Blinded By The Fashionable Ketones

I've been swimming in the interweb waves all day. I'm gathering, learning, relearning, trying to absorb, planning.

Things I know:

• You can not completely eliminate glutamate/glutamine from your diet...it's in every once living thing (except lard & most oils)
• Your body can create glutamine/glutamate when it wants it (thanks muscles and other less obvious trickery)
• You can eliminate glucose from your diet, but your body will just create it anyway (muscles save the day yet again)
• Limiting glucose and glutamine/glutamate is ideal for slowing tumor growth, but when hungry, a vegetable which may increase circulating glucose is better than eating a bit of meat (only because I'm IDH1 positive - the glutamine eater)

See, I knew, I had heard, I had read, I had discussed the fact that protein is a growth factor for all cancer. But I got bogged down with the whole ketogenic trend specific to brain tumors. I thought, perhaps we were bred differently. That we were special. That ketones were the key. I'm not saying the ketogenic diet doesn't help slow brain tumors, but from the research I've read it has to be calorically restricted. In its natural state the diet does not slow tumor growth (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819381/figure/F2). But in my mind, I figured, if I could do the restricted ketogenic diet (allegedly the ketones themselves fight tumor cells if you get a high enough blood serum level) at least most of the time, it would be better to reduce the glucose, and protein (not realizing it was specifically glutamine/glutamate I needed to focus on) with the RKD than be a vegetarian or even do Paleo. The problem continuously surfaced, though, that I would putter out of energy. And when that happened, instead of reaching for a vegetable (carbs kick you out of ketosis) I would reach for protein like peanut butter or a hard boiled egg. Exactly the wrong snacks for low grade IDH mutant brain tumors. I was essentially handing Herman a big ole glob of glutamine.

It's crazy, I remember a phone call with my nutritionist where she emphasized that my green smoothies (which are all vegetable save an avocado & lemon) turn directly into sugar in my body; that without protein with each meal and snack, I was killing myself. Not her words, but still. She was emphatic about the huge sugar spike that would surge through my veins, therefore feeding the tumor. IE: Killing myself. Same same. It put the fear of Hermie in me, driving home the whole protein must be included to survive mantra. Remember all the times I've written about feeling guilty about my apples? That was because of my nutritionist. As was my deviation from my green smoothies. It leaves you feeling crazy. Who's right? What do I do? Am I just supposed to pick the lesser of two evils? Glucose spike over protein consumption? Girl still gotta eat.

Things I know:

• Known unbiased tumor fighter = caloric restriction (click for a great study on the benefits). It doesn't seem to matter if you eat the calories from protein, fat, or carb, just be sure to take your BMR and cut it by 30% (some say 20% others 40%). That's the surefire way to hypnotize the giant. It won't stop him, but it'll sedate him, and maybe during that time we'll find just the right cocktail to kill him. It's also the thing I always forget. Or maybe I just don't want to deprive myself so I black it out from time to time. :)
• Healthy fats like omega-3's (fish oil) continue to be a great way to supplement my diet. One of the least burdensome of the food groups, in regard to the glucose/glutamine issue. However, not that palatable as a snack. Just sayin'.

Reviewing over my notes, it's clear about the caloric restriction, but I'm also wondering if perhaps soduim phenylbutyrate & metformin could really work together, like hit it out of the park, for IDH mutant tumors (along with all my other goodies, of course - my newest motto is never take away, only add). I know I repeat myself a lot, but it takes a lot of hammering things into my brain, and even then details and concepts, the most obvious of stuff, often slips away. I wish I could just blame it on the tumor, but I think the more you use your brain the more you have to make space. Happens to all of us.

Am I more scared about this MRI than usual? Maybe. It's the turning point that we hit and had tumor growth after the first brain surgery, so technically, this is when Herman should show back up. Not to mention the fact that the proliferation rate of this tumor was faster than the first. If they see tumor I won't be surprised, only disappointed. If they don't see tumor I will consider it a miracle. It's not that I'm pessimistic necessarily, I just don't take this no-visible-tumor stuff for granted. I don't assume that all of these treatments "have" to work. There have been so many that have gone before me that have given everything they had, and still, it wasn't enough, they were taken. I know that life is a gift, and although I'm scared, more than scared actually, with every exhale of breath I remind myself that I just enjoyed a luxury.

Time for lunch...

