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T315i mutations and BCAA

I found something really interesting and wants opinion from the CML veterans.  

TK domain mutations like T315i means an amino acid Threoine (T) have mutated to an isoleucine (I) at position 315 on the BCL ABL protein, thus T315i. A bit of context for the uninitiated, T315i is the worst mutation one can get since it is resistance to all TKI except Ponatinib with a 50-60% chance of response. 

https://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/...

What was interesting is that all of the worst mutations which confers the strongest resistance to TKIs (even to 2nd gen) ends with either a I (F317i, T315i), a V (E255V) or a L (V299L) !  I stands for the amino acid , Isoleucine, L stands for Leucine and V stands for Valine...

What is the common thread here? these 3 (I, L, V) amino acids are all Branched Chain Amino acid or BCAA ! 

they are called branched chain since there is an extra side chain sticking out which is probably also why TKI have problem fitting into the TK domain once these BCAA have mutated and replaced the original amino acid. (pure speculation on my end)

https://en.wikipedia.org/wiki/Branched-chain_amino_acid

What is interesting to me is that BCAA are called essential amino acid since it is commonly accepted that the body can't synthesize them and the only way to get it is FROM DIET. High BCAA food are meat, fish, egg, milk...mainly animal source. 

BCAA have long been implicated in longevity and cancer progression ( including CML !) through mTOR and IGF-1 pathways. 

https://www.ncbi.nlm.nih.gov/pubmed/28514443

https://nutritionfacts.org/2015/06/16/living-longer-by-reducing-leucine-...

https://nutritionfacts.org/video/treating-advanced-prostate-cancer-with-...

At least to me, the conclusion from all the above is pretty clear, If T315i uses lsoleucine and the only source of this amino acid (at least without BCAT1 involved) is from DIET, then we should consume a high fruit and vegetable diet and avoid high BCAA food like a plague to prevent mutations and CML progression. 

This is obviously 100% speculation on my end  and just looking for someone to bounce this idea off and any comments is welcomed. Probably the wrong place to post this but I am also a layman...and cancer patient. 

V.W. 

I found your posting to be very thought provoking and interesting.A lot of the research on the benefits of a low BCAA diet have come from animal studies and perhaps need further consideration as to whether the same applies to humans.However there are some studies that suggest  decreased consumption of branched chain animo acids improves metabolic health and especially improves glucose levels and affects the manner in which we manage or prevent the onset of daibetes As wellI have seen studies that suggest that a plant based diet would contribute to the effective management of early stage prostate cancer.

The argument for a high protein diet is that it promotes rapid recovery for athletes and improves muscular performance;in addition those that suffer muscle wasting diseases would be recommended to focus on a diet of high protein foods and or supplements.

Apparently high BCAA foods include milk,dairy,meat,poultry,fish,eggs,soya,whole wheat,brown rice,some beans and lentils,almonds and brazil nuts; some of these would hitherto have been regarded as very healthy as they contain fibre and high omega 3 s.

Because I suffer some substantial musculo skeletal issues probably as a side effect from long term use of imatinib recently have focussed on an anti-inflammatory diet but might need to rethink as to whether it would be wise to restrict the intake of many of the foods on the list above even though they contain some essentials like calcium from dairy milk and also healthy oils.

So should we as cancer sufferers seriously reconsider our diet as well as engaging in lots of exercise;for some time we have been aware that drastic changes to lifestyle might slow down disease progression and encourage longevity but is there now a substantial science based explanation for this?

I am just going to look up sources of plant proteins that are ideally anti inflammatory!

Best wishes

John

Thanks for your reply, John. 

 

In terms of clinical trials and human studies, this metastudy on veg and fruit consumption on Non hopkins Lymphoma survival is probably makes the strongest evidence we have for a plant base diet for CML. 

https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.27992

 

I am always thinking in terms of risk and reward, it took 50 years before it was accepted that cigarettes is a carcinogen and I am not holding my breath until a conflicted USDA comes out with recommendations on animal protein consumption. Too much special interest involved in human studies. Actually, the  WHO who might be more incorruptible  have already labeled red meat a carcinogen...

