Methionine Restricted Diet for DIPG/DMG & The Practical Experience

Updated: Dec 2023, "addition of a radiosensitizing methionine-restricted diet to radiation therapy."

Nov 4, 2023 added a note on cystine and note on foods for feeding tubes.

Oct. 14, 2023 added July 2023 paper Targeting Methionine Addiction of Cancer Cells with Methioninase

Oct. 1st, 2023 paper: "Synergy between methionine stress and chemotherapy in the treatment of brain tumor" ; Some food pics

Diet has been controversial in cancer treatments, KETO (or low-carb/sugars) has been often considered and used for epilepsy, but most oncologists will say there is no data to prove it helps for brain tumors and that the cancer will find its sugar no matter what.

Disclaimer: This blog is just a summary of my understanding (I do try to link sources). I am not an expert and have not fully vetted all sources so do consult an expert for any decisions/changes and use the info at your own risk.

Low-methionine (MET) has been gaining some traction in 2022, 2023 for DIPG after research findings by Cynthia Hawkins and her team were shared: showing that a zero-methionine diet, in-mice, showed impressive slowdown of tumor cells and even cell-death in-vitro. See this video where she talks/explains how she uses The Cure Starts Now grant for her

research and the MOA idea. Also Sameer Agnihotri PhD work published in Nature shows "The Achilles’s heel of these tumors is that they are rapidly growing and use a lot of nutrients,” said Sameer Agnihotri, Ph.D" ... “Combining metabolic approaches—changes in diet—with next-generation scientific tools might become a way of harnessing our understanding of how nutrient needs of cancer cells differ from normal cells and lead to more effective personalized cancer therapies in the future.”

Notably for brain cancer this 2020 paper: "Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice" reported "[the tumor] growth was arrested after the depletion of mouse plasma methionine (MET) ... MET depletion for 10-12 days induced mitotic and cell cycle arrest, apoptotic death, and widespread necrosis in tumors but did not prevent tumor regrowth after cessation of the regimen. ... single [chemo] therapy in any of the tumors ... [yielded] a more than 80-day [or 20] growth delay was observed"

More general cancer cells dependency and addiction to methionine is not new and known as the Hoffman Effect:

• A great summary paper July 2023 of most research and clinical trials on cancer + MET: "Targeting Methionine Addiction of Cancer Cells with Methioninase"

• "In 1959, Sugimura and colleagues reported a study where tumor-bearing rats were fed diets with the restriction of individual essential amino acids. Tumor growth was significantly affected by a methionine-restricted diet" Sugimura T., Birnbaum S.M., Winitz M., Greenstein J.P. Quantitative nutritional studies with water-soluble, chemically defined diets. VIII. The forced feeding of diets each lacking in one essential amino acide. Arch. Biochem. Biophys. 1959;81:448–455. doi: 10.1016/0003-9861(59)90225-5. [PubMed] [CrossRef] [Google Scholar]

• Addition of a radiosensitizing methionine-restricted diet to radiation therapy. A clinical trial "Normal cells can tolerate methionine deficiency, but most cancer cells are methionine auxotrophs, requiring dietary intake since they cannot synthesize it. In vitro, methionine deficiency causes cancer cells to undergo cell cycle arrest and cell death, and in vivo a methionine restricted diet (MRD) enhances radiosensitization without significant adverse effects."

• In 1973 it was shown: "L5178Y mouse leukemia cells in tissue culture required a minimum of 10.0 mg l-methionine per liter and 1.0 mg folic acid per liter to maintain a division time.." Chello PL, Bertino JR. Dependence of 5-methyltetrahydrofolate utilization by L5178Y murine leukemia cells in vitro on the presence of hydroxycobalamin and transcobalamin II. Cancer Res (1973) 33(8):1898–904. [PubMed] [Google Scholar]

• "Methionine addiction is a fundamental and general hallmark of cancer and is known [as] the Hoffman effect (Coalson et al., 1982; Hoffman and Erbe, 1976; Kaiser, 2020; Stern and Hoffman, 1984; Stern et al., 1983, 1984)" link

Note: Cystine restriction should also be considred at the same time, the good news most foods low in MET are low on Cystine as well. (This is very new and still being looked at).

In this blog, I will share:

1. What is MET and why there are signs it could help brain and other cancers?

2. A 5-year-old practical low-MET diet experience

3. Producers, brands, sites to buy from, international shipping ...

1. What is Methionine (MET) and its applicability to cancer

MET is one of the main amino acids. Amino acids are the main building blocks of proteins: so in a way, a low-MET diet will be a low-protein diet, to an extent the very opposite of KETO (modified Atkins diet).

