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.
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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