I think none of us expect a plant based diet to cure CML but if it can do what it does for prostate cancer ( as you mentioned) and prevent progression. Our TKI will be able keep us alive indefinitely. 

https://nutritionfacts.org/video/treating-advanced-prostate-cancer-with-...

I think BCAA is just drilling down into the details and optimzing a plant based diet...a french fries potato chip diet is vegan too...but I don’t think it is a coincidence that all these TKI mutations are driven by BCAA especially given that CML cells go so far as to actually manufacture their own BCAA using BRAT1 in blast crisis in which case it is too far gone and limiting consumption is too late.

All Cells are made from amino acid and limiting protein and BCAA is like taking away the fuel for cancer cell growth. They can’t replicate and proliferate without protein. Mutations happens from oxidative stress (ROS) and unfaithful DNA repair. There been many papers suggesting that antioxidant rich diet can prevent mutations. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041198

I have yet to seen anyone descirbe how BCAA fits into the picture on mutation development but I read somewhere that cancer cells have a preference for BCAA. 

In any case, Iimiting protein and a high antioxidant diet seems like common sense to me. I think BCAA just fans the flame in this whole process 

 

 

 

This is an alarming prospect, and worries me as I had recently elected to go the route of a low carb diet and attempt to build a lot of muscle mass. What were your oncologists' thoughts on this? Is it the bcat1 that increases through the cellular genetics or are bcaa's / amino acids that we ingest the cause of the issue? Very depressing to think flab and no meat are the best way to survive.

Hi,

My thoughts on this have been swayed by considering the work done by oncologists such as Professor Robert Thomas who in his book" Lifestyle after Cancer" takes a considered and research based approach that by limiting the consumption of certain foods that are regarded as being inflammatory and certainly feed the development of cancer cells we might allow ourselves longer in remission and less likely to develop new mutations such as might occur in us as CML patients.The obverse is that by focussing on natural products which are broadly described as polyphenols and these are plant based we take in suitable anti oxidants and immune system boosters.I dont regard myself as being vegan or vegetarian but having survived CML for nearly 14 years and now recently having been treated with ground breaking targeted radiation implants for early stage prostate cancer as well, I see survival as being based on a diet free from processed foods and most meats and a concentration on so called natural products (NPs) but not totally excluding some animal products.In addition the focus on daily exercise such as cardio and walking  for an hour or so regulates human metabolism.

I am off imatinib for 3 months or so as we are unsure of the interaction/side effects between the tki and the implanted radioactive isotope iodine-125 so I am giving a very focused diet and exercise regime a chance to see if it helps.

Research has indicated that many NPs inhibit CML cell proliferation and induce cell death through apoptosis and suppress tumor growth;it can reverse MDR or multi drug resistance.I have discussed this with my haema-oncologist who suggested that this would not reverse a rampant blast crisis in CML nor would it reverse an aggressive later stage prostate malignancy but as a combination or adjunct therapy is well worth a try.I would be as Robert Thomas indicated wary of relying too much on food supplements in the form of excessive use of vitamins etc(unless a deficiency was tested for and proven) but to rely mainly on natural foods.

At age 74 life has been good so I am doing my best to extend it via diet,exercise and lifestyle combined with the best treatments that medical excellence can provide.

I wish you well

John

Thanks for the reply and wishes, John, and same to you.

It's a double edged sword to me, and seems intuitive as well as factual that bcaa's must cause cancer and mutations after looking at the research. My problem is Bcaa's are extremely important and in so many foods, it would be daunting and maybe impossible to avoid them.

I read yesterday that free radicals are produced during exercise, so therefore by my understanding, exercising potentially causes cancer, and is kind of an apples to apples comparison here, I believe. I'm Damn sick of thinking everything i do will cause cancer. Lol.

I'm going to ask my onc his opinion, but I guess in the end it boils down to quality over quantity of life, too. Thanks for the listening ear.

I find this topic very interesting! Please would like more information on all of this. I'm willing to radically change my diet if all goes well. Thanks !

Following up on this topic. I found a paper that unequvicoally linked BCAA to cancer mortality. This is a retrospective study involving 3000 cancer patients. To make it as simple simple as possible, high BCAA protein consumption (4% of calories from BCAA) leads to a 200% higher chance of dying from cancer. 

