pitavastatin decreases pancreatic cancer and pancreatitis

 

A recent article suggested  that the anti-inflammatory effects of pitavastatin may prevent pancreatic cancer by decreasing pancreatic inflammation (see statin dec pancreat cancer NatCommun2024 in dropbox, or doi.org/10.1038/s41467-024-48441-8)

 

Details:

 -- see commentary below for more of the immunology and potential mechanisms

 

Results:

-- mouse studies assessing chronic inflammation in the skin and pancreas: they created inflammation and fibrosis, documented that IL-33 expression was downstream of a specific signaling (TBK1-IRF-3), and that chronic inflammation depended on IL-33 induction

-- they screened an FDA-approved drug library to assess the role of small molecules that would decrease IL-33 expression, finding 5 candidates.

-- they found that pitavastatin calcium was an effective suppressant of IL-33 (as well as the bisphosphonate zoledronic acid)

    -- pitavastatin suppressed a breast cancer cell line

    -- the function of pitavastatin was independent of its effect on lipids (adding more cholesterol to the cells did nothing to undercut the benefit of pitavastatin), though it blocks the mevalonate-mediated TBK1 binding to membrane (which seems to be required for its phosphorylation and downstream IRF3 activation)

    -- atorvastatin, another lipophilic statin, also had the effect of pitavastatin, though the hydrophilic rosuvastatin did not (perhaps being hydrophilic, there was less uptake in cells??)

    -- pitavastatin in mice decreased the induced chronic inflammation in the skin and pancreas (though not in IL-33 knock-out mice), blocked the progression of pancreatic uors in a pre-cancerous stage, and increased survival of the mice

 

-- human studies:

    -- in 15 matched samples of the normal pancreas pancreatitis, and pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC), IL-33 (and Interferon regulatory factor-3, IRF3, part of the signaling system noted above) were highly expressed in the nucleus of the epithelial cells of samples of pancreatitis and PDAC, with a strong correlation between cells with IL-33 and IR-3 across the samples

    -- epidemiologically, matched cohorts of patients form the TriNetX Diamond Network (a global health network containing electronic medical record-derived data from  >200 million patients across 92 health care organizations in North America and Europe) comparing patients on pitavastatin vs ezetimibe (which does not affect the above cytokine production per the mevalonate pathway) found:

        -- 29% fewer cases of chronic pancreatitis, OR 0.81 (0.729-0.9), p<0.0001

        -- 16% fewer cases of pancreatic cancer, OR 0.835 (0.748-0.932), p<0.0013

            -- which all suggests that the cholesterol-lowering statin pitavastatin (vs the cholesterol-lowering non-statin ezetimibe) was able to block the TBK1-IRF3-IL-33 signaling axis to prevent chronic pancreatitis and thereby the increased sequela of pancreatic cancer

     

 

 

 

Commentary:

-- pancreatic cancer has a terrible prognosis, with a 5-year survival rate <5%. It  is the 4^th leading cuase o fcancer-related deaths in Western Countries, estimated to become the 2^nd one by 2030.

    -- a recent analysis found that the incidence of pancreatic cancer is increasing, per the SEER database: https://gmodestmedblogs.blogspot.com/2021/12/pancreatic-cancer-increasing-incidence.html

-- chronic inflammation is associated with many of our current diseases (diabetes, depression, heart disease, COPD, collagen vascular diseases,…); An approximate 20% of cancers worldwide are associated with chronic inflammation

    -- several specific chronic inflammatory conditions are associated with a dramatic increase in cancer, for example:

        -- chronic pancreatitis is associated with an eight-fold increased risk of pancreatic cancer five years after diagnosis

        -- inflammatory bowel disease is associated with increased colon cancer

        -- hepatitis is associated with increased hepatocellular cancer

-- there are likely several chronic inflammatory mediators associated with the development of cancer, including M2 macrophages, mast cells, transforming growth factor-beta, interleukin 10 and interleukin 13 (all of these have been implicated in promoting carcinogenesis and chronic inflammation)

-- IL-33 is an epithelium-derived cytokine, which is a member of the IL-1 cytokine family, and triggers T helper 2 (Th2) cell and type II innate lymphoid cell activation. It serves as a critical initiator of chronic inflammation when it binds to its receptor. IL-33 and its receptor are expressed in chronic inflammatory diseases, including inflammatory bowel disease, pancreatitis, hepatitis, and COPD; IL-33 is upregulated specifically during the transition from acute to chronic inflammation

-- the overall immunology of the inflammatory response and signaling pathways for IL-33 are quite complex. This study did  find that the TLR3/4-TBK1-IRF3 signaling was the critical regulator of IL-33, and that blocking this axis prevented chronic inflammation and cancer sequela in mice with apparent similar effects in humans, per epidemiologic data

-- it should be noted that IL-33 does seem to have a diverse and complex role across multiple cancers, including anti-tumor effects reported in human colorectal cancer cells, yet other studies finding pro-cancer effects in glioma, gastric, and metastases in colorectal cancers

-- the likely physiologic explanation to a role of statins in cancer:

