HORSEMAN #3: TREATING AND REDUCING THE RISK OF CANCER

Every day a new breast cancer case is diagnosed in Trinidad and Tobago, killing two women every three days

This week, as promised, we will continue to explore Dr. Peter Attia’s research on cancer, the runaway cell, specifically, treatments and steps we can take to detect cancer early.  As I noted last week, I believe that this is the most frightening of the four killer chronic diseases because it usually involves lots of pain and suffering.  Dr. Terrence Deyalsingh, Trinidad & Tobago’s Minister of Health, in a recent speech, advised that breast cancer was the number one killer in the country, with a new case diagnosed every day and an average of two women dying every three days!

As we saw last week, obesity and type 2 diabetes seem to be driving increased risk for many types of cancers, including oesophageal, liver, and pancreatic cancer.  We learned that excess weight is a leading risk factor for both cancer cases and deaths, second only to smoking.  And we explored Dr. Attia’s research on cancer’s metabolism and the two qualities of cancer that may lead to new treatments: 

1. “Many cancer cells have an altered metabolism, consuming huge amounts of glucose—they devour it at up to forty times the rate of healthy tissues.
2. They seem to have an uncanny ability to evade the immune system, which normally hunts down damaged and dangerous cells—such as cancerous cells—and targets them for destruction.”

THE WARBURG EFFECT

Dr. Attia advises that aerobic cellular respiration by normal cells produces only energy, in the form of ATP (adenosine triphosphate), the cellular energy “currency,” plus water and carbon dioxide.  In normal aerobic respiration, a cell can turn one molecule of glucose into as many as thirty-six units of ATP.  But under anaerobic conditions, that same amount of glucose yields only two net units of ATP.  However, cancer cells fuel their own proliferation by consuming glucose, as opposed to the more normal and efficient oxygen, turning the same amount of glucose into a little bit of energy and a whole lot of chemical building blocks—which are then used to build new cancer cells rapidly. 

Cancer cells have a strangely gluttonous appetite for glucose devouring it at up to forty times the rate of healthy tissues to fuel their own proliferation.

This strangely gluttonous appetite for glucose by cancer cells is referred to as the Warburg Effect, after a German physiologist named Otto Warburg who discovered it in the 1920s.  He noted that cancer cells devour glucose at up to forty times the rate of healthy tissues.  The Warburg effect, also known as anaerobic glycolysis, is how cancer cells fuel their own proliferation.  But it also represents a potential vulnerability in cancer’s armour.

OBESITY, DIABETES AND CANCER

Dr. Attia notes that:

“… the association between obesity, diabetes, and cancer is primarily driven by inflammation and growth factors such as insulin.  Obesity, especially when accompanied by accumulation of visceral fat (and other fat outside of subcutaneous storage depots), helps promote inflammation, as dying fat cells secrete an array of inflammatory cytokines into the circulation.  This chronic inflammation helps create an environment that could induce cells to become cancerous.  It also contributes to the development of insulin resistance, causing insulin levels to creep upwards.

This insight comes courtesy of further work by Lew Cantley, who discovered a family of enzymes called PI3-kinases (PI3K) that play a major role in fuelling the Warburg effect by speeding up glucose uptake into the cell.  In effect, PI3K helps to open a gate in the cell wall, allowing glucose to flood in to fuel its growth.  Cancer cells possess specific mutations that turn up PI3K activity while shutting down the tumour-suppressing protein PTEN….  When PI3K is activated by insulin and the insulin-like growth factor (IGF-1), the cell can devour glucose at a great rate to fuel its growth. Thus, insulin acts as a kind of cancer enabler, accelerating its growth. 

This in turn suggests that metabolic therapies, including dietary manipulations that lower insulin levels, could potentially help slow the growth of some cancers and reduce cancer risk.”

NEW TREATMENTS

As Dr. Attia notes:

“Lew Cantley’s discovery of the PI3K pathway led to the development of a whole class of drugs that target cancer metabolism.  Three of these drugs, known as PI3K inhibitors, have been FDA approved for certain relapsed leukaemias and lymphomas, and a fourth was approved in late 2019 for breast cancer.  But they haven’t seemed to work as well as predicted, based on PI3K’s prominent role in the growth pathways of cancer cells.  Also, they had the annoying side effect of raising blood glucose, which in turn provoked a jump in insulin levels and IGF-1 as the cell tried to work around PI3K inhibition—the very thing we would want to avoid, under this theory.”

As Lew Cantley went on to explain to Dr. Attia:

“… the problem with PI3K inhibitors is that by turning down the insulin related PI3K pathway, they actually end up raising insulin and glucose levels.  Because glucose is blocked from entering the cell, more of it stays in the bloodstream.  The body then thinks it needs to produce more insulin to get rid of all that glucose, possibly negating some of the effects of the drug by activating PI3K.”