Evidently, there are thousands of research papers showing that Cancer cells are addicted to MET. Researchers like Prof. Robert M Hoffman from UCSD have spent over 50 years working on that (see a good list of resources on the topic). In short, the delta between normal and cancer cells' addiction to MET is much higher than that of sugar, this is the reason there has been some progress in using MET-PET-MRI (based on 11C-Methionine) to track active tumor cells vs. the FET-PET-MRI using glucose consumption (brain cells do not divide much and thus use less glucose than tumor cells). See this AI generated explainer video on the topic and Dr. Hoffman's work:

In addition, there is research showing that "Methionine restriction (MR) is one of only a few dietary manipulations known to robustly extend healthspan in mammals. For example, rodents fed a methionine-restricted diet are up to 45% longer-lived than control-fed animals". So there is an argument that we all should be on a low-MET diet.

2. Practical low-MET diet

We did come from a KETO diet and this was a big shift, but the complexity and challenges of adhering to it were similar: looking at food labels, searching for specialty foods, and knowing what to buy from which store/supplier. Finally, adjusting to new cooking products, ingredients, and recipes is manageable once in a steady state.

The Basics:

• Ideally 100-70% fruit and 0-30% vegetables, are very hard for kids but special medical foods come to the rescue.

• Vegan diet with further restrictions: grain-free and low-protein

• The goal is to get enough Calories per day

• The goal is to take 2mg of MET per day per kilogram of body weight (there is an oral enzyme "Methioninase" which breaks down MET in the gut and could help further.

Unfortunately, kids need much more calories per kg. weight and this makes the diet a bit more challenging. For example, a 5-6 year old might need 65-70kCAl/kg/day while an adult might need 30-35kCal/kg/day. Good Fats like high-quality olive/avocado oil are good add-ons to keep calories up and are often pointed out as supplements to prevent weight loss: providing calories and not MET. Weight loss is often reported in adults moving to this diet, we did not experience this possibly because of the medical foods and oils.

"Luckily" there is a rare medical condition in people who can not process Methionine. The condition is called HOMOCYSTINURIA and there are medical foods companies creating specialty medical foods: a lot/most of them are available without prescription: see the last section for links and ideas. !!! Note. Always check the labels as some of the products from the same brands have way too much MET for the above targets.

I will share my sheet where I track various products and produce based on the MET content per 100 grams and the resulting calories. In short, I look for products that can give enough daily calories and keep the daily MET amount (based on kg and calorie needs). Also, any add-on products that make our patients happy or can complete a favorite meal. Ideally, higher MET meals should be followed by a rMETase dose.

Other lists of MET content in foods: HowToStarveCancerNaturally.com, Texas Children's, Brenda Davis.

In my own list, I focus on mg of MET per 100mg of the product and also track the grams of protein and calories this provides. This yields a list of foods that will keep me under the daily target of 2mg/kg/day of MET.

An example of eating 2600 grams (2.6kgs) of apples only per day will provide enough calories and will keep our MET levels below the daily target. But the calculated ~4kgs of strawberries needed for the right calories intake will yield too much MET (yet still orders of magnitude lower than a traditionally diets). !!! Note: this is just a comparison assuming single product being consumed which is not sustainable, healthy or advisable, but provides an understanding from which products one can eat as much they want)

Main Products low on MET

FRUITS: Try to do fruits as much as possible: fresh, smoothies, etc. Cold-pressed juices might not be ideal as the pulp/fiber in fruits helps, there was some research (can not find the reference now) that patients eating whole fruits vs. drinking freshly squeezed juices had opposite effects vs. baseline in cancer patients. My thought is a natural sugar with natural fiber is good/OK.

Mostly used ingredients for us:

1. Low-proteins medical products:

   1. Pastas (may forms and shares)

   2. Rice (possible for sushi as well)

   3. Bread / flour (so many cooking options)

   4. egg-replacer (also a special treat the plant-based hard boiled WunderEggs - still 1.5g of protein/half so not great but a special treat: US availability only)

   5. some snacks: cookies, salt sticks ...

   6. milk

   7. burger mix

   8. ....

2. Jackfruit

3. Cassava/Plantain: chips, french fries, or any dishes ...

4. Water Chesnutt - kind of magical as there is no MET at all.

5. Tapioca

6. Konjac/Shirataki Noodles/products are palatable as they have unique texture (also KETO)

7. Low-protein coconut-based products (including milk, and yogurt).

8. Nuts/Grains: Macadamia nuts might be the only OKish option, but there are some concerns if the fats of Macadamia are good (I have not researched that but heard it in a NORI conference call).

9. STAY AWAY from Soy, pea, cashew, almond, etc. based Vegan foods they have lots of proteins :(. Yest also has high MET content. Thus for baking we do more naan-style bread and use banking powder.

I always bring either rice, pasta, or some kind of bread with me when going out to restaurants. Always bring some fruit.

!!! It is interesting to note that for the low-MET diet, there might be arguments to stay away from processed foods, artificial sugars, .... In short, in an ideal world, RAW might be the best option in addition to all of the above, but this might not be easily achievable.

Organic/Bio/Natural: might be good and preferred if economically possible, but various countries mean various things and these benefits could be questionable and possibly not quantifiable. The hope is fewer chemicals and artificial and non-natural ingredients.