My original thesis is no longer a conjecture but have real world consequences. Eat a lot of BCAA at your own risk, you have been warned. Not surprising, replacing BCAA with carbs (and even with fat) reduce cancer mortality by 50%. 

https://medicalxpress.com/news/2019-01-branched-chain-amino-acids-cancer...

 

Russell E. Ericksen et al. Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2018.12.020

"To determine if dietary intake of BCAAs correlated with cancer mortality in humans, we analyzed the National Health and Nutrition Examination Survey (NHANES) III dataset with linked mortality data. In this cohort, we calculated that the BCAAs comprised 17.3% of total protein intake. Given dietary recommendations for protein at 10%–35% of total kcal, we set the threshold for low-BCAA intake at 1.73% (10% protein/total kcal × 17.3% BCAA/total protein kcal). Few individuals consumed very-high-protein diets (>35% of total kcal), so we set the threshold for high BCAA intake at 3.89%, which is at the median of recommended protein intake (22.5% protein/total kcal × 17.3%BCAA/total protein kcal). Overall, individuals 50–66 years old in the highest tertile of BCAA intake had a 200% increased risk of death from cancer relative to the lowest tertile, even when adjusting for known confounders, as well as percent kilocalories from fat, carbohydrate." 

 

 

 

By the way, don't bother asking your oncologists about BCAA.  They will give you the politically correct answer of a "balanced diet"...whatever that means. 

Some cancer reserachers take a dim view of doctors, refering them as plumbers and car mechanics who have no idea of the underlying mechanism of cancer. Don't fall for the white coat and the "authority bias". They try to cover their ass with platitudes and ambiguity just like everyone else.

I like to quote William Gibson "the future is here, just not evenly distributed." I think scientist have learned a lot about cancer but that knowledge hasn't being disseminated to the public...or the doctors. (actually, that's not accurate, I found this paper on Pubmed avaialiable to everyone) I am not any exempted from that or "smarter" than anyone except that I am willing to do a bit more digging. I do believe there are matters we can take into our own hands as responsible adults. 

There is much evidence that a 'veggie' diet is anti-cancer:

https://www.huffpost.com/entry/vegan-diet-cancer_b_2250052

A low protein diet forces the body to "autophage" and digest old cells for amino acid parts. Cancer, by definition, requires a great deal of 'parts' in order to expand rapidly. Starving the body of protein forces cancer to implode. Of course this is no cure as cancer is insidious waiting in niches to expand, but a vegan lifestyle may very well cause much cancer to never progress - and better - enable our TKI's to be more effective.

This is why I do extended fasts (just concluded a 3 day one last week) several times a year and fast one day a week currently. Fasting does the same thing as depriving the body of protein periodically. Also - as BCAA (or lack thereof) targets the mTor pathway (up-regulates) and can have impacts on the body in other negative ways:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963881/pdf/nutrients-08-00...

I absolutely enjoy a great steak and other high protein sources from time to time - but more as a treat than as a staple. And high protein from time to time can help build lean muscle, cell repair and keep organs healthy. But just like in nature - high protein is scarce and only abundant "rarely" as when a lion catches a gazelle. They feast on the gazelle and then go without for days on end. I suspect short term BCAA input coupled with low supply enables our bodies to keep cancer in check naturally. Curcumin, for example, is a strong mTOR down regulator (i.e. it's a plant). Eating lots of plants (just like animals do after eating meat), may very well counteract the "stimulating" effect of BCAA's.

Another thought is to keep in mind "who" gets CML (and cancer overall). It's the older people starting in their 50's. CML is quite rare in younger people - most developing CML in their 50's (by a wide margin). There is evidence this is due to an aging immune system. Our immune system is what protects us from cancer. Cancer is a failure of our immune system. By adopting a lifestyle that enhances our immune system, we will go a long way to avoiding cancer despite exposure (i.e. environmental, diet or even genetic). This is why I fast - after 3 days, the body re-generates its entire immune system upon re-feeding primarily by generating many new stem cells. The fasting triggers this response.

https://news.usc.edu/63669/fasting-triggers-stem-cell-regeneration-of-da...

