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.

From The Darkest Place Comes Empowerment

Still trying to wrap my mind around glutamine vs glutamate. Boy, I didn't realize how easy I had it back in the days of the macronutrients of the restricted ketogenic diet. Thankfully, Stephen sent me a quick summation a few moments ago saving me from my dark rabbit hole of searching, "Glutamine is an amino acid that circulates in the blood at high levels, and glutamate is derived from glutamine by one enzymatic step. See the attached diagram. The cell can take in either glutamine or glutamate. Glutamine can be converted to glutamate, glutamate is converted to alpha-ketoglutarate, and the IDH1/IDH2 mutant enzyme converts alpha-ketoglutarate into 2-HG, which accumulates to high levels and causes tumorigenesis. IDH-non mutated lower grade tumours might have different metabolic needs."

Do I understand it now? Kind of. I think I'll need to keep reading it and rereading it in order to cement things. So glutamate is not in foods, but glutamine is. In the body glutamine can convert into glutamate which converts into that alpha thingy and my IDH1 mutated tumor will change that alpha thingy into 2-HG which causes the tumor to generate more tumor cells. Bad. Okay. Next step, I need to memorize that alpha hyphenated word (shouldn't be too hard since it starts with keto and glutarate is pretty similar to glutamate just switch the m to an r...I think I'm onto something) and intimately understand what 2-HG is/does so that I can recognize them in research. (What about 2-HighGlutarate? Okay, just Googled, and instead of high, I'll use the legit term of hydroxy and slam glutarate (which was a good guess) on the end, which makes sense. Bam. Not too bad.) Is your brain spinning, too? That was very successful. I feel a little accomplished, as if I just traversed my own mental wormhole.

Now this is where pathology becomes paramount. If you're wanting to dabble in preventing your tumor from growing, you need to know what you're working with. Every single tumor's pathology is unique, which makes it difficult. However most all tumors are on the spectrum for various categories regarding mutations (yes/no), proliferation rates (%), GFAP (also a % I believe), etc. In rare cases, they may not even be that similar to other brain tumors, instead they may be more similar to a breast tumor or pancreatic tumor (just throwing those out there). You never know. We need to look outside the box for our treatments learning from like-pathology correlations. We really don't have much to lose since standard of care is essentially failing most of us. I remember when I looked into my pathology for the first time, it was terrifying. It was depressing. It was the darkest place I had ever looked. But I pushed on because I wanted answers. I don't want to waste my time, my energy, my resources, on things that will not aid in my survival. Reading the pathology from the second brain tumor was equally scary, but I'd grown tougher skin. As they do, things had changed. The proliferation rate was higher, among other things, which of course is sobering, but it doesn't mean that you give up - panic a little but never give up. I'm learning more than ever, and constantly feel like I can almost touch a cure, or at least stability. Guess we'll know more on that front in a few weeks. I can't believe the MRI is in ten days.

Here's a link to the AO page that discusses the glutamine quandary, I forgot to include it in the last post. Don't forget, it seems specific to IDH mutations, not wild-type.

Lifting By The Roots

Alright, I've been thinking since yesterday's post, that life IS better with hair. (Maybe not easier, but definitely better.) Long hair. Hair I would want. Not hair I settle for, not odd lengths, and weird styles trying to disguise my infinite scar. Real hair with a style that makes me feel like the person facing me in the mirror looks me in the eyes, and smiles. She's been smiling at me for years, my whole life in fact, but since 2010 her smiles were more of sadness, of tender concern. They were never complimentary smiles, not confidence building. I would lower my gaze and walk away, loving her, but knowing I needed a break from the friendship. Her gaze was too hurtful, too knowing. So I pulled away from her, turned my back. These days, though, I peek out at her as I walk by windows, and I know she sees me. I know she knows I'm sorry. Thankfully, she is forgiving, and we rebuild our relationship glance by glance, nod by nod, smile by smile.

Our baby cucumbers are beginning to hatch. This is the first successful attempt at starting seeds in eggshells. I'm embarrassed to tell you that the first batch from a few weeks ago was a disaster - I failed to rinse the eggshells before adding the soil. Within three-ish days there was quite the funk wafting around the house. I had no idea what was causing it, so I wandered around sniffing, and the closer I got to my baby seedlings the stronger the stench. I had to throw the whole thing into our compost. Oopsie. Rinsing the eggshells is a crucial step, good to know. Guaranteed I will never again forget to rinse the eggshells. Never.

In the spirit of green things, and vegetables, I need to share with you a major advance in tumor diet differentiation. What I mean is that there are very different needs between brain tumor groups. For example, tumors that take up contrast on MRI scans (usually stage III & IV) are using mainly glucose as food. For people like me, low grade tumors, according to newer research, our tumors mainly feed on glutamate. This is a big deal. Most research about diet is with high grades, so a lot of lower grade tumor fighters copy that research hoping it will also apply to them. (For example, the restricted ketogenic diet.) But that seems to be very misguided. Glutamate is an amino acid found in all protein containing foods (including grains). As you can see, the restricted ketogenic diet which focuses on heavy amounts of fat (often derived from dairy and/or coconut oil), moderate protein (limiting glutamate), and low/no carbohydrate (restricting glucose), could be the wrong choice for those with low grade tumors. Or is it? I don't know. I'm in the process of trying to figure out how to modify my diet and lifestyle to be healthy and happy, and not provide excess food to Herman, but it's confusing. I now have to read up on the difference between glutamate, glutamine, and the foods that can convert into them; how they convert; what foods are safe. It's a whole new avenue. A good side note is that I shouldn't feel guilty about my love affair with vegetables - they seem to look safe. Or are they? I don't know. It is going to be a serious switch. I already feel very divided, torn, confused. It's hard to oscillate so quickly, and deviate so far from what you considered a lifestyle. Carbs were bad. Carbs were feeding Herman. Now it's the protein. Eeek. It's as if I'm jumping religions; Bhuddism, Christianity, etc. These diets become my belief system on food, on nourishment, on survival. Changing it spins your world, lifting you by the roots. I feel like a little plant in a terrible wind. Will it ever subside? Will I ever find a safe nook to just grow?

Obviously, research is constantly advancing. At the same time we find old research that tells part of the story, then we piece things together, and it never ends. Each time we think we have a stable, solid plan, we find more information, giving us new directions to explore. You can't take much time off of tumor fighting, you'd miss too much. You have to be out there, reading, putting two and two together, connecting the dots. I know I'm constantly referring to my friend Stephen (Astrocytoma Options), but I'm telling you he is an invaluable resource. He always takes the time to answer my questions, he directs me to new research, he is a northern star keeping on course. Recently, he added a spot on the AO website where you can submit your email for notifications and new links every time he adds updates to the website. It's fantastic! It's perfect for brain tumor fighters, we're notorious for being forgetful, or accidentally never following up. We have the best intentions, but we have literal variations of brain damage (depending on the individual). That's how doctors classify us. Brain damaged. It sounds crazy when I say that out loud, but it's true. If you're fighting a brain tumor, or perhaps you're researching for a loved one, you will love the updates. It's like having a specialist in your pocket. Research doesn't get much better than that. Just so you know, since I'm a walking, talking advertisement for AO, I want to stress that it's all my voice, my words, my thoughts. Stephen never knows when I post about him until after the fact. If anything, he's incredibly modest and maybe even embarrassed about how I go on and on about him, but I get so excited to share with you guys. He's such a valuable resource, and I want to spread the word so that you can benefit from his hard work.