We have just posted a Report on the use of metformin in Prostate Cancer. This is an update from an earlier 2015 Report.
Prostate cancer is a complex disorder and it also very heterogeneous. It is the most significant male cancer with a moderate mortality rate of about 25%. However, this mortality rate is quite confusing since genomic differences, demographic differences and even psychographic differences come into play. Namely there is a small group who have genetic variants which result in an aggressive disease. Second there are demographic groups who defer any testing until it is often too late. The cancer generally is slow growing, unlike ovarian or pancreatic cancer, and thus is properly attended to can be handled with minimal consequence. The problem often is getting the patients tested and followed.
In 2015 we produced a report discussing the research regarding metformin and statins in dealing with prostate cancer (PCa)[1]. This was one of several early reports addressing the use of metformin. In a sense it was an incidental observation. However, in the years since then a significant number of results have been provided further strengthening the utility of metformin before and after a PCa diagnosis.
There has been a great deal of progress in the past ten years in dealing with PCa. The chart below is from Beltram (as modified) and represents the multiplicity of therapeutics available. This chart presents the current general understanding on how to treat PCa.
As the disease progresses there are tools available to slow
and hopefully inhibit the process, even after metastasis and androgen resistance occurs.
Cancer has a complicated and intertwined ecosystem that initiates and supports it. It is not just the genetic disruptions alone that engender its overall aggressiveness. We lay out some of these below.
Specifically:
1. Genomic[2]: This is the internal disruption of normal homeostasis in a cell's status. Generally the focus has been on this element and the therapeutic approach has also been focused in disrupting this process.
2. MET, Mesenchymal Epithelial Transition[3]: Cancer cells lose their location specificity and not only proliferate but lose their basic location anchoring. For example, we see melanocytes moving from the basal layer upwards and then downwards. The same happens in PCa with basal and luminal interactions.
3. TME, Tumor micro-environment[4]: The environment surrounding cancer cells often is protective. The TME is a complex of a large set of these protective elements.
4. TAM, Tumor associated macrophages: Macrophages generally are the garbage collectors in the body. M1 macrophages perform a positive task even addressing cancer cells. However, M2 macrophages may exert a protective function for cancer cell clusters.
5. TAF, Tumor associated fibroblasts: We have discussed this at length elsewhere.
6. Metabolic[5], Epigenetic[6], miRNAs etc?: Cancer cells have a complex metabolic interaction and this is typified by Warburg processes. In addition, epigenetic issues such as methylation and acetylation have been shown to play a significant role as well. We also have such factors a miRNAs which play a role.
Thus it is essential that when providing a therapeutic we
address all of these elements. For example in immunotherapy we generally face
two obstacles. First is the TME and affiliated elements blocking cell attack.
Second, and this seems to be more critical as it is addressed, that
immunotherapy is used as an adjuvant. Namely it is used ex post facto to other
treatments, such as surgery or radiation. Recent studies indicate that if used
as a neo-adjuvant, namely when tumor burden is higher, it may be significantly
better having been trained on a larger tumor set.
Now for the topic of this note. Metformin is a classic
therapeutic for Type 2 Diabetes, T2D. As Zhao et al have noted:
Complex I, AMPK, mTOR, and mGPD have all
been suggested as molecular targets mediating the antitumor activities of biguanides. Consistent with
Complex I serving as a main target, biguanides preferentially target
subpopulations of slower-growing cancer cells that are more reliant on OXPHOS for
survival, creating therapeutic opportunities for the combination of biguanides
with drugs that act on rapidly cycling populations to
exert greater tumor clearance. Targeting compensatory metabolic pathways needed for cancer cells to survive metabolic
disruptions may also improve biguanide efficacy in combination.
In addition, biguanides exert effects on the TIME, with the potential
to influence the immune recognition and elimination of the tumor.
Interestingly, biguanides can also affect host pathophysiology by modulating
the gut microbiota, raising the possibility that biguanides may indirectly
impact patient response to cancer therapies.
Therefore, it is unknown whether biguanides affect direct targets in cancer cells, the tumor microenvironment, or
commensal microbiota, bearing in mind that none of these putative effects are
mutually exclusive. Finally, the pharmacodynamic properties of phenformin suggest that it may be preferred over
metformin for applications in cancer therapy, as
metformin has shown limited efficacy in recent clinical trials possibly due to its
more limited pharmacodynamic properties. While the toxicity profile of phenformin
is not ideal as a longterm maintenance therapy for type 2 diabetes patients, it
is well within the limits for treating cancer.
The incorporation of preclinical and clinical studies of
biguanides, including novel
derivatives, will help to elucidate biomarkers that predict therapeutic
efficacy, define proper patient
cohorts with sensitivity to biguanides, and guide clinical trials of both mono-
and combination therapies in cancer
Whitman et al have also noted:
Since epidemiological studies first demonstrated a
potential positive effect of metformin in reducing cancer incidence and mortality, there has been an
increased interest in not only better understanding metformin’s mechanisms of
action but also in exploring its potential anti-cancer effects. In this review,
we aim to summarise the current evidence exploring a role for metformin in
prostate cancer therapy. Preclinical studies have
demonstrated a number of antineoplastic biological effects via a range of
molecular mechanisms.
Data from retrospective epidemiological studies in prostate cancer has been mixed; however, there are several
clinical trials currently underway evaluating metformin’s role as an
anti-cancer agent. Early studies have shown benefits of metformin to inhibit
cancer cell proliferation and improve metabolic syndrome in prostate cancer patients receiving
androgen deprivation therapy (ADT). Summary While the
body of evidence to support a role for metformin in prostate cancer therapy is
rapidly growing, there is still insufficient data from randomised trials, which
are currently still ongoing. However, evidence so far suggests metformin could
be a useful adjuvant agent, particularly in patients on ADT
Thus, there appears to be significant potential for the use
of metformin as part of an overall therapeutic regime.
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