    -- statins have documented anti-inflammatory and immunomodulatory affects including including tumor apoptosis, inhibiting angiogenesis and suppressing tumor metastases

    -- statins inhibit HMGCoA reductase, which affects both cholesterol formation but also the entire mevalonate pathway

        -- the mevalonate pathway also leads to the production of several chemicals that have been shown to be essential for the survival of cancer cells: isoprenoids, dolichol, ubiquinone, and isopentyl adenine (see statin dec pancreat cancer meta-anal DIgLivDis2020 in dropbox, or doi.org/10.1016/j.dld.2020.01.008)

 

 

-- pitavastatin is a relatively new statin used for lowering atherogenic risk of lipids, with the following differences from some of the others:

    -- it is pretty clear that pitavastatin is an effective med to decrease cardiovascular events, with a recent study in patients with HIV (and, therefore, high risk of chronic systemic inflammation): https://gmodestmedblogs.blogspot.com/2023/09/hiv-infection-pitavastatin-dec-cardiac.html

    -- metabolism: it is not significantly metabolized by CYP3A4, and therefore has different drug-drug interactions than some of the other statins

    -- LDL reduction: pitavastatin 31-42%, atorvastatin 38-54%,  rosuvastatin 52-635, simvastatin 28-41%

    -- studies suggest it has a lower risk of myopathy

 

-- a 2020 meta-analysis (see statin dec pancreat cancer meta-anal DIgLivDis2020 in dropbox, or doi.org/10.1016/j.dld.2020.01.008 ) found that statin use was associated wit a decreased risk of death in patients with PDAC:

    -- 14 eligible studies with 33,137 PDAC patients for this meta-analysis (only one RCT in the mix). These were quite heterogeneous studies, making the conclusions less robust

    -- statins were associated with a 13% reduced risk of death, a 50% reduced risk in surgically resected patients (presumably with less advanced disease), but no effect in those with advanced disease (though pretty close to a statistically significant 22% reduction with p=0.07

    -- most studies did not include sufficient data on specific statins used, though, contrary to the above findings, rosuvastatin was the only one with a statistically significant benefit (atorvastatin was pretty close, but had very wide confidence intervals). There are suggestions in the medical literature that the hydrophilic statins do work better). Clearly, this needs to be studied much more rigorously

 

-- the findings of other medications leading to suppression of inflammation associated with IL-33 is intriguing but unclear:

    -- is atorvastatin, much more commonly used in the US and a more powerful antilipid med, as potent as pitavastatin in suppressing IL-33? What about simvastatin?

    -- what about the bisphosphonate zoledronic acid? Or perhaps risedronate (also lipophilic)? Alendronate is hydrophilic, but does that matter?

-- this study also found that TBK1-IRF3 activation has been linked to skin cancer. would pitavastatin or these other meds decrease skin cancer?

-- TBK1 inhibitors may also improve sensitivity to immunotherapy in several cancers (eg melanoma and liver cancer). And TBK1 signaling is associated with angiogenesis in several cancers including pancreatic cancer. would pitavastatin help as an adjuvant therapy?

 

Limitations:

-- this was largely a mouse-based study, where the pathophysiology was pretty clearly elucidated

    -- the number of human studies was limited: there were only 15 matched samples in the study showing that the pancreatic epithelium expressed the same pancreatic cytokines (IL-33, IRF3) in inflammation and cancer as in the mice

--

 

So, interesting stuff:

-- it has long been known that statins have an array of “pleiotropic” effects (ie, not just affecting cholesterol), including being anti-inflammatory, anti-oxidant, immunomodulatory, improving endothelial dysfunction, and antithrombotic.

    -- so it is not surprising that statins might well be useful for preventing cancer, especially those cancers that develop in the setting of chronic inflammation

    -- there is a suggestion that overtreating acute inflammation for patients with acute musculoskeletal pain (eg with NSAIDs/anti-inlammatory meds) may lead to more chronic pain in the future: https://gmodestmedblogs.blogspot.com/2022/05/acute-pain-anti-inflammatories-lead-to.html

    -- meds that decrease systemic inflammation (eg colchicine) may well have a role in preventing diseases associated with inflammation (MI’s): https://gmodestmedblogs.blogspot.com/2024/03/colchicine-decreases-cardiovasc-events.html

    -- the JUPITER study found that in patients with high CRP levels (eg systemic inflammation) but “normal LDLs” (median 108 mg/dL, which one might argue is on the high side for their population), that rosuvastatin decreased the level of inflammation and cardiovascular events (see cad jupiter trial NEJM2008 in dopbox, or10.1056/NEJMoa0807646)

-- so, statins are a reasonable candidate to be helpful in cancer prevention as well as decreasing the progression of early cancers

-- the obvious advantages of statins are that they are plentiful and lots of people are on them for their lipid effects, they are cheap, and it is great to have a well-tolerated med that is multifocal: helps with lipids, chronic inflammation, and

-- BUT: there really needs to be high quality studies confirming this. do statins really work in randomized controlled trials? Which ones are best, if they do? What about other commonly-used meds that modulate IL-33 expression?