Lifestyle Oncology Learning Academy: Metabolism

When treatment finishes, lifestyle is the new beginning.  This is my multi-faceted sandbox for learning and maintaining an anti-cancer lifestyle.  

I found the topic of cancer metabolism very interesting since I read 'How to Starve Cancer' (HTSC) by Jane McLelland.  Thank you to Jane for introducing me to this topic.  I think the neat thing about this theory, from my perspective, is that I can see a way to possibly mitigate my risks through supplements, diet & exercise.  This theory is evolved from the Warburg Effect1; which has more recently been revisited by Thomas N. Seyfried, Travis Christofferson and Dr. Nasha Winters & Jess Higgins Kelley.  Are all of these eminent scientists barking up the wrong tree?  It seems unlikely.  The current challenge is the tailoring for each cancer metabolic phenotype.

Mapping my Metabolic Phenotype (ER+ HER2-)

Since Jane McLelland invented a 'Metro Map' diagram to help people model their own cancer type, this complex topic is more communicable to non-specialists.  I've put the 'Metro Map' to the test against my ER+ metabolic phenotype which I found here (an excellent publication, thank you to the authors; citation in footnote2).  I appreciate the phenotype mapping is still an emerging science but I'm happy to look at the research scientists have achieved so far and 'have a go'.  There are also many other signalling pathways and growth factors mentioned in the 'HTSC' book but I'm just looking at metabolism based on the 'Metro Map' for the purpose of this experiment.  

With permission from Jane McLelland in advance, I have applied the McLelland 'Metro Map' to my metabolic phenotype (ER+).  The suggested off label drugs and/or supplements to block these fuel lines [pathways] can be found in the 'HTSC' book against the McLelland 'Metro Map' on page 319. 

So, here is my ER+ metabolic phenotype for my preventative prescription: no guarantee of it's correctness is given or implied based on this being an emerging science but this feels like excellent progress:


1. Glucose Pathways

- Glycolysis + MCT1 
- Glut 1 (Glucose Transporter 1)
- Lactate I've added this to the list as it is a key driver for glucose utilisation.  I target lactate with Magnesium supplements.   Magnesium is essential for the metabolism of Vitamin D so those Vitamin D supplements may do nothing if there is a deficiency in magnesium.  Vitamin D assists the homeostasis of Calcium and Vitamin K2 helps to transport Calcium to the bone and away from soft tissue.  (I have a history of fibroadenoma so for me this feels pretty important.)  I don't take calcium supplements as I don't want excess calcium levels, just healthy levels from plant-based foods.  (If calcium levels drop too low the bone tissue will release calcium back into the system anyway).  This publication confirms Metformin may be a therapeutic target for lactate which I have recently starting taking on the COC protocol.  This publication discusses excess calcium levels (hypercalcemia) and breast cancer.

PP Pathway (Pentose Phosphate Pathway) although this pathway is mentioned in the model I've referred to, it does not appear to be highly expressed in ER+ (Luminal A) tumours according to this publication so until I read anything to the contrary, I will not include this pathway for my phenotype.


2. Fatty Acid Pathways

- FASN/FAS (Acetyl CoA) 
- ACLY  (ATP Citrate Lyase/TCA Cycle)


3. Glutamine Pathways

- GS (Glutaminolysis)
IGF-14 (not in the ER+ phenotype diagram I've used, but I feel it is essential that IGF-1 be targeted for ER+. I've read extensively on IGF-1 and I avoid consumption of all foods which may fuel this pathway (all animal products, including dairy).



So that's a neat little experiment and now you need to purchase the book!  It's the best cancer book I've come across and I've read quite a few. 

In addition, the generic pathways which Jane suggests targeting, as a minimum, are listed on p328 of 'How to Starve Cancer'.  The list includes IGF-1 for all cancers so it is reasonable that I have added it to the list for ER+ breast cancer anyway.  In 'How to Starve Cancer' there is information on abnormal cell signalling and growth factors and treatment suggestions for blocking them, with full citation/referencing.  I have focused on the metabolism 'Metro Map' as I was stage III at diagnosis and will primarily use metabolism for  recurrence prevention with a blast at IBC for good measure, shown below.  For stage IV cancer there are additional suggestions designed to work alongside conventional treatment.  Jane is not suggesting a replacement for conventional medicine.....  'Integrated Oncology' is the aim which I am fully in favour of.

From everything I've read so far on cancer metabolism, blocking 1 and 2 above may up-regulate 3 so it's important to block all three.  The more advanced the cancer, the more it switches to 3 (glutamine) and beyond this it moves to MMPs and Macropinocytosis (this is explained nicely on p326 and p327).

Inflammatory Breast Cancer (IBC) has a relatively unknown micro-environment.  This means there is no metabolic phenotype specific to IBC as yet. 

