Tag Archives: methionine

How You Can Help Save 8 Million+ Lives per Year

I’m now officially a Living Beyond Breast Cancer (LBBC) Young Advocate!

LBBC Young Advocates Class of 2016

Shortly after getting back from Philly, I sat down to write a post about my experiences at the LBBC conference and plans going forward. But I began to feel that I was merely procrastinating – before anything else, I needed write the long-promised conclusion to my series on methionine.

Why do I keep stalling?

frustration

I’ve learned so much while reading about methionine research, but I don’t know how to act on that information except to report it.

Even after my advocacy training, I’m not sure what I can do besides lobbying for increased research funding. That’s important, but the whole legislative process is so so

Image by jesseakc

slow

 

 

 

 

In my last post on methionine, I found out about methioninase, an enzyme that causes methionine to degrade rapidly. Getting methioninase injections or taking methioninase pills would be far easier than trying to follow a methionine restricted diet.

For now, though, these pills & injections are the stuff of fantasy.methioninease-fairy-for-blog

I’d written to Charlene Cooper, COO of AntiCancer, Inc., the company that holds a patent for METase (a type of methioninase). I wanted to know when to expect human trials for this promising treatment.

Here’s Charlene’s reply:

Dear Marina,

Thank you for your email below.  We are very sorry about your diagnosis of metastatic breast cancer.

AntiCancer has developed recombinant methioninase through numerous pre-clinical studies, including primates and pilot clinical trials.  AntiCancer has had extensive discussions with the FDA and is ready to go forward with final toxicity studies and Phase I clinical trials.  The only hurdle is funding.

It is possible the “moonshot” initiative may be useful, but probabilities of funding from them are small.  I am attaching for you a paper (Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey.  Expert Opin. Biol. Ther. 15, 21-31, 2015) from our President, Dr. Robert Hoffman, and another two other very important new papers on the use of methioninase in combination therapy.

We manufacture recombinant methioninase on site at AntiCancer Inc.  It is highly pure, but out facility does not have a good manufacturing practice (GMP) license as yet.

We would like to help you and also would appreciate your views for funding methioninase, one of the most promising developing cancer therapeutics.

Best regards,
Charlene

Charlene M. Cooper
Vice President & COO
Grants and Contracts Administrator
Executive Assistant to Dr. Robert M. Hoffman
AntiCancer Inc.

I appreciated the articles, and the time Charlene took to reply to me. But (sigh) how can funding still be a hurdle when we have the Cancer Moonshot Initiative and Mark Zuckerberg & Priscilla Chan pledging 3 billion to end/manage all disease? I have no views or particularly good ideas for funding methioninase trials. dunno-bitmojiThere’s MetAvivor.org,  but 40k per year is the max for their grants – I suspect that’s pocket change to businesses like AntiCancer Inc. Even if their human trials could get fully funded, it would probably take years and years to see results, not to mention FDA approval.

Before frustration could take over, I researched another company in the enzymes for oncology therapies business: Aeglea BioTherapeutics.

Founded less than three years ago, Aeglea develops engineered human enzymes invented in a lab a few miles away from me, at The University of Texas at Austin. One of the enzymes it’s working on is cystathionine-γ-lyase. It can degrade methionine like AntiCancer, Inc.’s methionine-γ-lyase enzyme, but the patent for cystathionine-γ-lyase claims that it would require less frequent injections for the same effect. More importantly, as a re-engineered version of an enzyme already found in humans, cystathionine-γ-lyase should not elicit an immune system response.

The lead author of the 2012 article on the development of cystathionine-γ-lyase, Everett Stone, still works at UT Austin, so I reached out to him. Professor Stone kindly agreed to meet with me to speak about the status of human methioninase research. It was Professor Stone who pointed me toward Aeglea – the cystathionine-γ-lyase ball is now in their court.ball-in-court-for-blog-rotated

Aeglea does list cystathionine-γ-lyase (product candidate AEB2109) on their product pipeline page, but it’s only one of seven and not even at the phase of Pre-Investigational New Drug (Pre-IND) Application with the FDA. This application is required before any Phase 1 human trials can take place.

Again, I have no good ideas about what I can do to speed this process along. Any suggestions, dear readers?

This whole investigation into methionine & methioninase has left me feeling like:

sharksurfingIt’s been ever so much fun, dodging this toothy shark – wonderful exercise, really! But once this boat towing me along runs out of gas, it would be great to have another one on standby to take me back to the beach.

