Strategies to avoid the grim reaper of Cancer - Part I: Colon Cancer

[DeStrider]

This is a new treatment for Colon cancer just released by Eli Lilly - Fruquintinib. It’s an incremental improvement of survival for colon cancer patients but unfortunately not earth-shattering.

Better to get screened and not develop colon cancer in the first place.

FRUZAQLA® (fruquintinib) Study Results

http://www.hutch-med.com/elunate-fruquintinib-hong-kong-hospital-authority-drug-formulary-enlistment/

[RapAdmin]

Exact Sciences wins FDA approval for improved stool-based colon cancer test

[RapAdmin]

• Stress and working at night are both known to affect cancer risk, including colorectal cancer risk.
• Colorectal cancer risk and progression have both been linked to the microbiome, dysregulation of which has been linked to stress and disruption of the circadian rhythm.
• Recent research in mice has linked stress and a disrupted circadian cycle to disruption of the gut microbiome, and suggested that this may contribute to colorectal cancer progression due to its impact on intestinal permeability and inflammation.

Colorectal cancer: How do stress, sleep, gut imbalances affect it?

These were the findings of a study in mouse models of colorectal cancer, which appeared in Science Advances in September 2024.

[Neo]

https://www.acpjournals.org/doi/10.7326/ANNALS-24-00981

[RapAdmin]

This would seem to be the nail in the coffin for the carnivore diet:

Now, researchers from the National Cancer Center Singapore (NCCS), together with scientists from Singapore’s Agency for Science, Technology and Research (A*STAR), have identified the mechanism linking the excessive consumption of red meat to colorectal cancer.

Worldwide, colorectal cancer, which affects the large intestine or rectum, is the third most common cancer, accounting for around 10% of cancer cases. It’s also the second leading cause of cancer-related deaths. In addition to age and family history, lifestyle factors such as diet, inactivity, obesity, smoking, and excess alcohol consumption can increase the risk of this type of cancer.

Using fresh colorectal cancer samples, the researchers discovered that the iron in red meat reactivated the enzyme telomerase via an iron-sensing protein called Pirin, which drove the progression of the cancer.

Ironclad link between red meat and cancer identified

Paper:

Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers -...

Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.

Full Paper (open access)

Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers

Ferric

Relacionado:

• Iron: an underrated factor in aging

[tj_long]

Chicken and turkey meat don’t seem to be as harmful, apparently due to their lower iron content?

[RPS]

This headline suggests only the iron in red meat is the issue but not iron from vegetables like spinach, sweet potato or broccoli.
Of course that is totally misleading.

[tj_long]

Heme iron vs non-heme iron.

[RPS]

That wasn’t clear from the New Atlas article.
But I’ll stand corrected if that is the real reason.

[RapAdmin]

I haven’t read the paper yet, but even if its not making the distinction between heme iron / non-heme iron, the density is such that it would seem most vegetarians would likely get a far lower dose than a carnivore diet aficionado…

and for comparison, Salmon:

[RPS]

I guess it all depends on how well one absorbs iron.
Although I’m not on a carnivore diet I do eat a huge amount of red meat and yet my iron levels remain too low for me to be able to donate blood.
Maybe that’s why my recent colonoscopy showed no hint of a single polyp.

[RapAdmin]

That brings up an interesting question - is it the consumption of iron, or the amount in the blood. I would think you are right, that its the blood level that would matter. But perhaps once its in tissues, that is when it does the damage in the prostate / colon, etc.?

It would seem that its doing the damage even before its reaching the bloodstream, in this case, as its increasing the telomerase in the lining of the colon where the meat is passing through. Or - perhaps I’m wrong on this; any experts want to chime in?

[RapAdmin]

How you cook your eggs has an impact on your risk for cancer

https://www.msn.com/en-ie/health/other/how-you-cook-your-eggs-has-an-unexpected-effect-on-your-risk-of-cancer/ar-AA1t4Wd5

[DeStrider]

Why Avoiding Cancer is Now Easier Than Ever

[RapAdmin]

Newly available blood tests to screen for colorectal cancer sound far more appealing than a standard colonoscopy. Instead of clearing your bowels and undergoing an invasive procedure, the tests require only a simple blood draw. But are the tests effective?

A study led by researchers at Stanford Medicine concluded that the new tests are ideal for people who shy away from other colorectal cancer screening. However, if too many people who would have undergone colonoscopies or stool-based tests switch to the blood tests, colorectal cancer death rates will rise. Because the more established colonoscopies and stool tests are more effective at detecting early cancers and precancerous polyps than the emerging blood tests, their long-term impact is projected to be substantially greater than that of blood tests, the researchers found.

“The first generation of blood tests are a really exciting development in the colorectal cancer screening paradigm,” said Uri Ladabaum, MD, a professor of gastroenterology and the first author of the paper, published Oct. 28 in Annals of Internal Medicine. “But for now, if you’re willing and able to do a colonoscopy or stool-based test, don’t switch to a blood test.”

Don’t skip colonoscopy for new blood-based colon cancer screening, study...

[Neo]

@RapAdmin

However, if too many people who would have undergone colonoscopies or stool-based tests switch to the blood tests, colorectal cancer death rates will rise.

Interesting - are they saying blood test < colonoscopy but stool based test same order of magnitude as colonoscopy?

[RapAdmin]

Comparing effectiveness

Ladabaum and his collaborators collected previously published data on six commercially available or in-development blood- and stool-based screening tests as well as the gold-standard colonoscopy. Using this data, they modeled the relative rate of colorectal cancer and deaths among 100,000 average-risk people who used each screening approach.