In addition to my ER+ metabolic phenotype, I'm going to run with the following research papers in the meantime under two assumptions: 
1. IBC has metastatic5 tendencies, transitioning from epithelial to mesenchymal
2. The inflammatory nature may be an auto-immune feature similar to multiple myloma6 and rheumatoid arthritis

With these assumptions in mind I will be adding the following pathway targets for IBC.  This may be overkill but I'd rather over-prevent than under-prevent.  The list looks more daunting than it is as some of the drugs target multiple pathways and the treatments for my ER+ metabolic phenotype has already covered some of these pathways: 

TAM(p346)
MMP-2 (p346)
MMP-3 (p346)
MMP-9 (p346)
Macropinocytosis (page 337)
TGFB  (p345)
Snail1, Cadherin: Panax Ginseng
VEGF (p381)
Ras/Kras (page 378)
OXPHOS (p319 'Metro Map')
Th2/IL response (p381)
Stat3, Notch, NF-kB, Wnt/B-catenin, mTOR (p369)
mTOR (see also p319 'Metro Map')


Exercise

Within the field of metabolism, exercise is very important for reducing breast cancer recurrence risk.  Here is an extract from a recent publicationwhich suggests:
"...at least 30 minutes of moderate-intensity physical activity at least five days of the week, or 75 minutes of more vigorous exercise, along with two to three weekly strength training sessions, including exercises for major muscle groups. This recommendation has been endorsed by both the Canadian Cancer Society24 and the American Cancer Society.25 "
I know how you feel  *sigh* .....we all want to pop one magic pill instead of making a big effort, but effort is what's required here.  It does feel like a big effort at first but gradually becomes part of everyday life and you don't have to think about it once it's committed to autopilot. 

Fasting

Nightly fasting8 for more than 13 hours has been associated with reduced risk of breast cancer recurrence in vivo.

BMI

I keep my BMI below 24 as there is increasing evidence that maintaining a BMI below 24 improves recurrence risks.  Obesity9 is associated with poorer outcomes10.  The body (adipose) fat stores oestrogen so increased weight means greater oestrogen stores; especially important in ER+ breast cancer.  Before my diagnosis I was about a stone heavier, my BMI is now around 21.


References:

1 The Warburg effect:  How does it benefit Cancer Cells?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783224/

The Warburg Effect and the Hallmarks of Cancer
https://www.ncbi.nlm.nih.gov/pubmed/27804847

Elia, Ilaria & Schmieder, Roberta & Christen, Stefan & Fendt, Sarah-Maria. (2016). Organ-Specific Cancer Metabolism and Its Potential for Therapy. Handbook of experimental pharmacology. 233. 321-353. 10.1007/164_2015_10. 

Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer
https://www.hindawi.com/journals/dm/2018/9369358/

4 Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies.
https://www.ncbi.nlm.nih.gov/pubmed/20472501

Epithelial-Mesenchymal Transition Phenotype Is Associated with Clinicopathological Factors That Indicate Aggressive Biological Behavior and Poor Clinical Outcomes in Invasive Breast Cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600690/

Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells.
https://www.ncbi.nlm.nih.gov/pubmed/22824846

7 Lifestyle modifications for patients with breast cancer to improve prognosis and optimize overall health.
http://www.cmaj.ca/content/189/7/E268

Prolonged Nightly Fasting and Breast Cancer Prognosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982776/

9 Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling.
https://www.ncbi.nlm.nih.gov/pubmed/28186980

10 Triple-negative breast cancer and its association with obesity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740844/




Further reading:

Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862360/

Out of Warburg effect: An effective cancer treatment targeting the tumour specific metabolism and disregulated pH.
https://www.ncbi.nlm.nih.gov/pubmed/28122260

Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment
https://www.sciencedirect.com/science/article/pii/S2352304217300107

Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect 
https://academic.oup.com/carcin/article/38/2/119/2709442

A New inhibitor of glucose-6-phosphate dehydrogenase blocks pentose photphate pathway and suppresses malignant proliferation and metastasis in vivo:
https://www.nature.com/articles/s41419-018-0635-5

The effect of magnesium supplementation on lactate levels of sportsmen and sedanter.
https://www.ncbi.nlm.nih.gov/pubmed/17063625

Targeting Glutamine Metabolism for Cancer Treatment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746034/

Hypercalcemia in metastatic breast cancer unrelated to skeletal metastasis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786403/

Magnesium Supplementation in Vitamin D Deficiency.
https://www.ncbi.nlm.nih.gov/pubmed/28471760

Vitamin D, calcium homeostasis and aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068478/

Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566462/

Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis.
https://www.ncbi.nlm.nih.gov/pubmed/24089220

Ketones and lactate increase cancer cell “stemness”, driving recurrence, metastasis and poor clinical outcome in breast cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117136/

Achieving personalized medicine via metabolo-genomics
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117136/ 


Natural anti-clotting foods 
http://files.www.clotconnect.org/patients/resources/brochures/Natural_supplements-Brochure_May_2013.pdf

























Disclaimer:  I am not a medical professional.  I do not claim that anything which worked for me would work the same for you.  This blog is no substitute for the advice of your doctor.  Always seek medical advice if you have any concerns.  Always check with your consultant before taking any supplements.  This blog is my personal journey and a journal of how I coped.  I do not take any financial incentives from any products mentioned.

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