Saturday, June 2, 2012

Kill Sonic Kill Cancer?

             Pancreatic cancer is a death sentence. It is quick to metastasize, hard to detect, and resistant to treatment. Following resection, radiation and chemotherapy are used to eradicate the remaining bits of the tumor that are left behind. These have not proven all that effective at leaving the patients cancer free. Pancreatic cancer is quite hard to access using chemotherapy due to its poor perfusion and desmoplastic (growth of fibrous or connective tissue) stroma. To add to confusion, the therapeutic window, the balance between toxicity and efficacy, of many chemotherapies is quite small. (The researchers refer to this as the “therapeutic index”). Additionally, chemotherapies have very short half-lives and often do not reach their desired target because of this. Researchers speculate that by increasing vasculature and preventing the accumlation of connective tissues in the stroma, chemotherapies would more easily reach and apoptose their targets.
The Hedgehog Signaling pathway is involved mainly in embryo development but also has roles in adults. In cancer, a paracrine signal between neoplastic cells and stroma cells activates the hedgehog pathway in the stroma cells and leads to stromal desmoplasia. This effectively builds a wall of connective tissues around the new cancer cells and allows for the tumor to expand without being trimmed by chemo. One of the three pathways in the hedgehog pathway, sonic the hedgehog, is over expressed in stroma cells by these new cancer cells on the perimeter of the tumor. By inhibiting the hedgehog pathway, medicine could more easily reach its target.
Figure 1. E. Survival rate of mice with varying treatments. Blue=Vehicle, Red=Gemcitabine, Green=IPI-926, Purple=IPI-926/Gemcitabine cocktail. F. Percent of mice with pancreatic tumor metastasis to the liver. Blue=Vehicle, Red=Gemcitabine, Green=IPI-926, Purple=IPI-926/Gemcitabine cocktail.
The drug IPI-926 is a drug that inhibits the transmembrane receptor SMO that is responsible for activating the sonic the hedgehog pathway. The drug has a long half-life and fits in as a pivotal ingredient in a pancreatic cancer drug cocktail. When treated with IPI-926, mice had SMO inhibited. This led to an increase in tumor perfusion and a decrease of desmoplasia. The increase in tumor perfusion was so significant, that the vasculature of the pancreatic tumor matched that of regular pancreatic tissue. Researchers tested genetically modified mice that developed their own pancreatic cancer with these drug cocktails to see if IPI-926 was significant. The delivery of the drug doxorubicin was 60% effective when using the chemo/IPI-926 cocktail. When treated with a IPI-926 and gemcitabine (replaces cytidine during replication) cocktail, mice had doubled survival rates and had a decrease in tumor size. Additionally, metastases to the liver decreased by 4 fold. Researchers feared that while the cocktail they brewed is effective at knocking down the walls that cancer builds, increasing perfusion, and attacking it, what if cancer was building an immunity to IPI-926 as it had to other chemos? When looking at the resistance genes for gemcitabine there was no difference found between gemcitabine alone and the IPI-926 cocktail. So what? This recently published study about IPI-926 in combination with early detection techniques greatly improves the fight against pancreatic cancer. By improving detection, resection, and post-operative chemotherapy we have better tools to better fight pancreatic cancer. The in-vitro results of other scholars regarding the potential of IPI-926 have now been replicated in mice as shown by their increased survival rate when treated with gemcitabine+IPI-26. Mice with this treatment outlive all other mice in the study. (IPI-926, gemcitabine, and vehicle). Additionally, IPI-926+gemcitabine decreased metastasis, one of the reasons pancreatic cancer is so deadly. While these results are promising and exciting, I do not know how significant they are until they are repeated with a larger sample size. In fact, I could not even find how many mice were being studied. The only evidence of this is part F of figure 4. This experiment, aside from a messy methods section that is not explicitly written (maybe on purpose), could be repeated. It would be interesting to pair IPI-926 with another chemotherapy drug to see if it still works as well as when paired with gemcitabine. There is a possibility that IPI-926 will work very well with one drug, possibly producing astounding results. The researchers mentioned, in other studies, that the hedgehog pathway is known to be pro-angiogenic in adults. IPI-926 works by inhibiting the receptor that initiates the hedgehog pathway but in this case it led to an increase in tumor vasculature. How by inhibiting something that causes angiognesis do researches see angiogenesis? Either the study that concluded that the hedgehog pathway was proangiogenic is flawed or maybe these researchers are not taking into account a drug interaction or another angiogenic pathway. This confuses both me and I’m sure the researchers. The best way to see if this is a significant way to prevent secondary tumors from arising post-operatively is to test this drug cocktail on a human. (after much more research of course). If it still proves to be effective this would be a small advance in the fight against pancreatic cancer. Check this article out