Flubbed The Obvious

I had an obnoxiously long blog post full of crazy information and charts, and things about glutamine - I had been working on it all day - then my mind was blown with a shattering epiphany, things started piecing together. If low grade tumors feed mostly off of glutamine/glutamate, then what's the story with glucose? So I talked it out with Dan and as we both started searching online (boy do we have some sexy phone dates) we finally started asking the right questions. What is in my special F-DOPA PET scan that I fly down to UCLA for? I felt like a moron, how had I never wondered that? If they weren't measuring glucose, which they clearly stated, what were they measuring? We typed it in and bam, if I'm understanding this correctly, the F-DOPA PET is essentially measuring an amino acid on the glutamine-glutamate pathway (click for a study).

How did I not ask that? How did I not figure it out? I remember being completely distracted by the fact that they were using radioactive particles. I guess that's where my mind went. It never occurred to me to wonder what was being mixed with those particles. I remember talking to my doctors after the surgery, in the neruosurgery ICU, about the idea of me going on the restricted keto to slow tumor growth. They thought it was great. How did it not come up that glutamine is the food source for my type of tumor, not glucose? Had they not pieced that together either? It seems as if they would have, yet, clearly they didn't or I think they would have said something. It's the whole point of this latest fancy scan, this exclusive machine that's only available at a few centers across the country, to measure the glutamine-ish stuff going on in my low grade tumor. How are the fragments of knowledge scattered so far apart throughout the tumor world that it's this hard for tumor patients to piece it together? What's going on? Oh, I feel sick. We really do have to figure stuff out on our own. Thank God I give a fart. At least now I can adjust. If I would have stayed on the Paleo diet it would have sped up tumor growth. The way that I have been eating has been full speed down the pro-amino acid freeway. No stoplights. And according to what I'm reading, the more glutamine in your system, the faster your tumor shifts into using glucose as fuel. It's a catalyst. Hello faster growing tumor. Hello death. I am literally glaring at an imagined Grim Reaper right now. I just told him I'm not ready, and if he comes near me he's going to regret it. Scythe or no scythe, this girl is scrappy.

Here's a scary, but necessary read about glutamine (for the record, I have shifted from Coldplay to straight up Enya's greatist hits - in dire need of some uplifting):

 

Glutamine promotes hallmarks of malignancy (click for full article)

Deregulated energetics. One hallmark of cancer cells is aberrant bioenergetics (26). Glutamine’s involvement in the pathways outlined above contributes to a phenotype conducive to energy formation, survival, and growth. In addition to its role in mitochondrial metabolism, glutamine also suppresses expression of thioredoxin-interacting protein, a negative regulator of glucose uptake (27). Thus, glutamine contributes to both of the energy-forming pathways in cancer cells: oxidative phosphorylation and glycolysis. Glutamine also modulates hallmarks not traditionally thought to be metabolic, as outlined below. These interactions highlight the complex interplay between glutamine metabolism and many aspects of cell biology.

Sustaining proliferative signaling. Pathological cancer cell growth relies on maintenance of proliferative signaling pathways with increased autonomy relative to non-malignant cells. Several lines of evidence argue that glutamine reinforces activity of these pathways. In some cancer cells, excess glutamine is exported in exchange for leucine and other essential amino acids. This exchange facilitates activation of the serine/threonine kinase mTOR, a major positive regulator of cell growth (28). In addition, glutamine-derived nitrogen is a component of amino sugars, known as hexosamines, that are used to glycosylate growth factor receptors and promote their localization to the cell surface. Disruption of hexosamine synthesis reduces the ability to initiate signaling pathways downstream of growth factors (29).

Enabling replicative immortality. Some aspects of glutamine metabolism oppose senescence and promote replicative immortality in cultured cells. In IMR90 lung fibroblasts, silencing either of two NADPH-generating isoforms of malic enzyme (ME1, ME2) rapidly induced senescence, while malic enzyme overexpression suppressed senescence (30). Both malic enzyme isoforms are repressed at the transcriptional level by p53 and contribute to enhanced levels of glutamine consumption and NADPH production in p53-deficient cells. The ability of p53-replete cells to resist senescence required the expression of ME1 and ME2, and silencing either enzyme reduced the growth of TP53^+/+ and, to a lesser degree, TP53^–/– tumors (30). These observations position malic enzymes as potential therapeutic targets.