Also - staying in Ketosis following a fast continues the body's regeneration - not just of intestinal stem cells but bone marrow as well.

https://www.news-medical.net/news/20190826/Ketogenic-diet-shown-to-suppo...

Just a thought next time you decide whether to have a steak or not. I will still enjoy mine - mindful of BCAA's, but also mindful that is why we have an immune system standing vigilant and the benefit of ketosis in immune system health.

 

Hi Scuba

 

1) I think cancer patients need to be on a customized vegan diet. Some things are off-limits. Tofu, beans and nuts contains a lot of BCAA and methionine ( another no-no). Even more than meat on weight basis. Fruits contain none. Cruciferous veggies like watercress and broccoli are good since PEITC and glucosinolate kill cancer stem cells. I am big on curcumin like you but I take it in form of turmeric. I also add green matcha tea to my regime.

2)  I can totally understand the animosity toward veganism. I hate the diet and I don’t advocate a “100%” vegan diet. I seem to get a lot of pushback whenever I talk about diet and cancer and I get it. It is like guns in america, saying you can’t have meat and steak is attacking a person’s identity and his freedom!  As I said, the data are here now so people just need to make a choice they are comfortable with. I am 95% vegan and have my liberties when I feel like it. 

I am not going to tell the waiter I am Vegan in a Michelin 3 star Resturant. I eat whatever they serve me on the tasting menu. Life is not worth living without Wagyu and Scampi.  At home, I eat like a ascetic monk. The key about BCAA is the levels consumed. If I am eating meat once every 2 weeks, nothing bad is going to happen to me.  Having a quota system make sense so you don’t waste your protein allocation on mcdonalds. Keeping protein below 10% of calories is the target as the paper indicated. Meat is 40% protein. it is portion size and frequency. This video by Dr Campbell who did the China study is illuminating and all cancer patients should watch it : 

https://youtu.be/aN9P7jXyhII

3) I  have been doing intermittent fasts in the last 2 weeks to balance out the reckless abandon during the holiday. I can’t last more than 36 hours. Kudos to you for 3 days ones. I tried measuring my IGF-1 levels in blood serum before and after a fast, it went from 190 to 160. 

 

4) I am measuring my vitamin D level now. I am at around 100. thanks for sharing this info with the community. It is sad the docs don’t  talk about this since it does lowers cancer mortality. 
 

 

X

You want your vitamin D level to be lower than 100 /ng/ml with 50 - 70 ng/ml ideal for cancer fighting and disease 'minimization' in general. Dorup's work in 2012 documents a "J - shaped" response to increasing levels of vitamin D beyond a maximum benefit:

https://academic.oup.com/jcem/article/97/8/2644/2823270

Figuring out a correct dose to take in order to maintain a given level is very individualized (see graph below). What is sufficient for you may not be enough for someone else. I test twice a year and adjust my dose accordingly. Even on a high vitamin D3 dose, my serum level on one test fell as low as 40 ng/ml. Another test I was at 100 as you. In each case I took more or cut back, but always between 5,000 and 10,000 I.U.s. Overall, on most tests I hover between 60 - 70 ng/ml. I suspect vitamin D level in the blood is a dynamic process based on need by the body. It's clear, however, that staying above 40 ng/ml is vital for health.

I am of the opinion (based on research), that vitamin D is the single most important nutrient we can take for immune system health. Insufficient blood level vitamin D invites cancer and a host of other diseases. I wish I had known this before CML diagnosis. I feel strongly that I would never have developed CML if my blood level vitamin D was where it is today. At diagnosis my vitamin D level was 17 ng/ml.

The link below is to a good video summary on the science behind vitamin D benefits overall (it's 90 minutes so scanning it can get to more interesting parts):

https://youtu.be/z6M1ARtCi6c

Regarding Turmeric - Curcumin is only 3% by weight in Turmeric. But I suspect the Turmeric root has other beneficial properties. I use Turmeric in cooking and very much enjoy south Asia cuisine. I take Curcumin supplements to get the medicinal benefit (anti-inflammatory and not a friend of CML).

GARLAND. FRENCH . BAGGERLY. HEANEY