Wooohooo, I see some boats in the distance, close enough to wave at. Hey boats, can one of you come give me a lift? Boats? Why are you crawling along so slowly? This is an especially toothy shark that I’m dealing with here, hellooooo…

Still, I refuse to give up hope for a cure, or at least more & better treatment options. Here then is my message in a bottle:

sea-bottle
Image by Comfreak

We all need to raise our voices to demand that  research on metastatic cancer be prioritized and well-funded. One easy way to do this is follow and support MET UP, whose legislative advocacy goals include:

  • Additional research funding for all cancer types. The National Institute of Health (NIH) currently funds ~ 8% of the grant applications it receives. That number needs to increase to 25% at the very least.
  • Allocating 30% or more of federal breast cancer research dollars to metastatic research – an appropriate goal considering that ~ 30% of those who survive earlier stages of breast cancer go on to develop metastatic disease.

Together, we could help build a boat big and fast enough, as it were, to save over half a million Americans who die from toothy shark – er, cancer each year.

On a global scale, cancer cures/effective treatments would prevent the death of > 8 million people per year! Since nearly 40% of people in the US will be diagnosed with cancer at some point in their lifetime, you might be helping yourself or your family just as much as you’d be helping me.

On The Case: Methionine & Cancer Part III

Before launching into more shocking truths about methionine, I want to share a story told by Chef Ryan Callahan in the August issue of Conquer magazine. Chef Ryan’s best friend, Tommy, was diagnosed with stage 4 liver cancer at 21 years old and died just 2 months later. Chef Ryan writes that Tommy had a 4th-degree black belt in Taekwondo and a healthy lifestyle overall. However, once Tommy began an aggressive course of chemo, he could only manage to eat salty junk foods and cookies.

Chef Ryan believes that if he’d understood and been able to teach Tommy’s family cooking techniques for countering chemo’s eating-related side effects, Tommy would not have died so soon.

Tommy’s story does make me curious about the role of Registered Dietitians during the course of his treatment – an RD should have assessed Tommy’s nutritional status and counseled him and his family about all the available options. But whatever the case may have been, this tragic story highlights the critical yet all-too-often ignored component of fighting cancer:

nountprriwtxicoin-use-use

truedat

Nowadays, patients and their families do have great resources. Chef Ryan was inspired to write a cookbook and offers tips and how-to videos. A reader also recently reminded me about Rebecca Katz,

rebecca-katz
Rebecca Katz wearing a zucchini noodle necklace

whose cancer-fighting food workshop I attended years ago as a dietetic grad student in Seattle. Rebecca has authored several cookbooks and released the Cancer Fighting Kitchen online course last month.

I’ve resolved to delve deeper into the material these two have developed as I continue to work on my cooking skills. Speaking of which, this weekend my fiance and I collaborated on making hamburger patties. We got a pound of grass-fed ground beef and mixed it with 1 pasture-raised egg, 2 cloves of minced garlic and a ½ teaspoon of turmeric along with salt & pepper.

burger
My fiance’s turmeric burger – I had mine sans bun alongside veggies

This was enough for three patties, and I had the leftovers for my Sunday lunch. We both enjoyed the beef but couldn’t really taste the turmeric, which was fine by my fiance. Still, the next time we make burgers, I might use a whole teaspoon of turmeric. If my fiance objects, I can up the seasoning on my portion only.

I’m leading this post with tales of my kitchen experiments in order to emphasize that the scientific literature on methionine restriction has not swayed me to cut out meat or otherwise alter my diet. As I’ve concluded in my previous post, far too much is still uncertain and the changes required would be maddeningly complicated at best – dangerous at worst.

Even if I could follow an ultra-low-methionine diet without jeopardizing my physical and mental health, the anticancer effect would not be assured. After all, researchers documented numerous cancer cell lines that were only slightly or not at all dependent on methionine. As far back as 16 years ago, an article in Cancer Research called for the development of a genetic test to identify methionine-dependent tumors in order to incorporate that information into efficacy studies for methionine-lowering treatments.

So where was this genetic test? Where were those efficacy clinical trials? Why did this promising research seemingly stall after Dr. Epner et al. published findings from a Phase I trial in 2002?

Google told me that Daniel Epner, M.D., was a Professor at The University of Texas MD bitmoji1174324671Anderson Cancer Center in Houston, TX. I reached out to Dr. Epner via email  to ask him why he left the field of methionine restriction research. To my surprise, he actually responded:

Marina,

I am sorry to learn about your cancer diagnosis. I wish you the very best in your treatment.