Resisting cell death. Although many cancer cells require glutamine for survival, cells with enhanced expression of Myc oncoproteins are particularly sensitive to glutamine deprivation (8, 12, 16). In these cells, glutamine deprivation induces depletion of TCA cycle intermediates, depression of ATP levels, delayed growth, diminished glutathione pools, and apoptosis. Myc drives glutamine uptake and catabolism by activating the expression of genes involved in glutamine metabolism, including GLS and SLC1A5, which encodes the Na⁺-dependent amino acid transporter ASCT2 (12, 16). Silencing GLS mimicked some of the effects of glutamine deprivation, including growth suppression in Myc-expressing cells and tumors (10, 12). MYCN amplification occurs in 20%–25% of neuroblastomas and is correlated with poor outcome (31). In cells with high N-Myc levels, glutamine deprivation triggered an ATF4-dependent induction of apoptosis that could be prevented by restoring downstream metabolites oxaloacetate and α-ketoglutarate (15). In this model, pharmacological activation of ATF4, inhibition of glutamine metabolic enzymes, or combinations of these treatments mimicked the effects of glutamine deprivation in cells and suppressed growth of MYCN-amplified subcutaneous and transgenic tumors in mice.

The PKC isoform PKC-ζ also regulates glutamine metabolism. Loss of PKC-ζ enhances glutamine utilization and enables cells to survive glucose deprivation (32). This effect requires flux of carbon and nitrogen from glutamine into serine. PKC-ζ reduces the expression of phosphoglycerate dehydrogenase, an enzyme required for glutamine-dependent serine biosynthesis, and also phosphorylates and inactivates this enzyme. Thus, PKC-ζ loss, which promotes intestinal
tumorigenesis in mice, enables cells to alter glutamine metabolism in response to nutrient stress.

Invasion and metastasis. Loss of the epithelial cell-cell adhesion molecule E-cadherin is a component of the epithelial-mesenchymal transition, and is sufficient to induce migration, invasion, and tumor progression (33, 34). Addiction to glutamine may oppose this process because glutamine favors stabilization of tight junctions in some cells (35). Furthermore, the selection of breast cancer cells with the ability to grow without glutamine yielded highly adaptable subpopulations with enhanced mesenchymal marker expression and improved capacity for anchorage-independent growth, therapeutic resistance, and metastasis in vivo (36). It is unknown whether this result reflects a primary role for glutamine in suppressing these markers of aggressiveness in breast cancer, or whether prolonged glutamine deprivation selects for cells with enhanced fitness across a number of phenotypes.

I am mortified and kicking myself that this fell through my fingers. There is en masse of information out there about what to do, what to eat, how to survive cancer, and the hard part is that much of it contradicts. You never know which boat to jump on, but one thing is for certain you'll never survive long if you are stuck treading water. But how did I not follow the tracks? The obviousness of the F-DOPA; the uptake of an unknown substance that was allowing my tumor to glow on this special scan. How did I not think to ask what caused the illumination? I feel like a fool. It saddens me that I've spent a year and a half headed in the wrong direction, eating almost exactly what I shouldn't have. The nauseating irony. All this falls right before my MRI. I have spent the last four months eating glutamine rich foods, just nurturing old Hermie, pampering him. I've already called my doctor to get the ball rolling on adding sodium phenylbytrate (a plasma glutamine lowering drug) at my June 25th appointment - gotta sign some legal documents since it's off label. The crazy thing is that my team of nutritionists who specialize specifically in brain cancer patients were emphatic about me having protein with every meal, and snack, to keep blood glucose stable. The peanut butter was pushed to join in with the apple. But now I know, from checking the levels, peanut butter has a crazy high volume of glutamine. It looks like I would have been better off with just my original apple. How crazy is that!? It's so confusing.

I gotta go decompress. Time restart Enya's greatest hits or something. And maybe munch on one of those juicily tart apples.

Cool thing of the day: Earlier I got an email from Julene, a very sweet blog reader. We had never met, but she offered to drop off a care package to help me survive until Dan arrives (saving me from resorting to my mom's granola bars - definitely not on the new diet).

It was just what I needed. I met a new friend, I stole a few much needed hugs from her, and little did I know that vegetables were going to be paramount in my new diet. And apples have one of the lowest concentrations of glutamine in foods. Why wasn't I listening to my gut!?!? You guys know I love apples. Ugh. FOOL.