Among 100,000 people who receive a colonoscopy every 10 years, 1,543 would develop colorectal cancer and 672 would die from the disease, they determined. For stool-based tests every one to three years (depending on test) the incidence of colorectal cancer ranged from 2,181 to 2,498 cases per 100,000 people, and deaths ranged from 904 to 1,025. For the new blood tests, recommended to be conducted every three years, the cases ranged from 4,310 to 4,365, and deaths ranged from 1,604 to 1,679 — about two and a half times as many deaths as in the colonoscopy group.

Among those who receive no screening, 7,470 would develop the cancer, and 3,624 would die from it.

Moreover, when the group looked at the costs associated with each test, they found that colonoscopies and stool-based tests were more cost-effective than the blood-based tests.

“The blood tests are certainly much better than nothing, but you’ll worsen the population outcomes and raise health care costs if you see people switching from colonoscopies to first-generation blood tests,” Ladabaum said.

Sadly, a Paywalled Paper:

https://www.acpjournals.org/doi/10.7326/ANNALS-24-00910

[Neo]

@RapAdmin

every one to three years

Wonder how much those stats improve for stool (and blood) if it really is every 12 months or even every six months compared to every 3 years?

—

Could see a compressive, holistic strategy being something like:

• colonoscopy every 10 years or so (depending on risks and past colonoscopy results)

• stool test once a year (and do it for other things too, for microbiome, etc at the same time to get most from the “logistics” at once)

• blood test (depending on how much cost be driven down) a few times in between as part of normal routine (biohacker) blood work

[RapAdmin]

Vitamin K supplement slows prostate cancer in mice, researchers discover

[John_Hemming]

The original paper

https://www.science.org/doi/10.1126/science.adk9167

Editor’s summary

In light of emerging evidence that antioxidants can have cancer-promoting effects, Swamynathan et al. tested potential pro-oxidant interventions (see the Perspective by Pannia and Dowling). In particular, the authors focused on menadione sodium bisulfite, a water-soluble precursor of vitamin K. As the authors anticipated, this menadione derivative suppressed prostate cancer growth. The researchers then examined its mechanism of action and identified the kinase VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) as its target. Fortuitously, they realized that a fatal genetic muscle disease called X-linked myotubular myopathy is also linked to a relative excess of VPS34 activity owing to the loss of its antagonist, and dietary supplementation with menadione proved beneficial in a mouse model of this genetic disorder. —Yevgeniya Nusinovich

Structured Abstract

INTRODUCTION

Prostate cancer (PC) is the most commonly diagnosed cancer in men, with more than 299,000 new cases anticipated in the United States in 2024. The majority of these men will present with slow-growing disease that can turn into life-threatening PC that resists all available treatment options. Therefore, there is a strong interest in defining well-informed lifestyle, dietary, and supplement choices that can slow down disease progression. This has spawned large-scale human trials, including one on the benefits of dietary antioxidants: The SELECT trial (Selenium and Vitamin E Cancer Prevention Trial) followed 35,533 healthy men for more than 10 years. Against expectations, SELECT showed significantly increased risk of developing PC among men who took the antioxidant vitamin E supplements.

RATIONALE

The PC-promoting effect of antioxidant vitamin E supplements immediately raised the question whether, conversely, pro-oxidant supplements can help prevent the disease. Genetically engineered mouse (GEM) models of PC provide a platform to ask this question. Specifically, we use the RapidCaP GEM model, which allowed us to determine whether and how fast a cancer in the prostate progresses to the metastatic form.

RESULTS

We treated RapidCaP animals with the pro-oxidant menadione supplement [menadione sodium bisulfite (MSB)], a precursor of mammalian vitamin K that is present in circulation after consumption of plant vitamin K from greens. Daily MSB supplementation in drinking water suppressed PC progression, yielding durable responses. Systematic analysis of cell death pathways revealed that MSB kills cancer cells through a distinct oxidative cell death mechanism that we propose to call triaptosis. We used genome-wide CRISPR screens to understand the underlying biological principle and found that MSB depletes the early endosomal (EE) membrane lipid phosphatidylinositol 3-phosphate [PI(3)P]. PI(3)P defines the EE compartment, allowing sorting of derived vesicles back to the plasma membrane or into the lysosomal degradation system. Video microscopy revealed that the distinctive feature of triaptosis is the accumulation of large PI(3)P-negative, deidentified endosomes followed by cell blebbing and plasma membrane rupture. We found that MSB directly oxidizes essential cysteines on class III PI 3-kinase VPS34, thus inactivating the PI(3)P-producing enzyme. Notably, supplementing cells with extra reducing agents completely abrogates cell death induced by MSB. The ability of menadione to suppress PI(3)P production prompted us to test whether it could suppress a fatal inherited disorder: X-linked myotubular myopathy. This incurable disease is caused by inherited mutation of the MTM1 gene. MTM1 is the phosphatase that directly antagonizes PI 3-kinase VPS34. Therefore, boys with this disease suffer from unopposed PI(3)P production, causing a failure of muscle buildup. Mtm1 knockout mice recapitulate the most severe phenotype, lethality of infant boys. Supplementing MSB in drinking water doubled the overall survival of these mice to a median of 2 months. The treatment also improved animal weight gain and muscle histology.

CONCLUSION

Our results suggest that dietary menadione could form the basis of new therapeutic approaches in multiple disease settings. This is because MSB is an oxidative antagonist of PI 3-kinase VPS34, the enzyme that produces the phospholipid PI(3)P. In PC cells, the oxidative stress lowers PI(3)P, causing cell death by triaptosis. We infer from our data that normal cells have sufficient reserves in reducing power to withstand this insult. In myotubular myopathy, menadione may curb the unopposed VPS34 kinase activity and bring PI3P back to levels that can improve muscle development. Collectively, our findings contribute to the emerging understanding of pro-oxidant agent selectivity and show how definition of the pathways that they impinge on can give rise to unexpected therapeutic opportunities.