I led a basic science program for about 10 years at the beginning of my career during which I focused on abnormal nutrient metabolism as a potential target for cancer treatment. One of my main interests was methionine metabolism, since animal studies showed that dietary and or enzymatic methionine deprivation had anti-tumor activity. Methionine plays a key role in methylation of nucleic acids and proteins and is a key precursor for polyamines, both highly relevant to tumor growth.

We had support from Abbott laboratories for the phase I trial you mentioned in your email. In addition, Abbot supported a second clinical trial on which I collaborated with an investigator at MD Anderson (when I was still on the faculty at Baylor College of Medicine, before I moved to MD Anderson 8 years ago). That trial involved combining the experimental diet with chemotherapy for patients with primary brain tumors. However, my collaborator was unable to enroll a sufficient number of patients on that trial for reasons that were never clear to me. Perhaps his colleagues did not have faith in the strategy or perhaps patients were not enthusiastic about adhering to a strict dietary regime. Over time, Abbott became less enthusiastic about supporting the methionine restriction work since they did not think dietary methionine restriction would be commercially viable. 

Coincidentally at around that time, my career interests naturally evolved. I became very interested in psychosocial aspects of oncology, and I came to appreciate the power of relationships between doctors and their patients and families. This career evolution led to my interest and involvement in teaching communication skills and writing about relational aspects of oncology. Over time, my colleagues and I at MD Anderson decided I should transition to the department of Palliative Medicine, where I now reside, after having practiced medical oncology for about 20 years.  My main academic focus is now communication skills training and narrative medicine.   I still think methionine restriction is potentially viable as cancer treatment, but I have not actually worked in the field for many years. I know that Robert Hoffman PhD at Anticancer Inc. in San Diego has developed methioninase, the methionine degrading enzyme, as cancer treatment, but I do not know where that work stands now. You may want to contact him for an update and read his recent publications.

I still believe methionine deprivation is a very promising strategy from the purely scientific standpoint if you put aside marketing and other considerations. Nonetheless, I would strongly advise against anyone with cancer pursuing a methionine restricted diet outside of a clinical trial approved by an institutional IRB, just as I would advise against anyone receiving any form of experimental therapy outside of a clinical trial.

My thoughts and prayers are with you as you battle cancer.  I hope this information is helpful.

Best Regards,
Daniel E. Epner, MD, FACP

I appreciated his thoughtful reply. He confirmed my suspicion that funding was one of the barriers to moving forward with clinical trials, but also gave me a fuller picture of some of the other factors at play.

I do wonder why the follow-up clinical trial that Dr. Epner and his collaborator attempted had to focus specifically on brain cancer rather than, say, breast cancer or all metastatic cancers for that matter. But it’s usually not productive to ruminate about the past.ryanlerch-warning-cows-roadsign-2400px Besides, Dr. Epner had given me another lead to follow: Dr. Robert Hoffman. Searching for his work led me to AntiCancer, Incorporated. This company has a patent for and sells L-Methionine-g-lyase (METase), an enzyme that degrades methionine. genious-emoji

So there’s no need to follow a complicated diet, methioninase can do the job of breaking down methionine before tumor cells have a chance to feed on it, right? If that’s the case,  where are the clinical trials? Why aren’t researchers jumping on the chance to test this potentially life-saving treatment?

I emailed the company’s COO, Charlene Cooper, to find out if any human studies with methioninase were planned. I’ll share her reply, and more about methionine degrading enzymes as a treatment option for cancer, in my next post.
Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

The Shocking Truth About Methionine: Part II

recap

In my last post, I discovered that many types of cancers have an absolute requirement for the essential amino acid methionine. When methionine is absent from petri dishes, malignant cells don’t grow and sometimes even die out completely. Normal cells in petri dishes can do ok without methionine provided they’re given homocysteine, methionine’s metabolic precursor.

That’s what happens in the lab. But how would it work in the real world? Methionine is in a lot of foods, especially animal foods. Yet becoming a Vegan wouldn’t be enough to eliminate dietary methionine –  it’s also abundant in seeds, nuts, soy, and beans. Besides, most every food has some amount of methionine, so a completely methionine-free diet isn’t feasible. And browsing through all those nutrition tables trying to approximate methionine content per typical portion was starting to drive me a bit crazy. aint nobody got time for that emoji

Still, if I could stick to an ultra-low methionine diet, would that help shrink my tumors? Is such a diet practical, or even safe? And would it be effective outside of petri dishes?

