For my final post I wanted to focus on the topic that our
cancer project centers around: the use of the anti-diabetic drug metformin as a
potential chemopreventative for pancreatic cancer. Many papers, including the paper I have chosen to analyze, focus on the link between pancreatic cancer (PC) and diabetes mellitus. It is because of this link that researchers believe the answer to decreasing the vast number of new cases of PC developing in the world is in a drug used to treat diabetes mellitus. Pancreatic cancer, with the
most common type being pancreatic ductal adenocarcinoma (PDAC), is
characterized by uncontrolled cell growth in the tissues of the pancreas (Ref. 1). According
to various epidemiologic studies, there is an increased risk of developing PC associated with diabetes mellitus (Ref. 2). Diabetes
mellitus is characterized by an abnormality in the body’s ability to either
produce or use insulin efficiently, known as insulin resistance (Ref. 1). Both
of these situations result in chronic hyperglycemia in the blood stream. PC is
one of the deadliest forms of cancer with more than 38,460 deaths in a single
year (of the 42,220 total new cases) (Ref. 2). There is a desperate need for a
preventative drug or an effective treatment to inhibit the cell cycles in tumor
cells or prevent the hyperactivation of certain pathways.
It has been
estimated that approximately 80% of patients with pancreatic cancer have some
form of diabetes (Ref. 2). Metformin (1,1-dimethylbiguanide) is reported to be
one of the most commonly prescribed drugs for type 2 diabetes mellitus (T2DM)
(Ref. 2). Already, these two statements have me thinking. If such a large
percentage of PC patients have diabetes and Metformin is already the most
common drug used to treat diabetes, why are our incidence levels of pancreatic
cancer still so high? If Metformin really had such an impact and could be
considered as a chemopreventative for pancreatic cancer, the number of cases of
pancreatic cancer should be decreasing, at least since the point of the
integration of Metfomin into the T2DM community. Instead, we still see a huge
number of pancreatic cancer cases every year. Perhaps the dosages prescribed
for treatment of diabetes is not enough to have an effect on pancreatic cancer
cells, which would account for the lack of impact the seemingly popular drug
has on pancreatic cancer cases. If this is the case, then I believe the
possibility of using this drug as a chemopreventative is still a valid option,
otherwise the statements simply do not line up.
One of the
significant pathways involved in unrestricted growth of tumor cells is the
hyperactivation of the mammalian target of rapamycin (mTOR) pathway. According
to researchers, “In vitro and
preclinical animal models confirmed that metformin induces AMPK activation,
inhibits the Akt/mTOR pathway, and also eliminates cancer stem cells (CSCs) and
inhibits tumor growth” (Ref. 2). While the AMPK activation and elimination of
cancer stem cells is vital to halting the uncontrolled division of pancreatic,
and other, cancer cells, I am choosing to just focus on the Akt/mTOR pathway,
with an emphasis on mTOR. mTOR in part controls the ATP:AMP ratio which
determines energy available to the cell and plays an integral role in
regulating the cell’s division (mitosis and all of the replication
proteins/machinery needed requires a lot of energy).
The study
conducted in this research article consisted of investigating the effects of
metformin on PanIN and their progression to PDAC in p48Cre/+.LSL-KrasG12D/+
mice. PanIN stands for pancreatic intraepithelial neoplasia, which is
essentially tumor growth of the pancreatic tissue (Ref. 2). This investigation
was carried out in part (which is what I am choosing to focus on) by examining the
mRNA expression of mTOR via quantitative “real time” PCR (Ref. 2). The results of
this analysis can be seen in the following figure (I apologize for the poor quality when the photo was enlarged).
Figure 4a. Effect
of metformin on the expression of mRNA for mTOR as determined with quantitative
real-time PCR. Column labeled at 0 on the x-axis represents the p48Cre/+.LSL-KrasG12D/+
mice while the 1000 and 2000 represent dosages of metformin (ppm) given to
transgenic mice.
According to the figure, the mice who were fed metformin-supplemented
diets showed a significantly lower relative expression of mTOR mRNA. The column
representing mice who were not fed metformin reaches approx. 1.0 on the y-axis
scale. The columns representing mice who were fed diets with 1000ppm and
2000ppm supplements of metformin reached approx. 0.5 and 0.55 respectively.
This shows nearly a two-fold decrease between mice without and mice with
metformin in their diets. The slight difference between the two dosages is not
significant enough (see p-values) to say that a larger dose of metformin may
lead to an increase in mRNA expression again of mTOR, however toxicity of drugs
is always important to keep in mind.
A quick note that I wanted to bring
up is the diabetic state of the mice is not defined in this paper. Whether that
be a detail that is inherent in the type of mice used, I do not know. This bit
of information would be important to know when analyzing the results of these
tests. What is the health state of the mouse before give metformin or not given
metformin? We should be cautious of the accuracy of the results and their
relevancy to human patients in that we do not have knowledge of how severe the
pancreatic tumor is, if there is metastasis in the tumors, do the mice have a
form of diabetes or was this controlled, etc.
In another study in the paper, it is clear that PanIN lesions are
currently present and that the metformin seemingly halts the further progression
however is this true across all of the studies done in this particular paper?
These are all questions I came up with while reading the paper.
In conclusion,
I find that the data supporting the idea that metformin helps prevent
pancreatic cancer hopeful yet inconclusive at this early of a stage. They
certainly point towards metformin having a positive impact and decreasing
expression of the mTOR pathway, which plays a vital role in regulating “cell
growth, cell proliferation, cell motility, cell survival, protein synthesis,
and transcription,” all functions crucial to cancer development (Ref. 3). The mTOR
pathway communicates with upstream pathways, including insulin and growth
factors such as IGF-1 and -2, and in normal cells, regulates proper cell growth
and senses the nutrient, oxygen, and energy levels of a cell (Ref. 3). In PC
cells, this normal regulation is overridden by the cancer’s objectives: cell
growth. While metformin seems to decrease the mTOR expression, we do not know
if this new level is sufficient to sustain normal cell cycles and growth, or if
it will result in toxicity for the healthy cells. The mTOR pathway is vital to
living, normal cells; take it away and how can you keep all cells in the body
from halting their proliferation? I would like to see more research and data on
this exact topic and look forward to delving deeper when investigating for our
wiki project. There is simply not enough data, or else the data is not quite
presented in a clear enough manner to convince me of metformin being the next
PC “wonder drug”, however the preliminary research is promising and starts us
in the right direction.
References:
- "Diabetes Mellitus: Types, Symptoms, Causes, Treatments." WebMD. WebMD, Web. 17 May 2014. <http://www.webmd.com/diabetes/types-of-diabetes-mellitus>.
- Mohammed, Altaf, Vaneena B. Janakiram, and Misty Brewer. "Antidiabetic Drug Metformin Prevents Progression of Pancreatic Cancer by Targeting in Part Cancer Stem Cells and mTOR Signaling." Translational Oncology 6.6 (2013): 649-659. Print
- "PI3K/AKT/mTOR pathway." Wikipedia. Web. 19 May 2014. <http://en.wikipedia.org/wiki/pi3k/akt/mtor_pathway>.