Ketogenic Diet

Based on a study conducted by Lew Cantley and Siddhartha Mukherjee, the results of which were published in Nature in 2018, it was found that a combination of a ketogenic diet and PI3K inhibitors improved the responses to treatment of mice that had been implanted with human cancer tumours.

Dr. Attia also describes the experience of the wife of one of his very close friends who had been diagnosed with breast cancer that had already spread to her lymph nodes and her bones.  She qualified for a clinical trial of an experimental PI3K-inhibitor drug, in combination with standard therapies.  As he notes:

“Sandra (not her real name) was a very motivated patient.  From the day of her diagnosis, she had become obsessed with doing anything possible to stack the odds in her favour.  She devoured everything she could read on the impact of nutrition on cancer, and she had concluded that a diet that reduced insulin and IGF-1 would aid in her treatment.  So, she worked out a regimen that consisted primarily of leafy vegetables, olive oil, avocados, nuts, and modest amounts of protein, mostly from fish, eggs, and poultry.  The diet was just as notable for what it did not contain: added sugar and refined carbohydrates.  All along, she underwent frequent blood tests to make sure her insulin and IGF-1 levels stayed low, which they did.

Over the next few years, every other woman who was enrolled at her trial site had died. Every single one.  The patients had been on state-of-the-art chemotherapy plus the PI3K inhibitor, yet their metastatic breast cancer had still overtaken them. The trial had to be stopped because it was clear that the drugs were not working.  Except for Sandra.  Why was she still alive, while hundreds of other women with the same disease, at the same stage, were not?  Was she merely lucky?  Or could her very strict diet, which likely inhibited her insulin and IGF-1, have played a role in her fate?”

Fasting

Dr. Attia also shares the impact of fasting or fasting-like diets and he notes:

“Other types of dietary interventions have been found to help improve the effectiveness of chemotherapy, while limiting its collateral damage to healthy tissues.  Work by Valter Longo of the University of Southern California and others has found that fasting, or a fasting-like diet, increases the ability of normal cells to resist chemotherapy, while rendering cancer cells more vulnerable to the treatment.  It may seem counterintuitive to recommend fasting to cancer patients, but researchers have found that it caused no major adverse events in chemotherapy patients, and in some cases, it may have improved the patients’ quality of life.”

The bottom line is that we should not increase the level of insulin in someone who has cancer.

As Dr. Attia advises:

“More studies need to be done, but the working hypothesis is that because cancer cells are so metabolically greedy, they are therefore more vulnerable than normal cells to a reduction in nutrients—or more likely, a reduction in insulin, which activates the PI3K pathway essential to the Warburg effect.

… there is rarely only one way to treat a cancer successfully.  As Keith Flaherty, a medical oncologist, and the director of developmental therapeutics at Massachusetts General Hospital, explained, the best strategy to target cancer is likely by targeting multiple vulnerabilities of the disease at one time, or in sequence.  By stacking different therapies, such as combining a PI3K inhibitor with a ketogenic diet, we can attack cancer on multiple fronts, while also minimizing the likelihood of the cancer developing resistance (via mutations) to any single treatment.”

EARLY DETECTION

When cancers are detected early, in stage I, survival rates skyrocket!

The most important tool in our anticancer arsenal is early, aggressive screening.  The evidence is overwhelming that catching cancer early is almost always beneficial.

Unfortunately, as Dr. Attia notes:

… too many cancers are detected too late, after they’ve grown and spread via metastasis.  Very few treatments work against these advanced cancers; in most cases, outside of the few cancers that respond to immunotherapies, the best we can hope for is to delay death slightly.  The ten-year survival rate for patients with metastatic cancer is virtually the same now as it was fifty years ago: zero.  We need to do more than hope for novel therapies.

When cancers are detected early, in stage I, survival rates skyrocket.

Of all the Horsemen, cancer is probably the hardest to prevent.  … The only modifiable risks that really stand out in the data are smoking, insulin resistance, and obesity (all to be avoided).  … Until we learn how to prevent or “cure” cancer entirely, … we need to focus far more energy on early detection of cancer, to enable better targeting of specific treatments at specific cancers while they are at their most vulnerable stages.  If the first rule of cancer is “Don’t get cancer,” the second rule is “Catch it as soon as possible.”

So, screen early.  Women get your mammography and pap smear tests.  Men get your blood tests for prostate-specific antigen (PSA).  Do your colonoscopies and gastroscopies and combine these with ultrasounds and MRIs. 

Next week I will share Dr. Attia’s research and advice on the fourth horseman: Alzheimer’s and Other Neurodegenerative Diseases.  Again, I strongly urge you to read Outlive and I hope that these excerpts will help convince you to do so.

Have a disciplined week as you work to build your financial freedom and improve your health span.  If you find this advice helpful, please share with your friends and colleagues.  As usual, I look forward to your questions and comments.  Be safe.  Take good care, and if you can, help someone in need.

Cheers, Nigel

Nigel Romano, Senior Director, Moore Trinidad & Tobago, Chartered Accountants