I turned to 720px-US-NLM-PubMed-Logo.svg .gov for answers. Studies testing the anticancer effects of methionine deprivation in mice looked promising. In one study, researchers injected 21 nude mice with Yoshida Sarcoma, a commonly used cancer cell line. One group of mice was fed 8.2g of methionine per kg, while the other group of mice got 0g of methionine per kg.

By day 12, all the mice with methionine in their diet were dead. In contrast, mice fed a methionine-free diet had slower tumor growth and even some regression of their tumors. At day 30, all the animals on the methionine-free diet were still alive, though the whole group died by day 38. Poor mice!

This literature is not the most fun to read. Still, survival time for one methionine-free mouse more than tripled, so they’ve gotta be onto something, right?

Researchers from the M.D. Anderson Cancer Center in Houston cast doubt upon these findings in a 1988 article; they reported that while three of the seven rodent tumor cell lines tested failed to grow in a petri dish without methionine, all 17 of the human tumor cell lines tested were able to grow in the methionine-free petri dishes. I'm over it emojiThe researchers concluded that methionine dependence is less likely to occur in human tumors than rodent tumors.

Just as I was about to dismiss the whole idea of methionine restriction, I found a study that was novel in its use of human (as opposed to rodent) breast, colon and lung tumors. Growth of these human tumors (transplanted as usual into nude mice) was significantly inhibited in the mice fed a methionine-free diet. This demonstrated that at least some types of human cancers require methionine in living (albeit all-too-briefly-living) animals. Maybe this did warrant further exploration.

Fast forward to 2016: scientists still seem stuck on using nude mice to investigate the role of methionine in cancer progression. One such study published this year focused specifically on breast cancer. Mice were injected with immortalized human breast cells and fed either a control diet consisting of 0.086% methionine or a methionine restricted diet with only 0.012% methionine. After 12 weeks, all the mice were euthanized (when will these poor little creatures catch a break?) and examined. Tumors weights in the methionine restricted mice averaged 11.4±4.0 mg compared to a 20.2±6.1 mg tumor weight average in the control mice. That’s a 55% tumor weight reduction for the methionine restricted diet vs. a standard control diet.

I’d be super excited by these results…sticker.crazyhamsterif I were a rodent injected with malignant cells (but not marked for euthanization).

More than 40 years have passed since the initial discovery at the University of California. Where were the human clinical trials? Ridic emojiI did finally dig up a small Phase I clinical trial from among all the mouse and petri dish experiments. This trial had modest objectives and only eight patients with various types of metastatic cancer.  Participants followed a methionine restricted diet for an average of approximately three months, and their plasma methionine levels fell by an average of 58%. The authors concluded that a methionine restricted diet can be safe and tolerable in adults with advanced cancer.

Not much more than that can be learned from a trial with so few participants, but I still felt underwhelmed by the results (or lack thereof). Certainly no miraculous recoveries for any of those eight patients. One patient with prostate cancer had a 25% reduction in serum prostate-specific antigen (PSA) after three months on the diet, and another patient with renal cell cancer experienced “an objective radiographic response.”

Otherwise, the trial didn’t find any notable anticancer effects from methionine restriction, not even in the patient who followed the diet for 38 weeks. Maybe a 58% drop in plasma methionine isn’t enough to cause the tumors to regress? In any case, I doubt I’d manage to be much more strict with my methionine intake than these eight trial participants.

The researchers called for more clinical trials to determine whether methionine restriction could enhance the anticancer activity of chemo and other treatments. Why couldn’t I find any of those follow-up trials?

what Happened emoji

I decided to contact one of the authors, Dr. Epner, to ask him directly why he abandoned this line of research after publishing the Phase I trial results in 2002. I’ll save Dr. Epner’s response and further adventures in methionine research for my next installment.

As for my progress in cooking turmeric dishes, I’ve been sticking with the tried and truly delicious turmeric potato salad.  I made and devoured it three more times since my last post. Maybe I’ll feel more venturesome and try a new recipe this week. Stay tuned!

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

The Shocking Truth About Methionine

I’m experimenting with my headlines – apologies if this one seems too click-baity.

Yet the headline is not misleading. In my journey down the proverbial rabbit hole of methionine research, I experienced multiple shocks.

