced stages of these cancers will die. When cancer cells spread from a primary site to a new location that cancer is considered advanced. Therefore, understanding the process behind how cancer spreads to other sites and developing novel treatments is crucial. In order to travel around the body, cancer cells break off from the main tumor and travel through the blood stream. Scientists have shown that these moving tumor cells construct a cloak using blood clots to cover them, allowing the cancer cells to move through the bloodstream without the body recognizing them as a threat. Understanding how the cancer cells make these blood clots is important. Blood clots are made through a series of reactions with different proteins or clotting factors in the plasma. As of now, it is believed that the only clotting factor made by cancer cells is one called Tissue Factor which interacts with the other clotting factors from the blood plasma to make a clot. We hypothesized that cancer cells have the ability to produce the clotting factors needed to make the cloak without help from the plasma, making them self-reliant and more capable to migrate through the blood. In some very new and novel data from our lab, we have shown that Neuroblastoma and Wilms' tumor cancer cells express several clotting factor genes, supporting our hypothesis. Therefore, we want to further explore this observation with the following four objectives: i)To determine expression of hemostatic factors proteins: We will prove that the genes result in clotting factor proteins being produced and we will measure how much of these proteins are being made. ii)To study how clotting factor genes are affected by chemotherapy drugs: One study stated that when cancer cells were treated with the chemotherapy drugs there was an increase in Tissue Factor. This is definitely worth investigating as it suggests that if chemotherapy drugs increase the amount of clotting factors made by cancer cells that might lead to an aggressive form of cancer. iii)To block the NFKB pathway and study the expression of clotting factors: Determining which expression pathway these genes are regulated by will take us one step closer to knowing how cancer cells spread. We do this by blocking pathways with chemicals specific to the pathways to see if we can stop the genes from being expressed. We will be blocking a pathway called the NFKB pathway because that pathway has been shown to influence the production of the clotting factor, Tissue factor. We believe by blocking this pathway we can observe changes in genes of other clotting factors as well. Determining what pathway to block will lead to novel pediatric cancer treatments. iv)To determine the presence of genetic markers that predict severity of cancer: We will discover genetic markers from the cancer cells that can independently tell us how sick the child will become. The results for this study will help us understand the way that cancer spreads to other locations, enabling us to combat these childhood cancers by developing novel therapeutics. The results will ultimately lead to a reduction in childhood cancer deaths.