Methioninase (rMETase)

rMETase (oral version o-rMETase) is relatively new, not FDA-approved as a drug, but is a food supplement and thus following all of the FDA rules for food supplements. The only place that I am aware to produce it is the Anticancer Inc supported by the Robert M Hoffman Foundation for Cancer Research. Anticaner Inc. holds a US patent(s) for oral methioninase (ref 2). On their website you can also find a good list of peer-reviewed publications on Methioninase.

Form factor of the rMETase

Dr. Hoffman has shared that he is committed that o-rMETase should remain a food supplement and his foundation has been raising donations to scale production.

There is no concrete data on how much rMETase lowers your MET level, but the rule of thumb that we use is to take one vial (1ml) 30 mins after each major meal (up to 3 times per day. Note 6 viles per day work withour problem as well). This publication reported a case of 50% drop in the blood within 4 hours.

It tastes like salty water and my child loves it. Anecdotal data of personal experiments: eating a cheeseburger, taking a vial of rMETase, and then going for a blood-test Amino Acid panel (in most of the USA one can order it here there are other provides do google/ask) and showing remarkably low values.

Baby/powder Food (or feeding tube): most brands have baby-food powders and formulas as meal replacements: Example Loprofin and Hominex 1 and 2 by Abbot Labs or other Amino Acids additives. Mostly by prescription and definitely talk to an expert.

3. Producers, brands, sites to buy from, international shipping ...

Medical Low-Protein Brands:

• pku-versand-huber.de (global shipping) own brand, Loprofin and 3rd party brands.

  • pastas, rice, bred, couscous ....

  • Fresh bread will go bad when shipping to the US (from Germany), but they have pre-packaged bread that will last for longer)

• Loprofin products from Italy (global shipping through various suppliers) As of recently they stopped selling them in North America, although still on the site - The DACH countries have a wide selection). This has been the 1st brand I found and main go-to products, I am constantly testing new ones.

• Promin (Australian brand local shipping only, google it by product as I found one pharmacy in the USA for example offering some of those products)

  • they offer scrambled edges replacement - yet to try them, but exciting as well as a burger mix (although the MET content is a border line, still lower than the jackfruit or cassava made options)

• Mevalia ( they have a pizza base, burger mix, 0 protein milk replacment, pastas ... )

• Metax.org (the best rice option IMO)

• US shop for dry croceries and frozen meal that are low-protein

• Do share any of your findings so I can update the list.

General Products/dishes

• Vegan: Cheese slices, graded and feta cheese (many brands look for no or very little protein: 1g per 100g and do not make this your main food :))

• vegan butter - various brands

• Bruschetta or toasted bread (low-protein/medical) with various vegan spreads (cheese, tomato, or eggplant-based)

• Past, a: many vegan types Tomato based pasta

• Pizza (with the medical food products for baking)

• Sushi: Rice bow with pieces of seaweed and cucumber

• Crepes/pancakes: with the egg-replacer and the med. baking mix, and vegan low-protein butter

• Fruit smoothies (not juices) 3x per day various mixes, just fruit and water in a blender: there are reusable pouches for convenience

• Rice dishes: many of vegan based dishes from Indian, Thai, Nepali, some Latin-American (cassava fries mainly) etc. restaurants (always bring/use your low-protein rice)

• Cassava/Yuca fries, even mashed "potato" Note on cooking cassava for 1st timers as it could be toxic!

• Cauliflower stake (a bit more of a stretch so just before taking Methioninase)

• The Loprofin and most medical-food sites have many recipes (example for Loprofin incl. Lasagna, pasta, desserts...)

• Coconut-base vegan gelato: using coconut-milk (low to no protein), dates and raw cacao - other fruit, options are OK, but outside of mango some extra sugar might be needed (I use coconut) might be needed.

• ...

Vegan Brands

• Medical Foods Brands

  • Loprofin (selection varies per region, so look for your local site)

  • Promin

  • pku-versand-huber.de

  • Mevalia

  • Metax.org

  • Vitaflo (as with others selection widely ranges per local

• So Delicious: coconut drinks (~zero protein), yogurts (<1g of protein) Great for cooking

• Daiya cheese, cheesecake, pizzas (but for low-Met make your own pizza-base or look for/under medical products), chees... USA/Canada/Mexico mainly

• Meati: mushroom root base meet replacement). high protein but very high MET. Still, some open questions about how good this is and the US only as it is a new start-up.

• Jovial : Cassava based pasta. A good option, but medical pasta is much lower in MET

• Siete Foods Cassava-based tortilla chips, Cassava-based tacos, even some of their cookies can fit into the low-MET diet ...

• Violife (the best Feta replacment with 0 proteins, but other cheeses and spreads)

• ... (most larger supermarket brands have their own brands now)

!!!Note: Do Google-specific products you like and "low-protein" food, as local pharmacies and resellers might offer it. Ask expert dietitians as they might have resources for HOMOCYSTINURIA as well: the Children's Hospital in Zurich did have some great tables and brochures to start, thank you Dr. Moor.

Some meals I happened to snap pics of over the past 2-3 months