There’s nothing inherently shocking about methionine. It’s one of the nine essential amino acids – building blocks of protein that our bodies cannot make and therefore must come from our diet. Once our digestive system breaks down the proteins that we eat into amino acids, they can be used for energy or as components in proteins that we need for normal growth and repair. Elementary stuff that I learned in Bio 101.

265px-Methionin_-_Methionine.svgCanonical form of methionine

But until a friend sent me an article from Dr. Gregor’s Medical Nutrition Blog, I had no idea that many cancer cells have a metabolic defect – an absolute dependence on methionine.

Researchers at the University of California became aware of this defect in cancer cells back in 1974. They reported that when normal and malignant cancer cells are put in a growth medium that includes methionine, only malignant cells remain in the flask after three weeks. That flask serves as the control in which the crowding out of normal cells by the malignant cells is expected.

In contrast, if the medium contains homocystine (a methionine precursor) but no methionine, the cancer cells die. After just one week, only normal cells remain in the methionine-free flask.

Amazing bitmoji

How had I never heard of this? How do I get that to happen to the cancer cells inside me?

In the article my friend had sent me, Dr. Gregor advises lowering methionine intake through a “predominantly vegan diet.” So I need to go vegan after all? What exactly would it mean to drastically decrease my intake of this one amino acid?

Sorting foods by methionine content in the National Nutrient Database for Standard Reference Release 28 shows that parmesan cheese, eggs, many different types of fish and seafood, as well as beef, lamb, pork, turkey, chicken, ostrich and antelope have the highest amounts of methionine per 100 grams (g) of each food.

Methionine Nutrient Lists 1st 25 USDA

It’s clear that high-protein animal foods are rich in methionine, but sesame flour actually has more methionine (1.66g methionine per 100g of flour) than whale meat (1.35g methionine per 100g of meat).

image by yamachem
image by yamachem

Spirulina (a form of blue-green algae), soy protein isolate and brazil nuts are also up there, with 1.15g, 1.13g and 1.12g of methionine per 100g, respectively. In comparison, chuck eye beef and a hind-shank of lamb have only 1.06g of methionine each per 100g.

Looks like restricting dietary methionine isn’t quite as simple as just following a vegan diet. It would have to be a vegan diet with quite a few additional restrictions.

Skipping to page 201 of the 200+ pages of foods ranked for methionine content by the

Methionine Nutrient Lists last pages USDA

National Nutrient Database for Standard Reference Release 28 reveals that I wouldn’t even have to be strictly vegan. I could successfully follow a virtually methionine-free diet by making duck, turkey and goose fat my staple foods. Along with various hydrogenated vegetable oils and beer.Best Buds emoji

True, many great veggies and fruits have 0.01g of methionine per 100g or less. So, all joking aside, I do believe that I’d have the discipline to follow an ultra-low methionine diet. I could give up cheese, salmon, seeds, nuts, whale and countless other foods in favor of mostly fruits and veggies. Of course, I’d need to supplement with pea protein powder, which is naturally low in methionine.pea-protein-amino-acid-profileWhile there’s still about 0.15g of methionine per serving, that’s a trade off I’d have to make to ensure I’m getting enough of all the other essential and conditionally essential amino acids.

Plus, I’d need to take vitamin B12, vitamin D3, vitamin K2, omega-3 fatty acids, zinc, calcium, iron pills and likely other nutrients that I haven’t even thought of.

The change would be costly and might leave me slightlyHangry bitmojiat times. Despite all that, it would be worth it if the drastic reduction in methionine killed all my cancer cells. But would the same thing that happened in that methionine-free flask happen in my body too? I want to believe emoji

For how long would I have to restrict methionine? Would I be risking my health by keeping methionine intake so minimal?

Surely, scientists must have answered these questions over the 40+ years since the breakthrough discovery was made at the University of California.

In my next post, I’ll dig into this 40+ years of research to uncover more shocking truths.

As for my turmeric cooking adventures, I must report that I haven’t tried making any new turmeric dishes since the last post. However, I have again successfully prepared both the turmeric potatoes and the turmeric stew that I blogged about in my previous postsSide by Side turmeric

That’s two turmeric dishes in one week! I’m especially proud of my kitchen prowess since this second week of cycle 4 on my Xeloda chemo meds has zapped my energy levels. Nothing like the promise of good food to rally me off the couch and to the stove.

 

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save

Save