The document discusses cancer from the perspective of the mitochondrial metabolic theory. It proposes that cancer originates from mitochondrial dysfunction and defective respiration, rather than from genetic mutations alone. Cancer cells generate energy through substrate-level phosphorylation of glucose and glutamine without oxygen, resembling primitive prokaryotes. The document outlines a 3-level approach to cancer intervention focusing on lifestyle modifications like ketogenic diets and fasting to support mitochondrial health, supplementation, and potential drug therapies aimed at modulating cancer metabolism and inflammation.

1. Cancer as a Mitochondrial
Metabolic Disease
Tomás Duraj, M.D., Ph.D.
Dr. Seyfried laboratory
Boston College
From theory to clinical
application

2. The power
plant of the
cell?

3. Generation of energy
in eukaryotic cells:
• OXPHOS ≈ 90% ATP
(oxygen)
• Substrate-level
phosphorylation
(SLP) ≈ 10% ATP (no
oxygen)
• Photosynthesis Duraj, T et al. "Metabolic therapy and bioenergetic analysis: The missing
piece of the puzzle." Molecular metabolism 54 (2021): 101389.

4. What else is worth knowing
about the mitochondria?
Chondriome = sum of all the mitochondria in any given cell
≈ 0 differentiated erytrhocytes, 100-1000 in mature
tissues, 100.000 in mature oocytes

5. What else is worth knowing
about the mitochondria?
Chondriome = sum of all the mitochondria in any given cell
≈ 0 differentiated erytrhocytes, 100-1000 in mature
tissues, 100.000 in mature oocytes

6. What else is worth knowing
about the mitochondria?
1.5 to 2 billion years ago: oxidative alpha-
proteobacteria (OXPHOS) + hypoxic prokaryotic
precursor (SLP) = eukaryotic cell capable of
generating ATP from chemical substrate and oxygen
Lynn Margulis – 1967
Mitochondria, plastids and flagella
Chondriome = sum of all the mitochondria in any given cell
≈ 0 differentiated erytrhocytes, 100-1000 in mature
tissues, 100.000 in mature oocytes

7. Theories of carcinogenesis
Brücher, B. L., & Jamall, I. S. (2016). Cellular Physiology and Biochemistry, 38(5), 1663-1680.
Somatic mutation theory (SMT) = cancer is a genetic disease
Mutations in oncogenes and tumor
suppressor genes
• Inherited (rare)
• Spontaneous, random, bad luck
(most of cancers)
Mid XX century -> DNA structure ->
1990s Human Genome Project ->
Mistakes in the code of life = cancer
and many other diseases
DNA damage -> sometimes* cancer
phenotype (cause-consequence)
Don't want cancer? Avoid mutations.
Don't want mutations? Avoid aging.

8. Problems with the somatic mutation theory
Somatic mutation theory: infinite
complexity, ad hoc solutions, too late
Patient A
Patient B
„Exactly“ the same tumor
characteristics
Different tumor mutations
• Fiala, C., & Diamandis, E. P. (2020). Mutations in normal tissues—some diagnostic and clinical implications. BMC medicine, 18(1), 1-
9.
• Li, Ruoyan, et al. "A body map of somatic mutagenesis in morphologically normal human tissues." Nature 597.7876 (2021): 398-403.
• Lee-Six, Henry, et al. "The landscape of somatic mutation in normal colorectal epithelial cells." Nature 574.7779 (2019): 532-537.
• Sun, S., Wang, Y., Maslov, A. Y., Dong, X., & Vijg, J. (2022). SomaMutDB: a database of somatic mutations in normal human tissues.
Nucleic acids research, 50(D1), D1100-D1108.
92 new cancer therapies approved by FDA between 2000 – 2016:
absolute increase in OS was 2 months
• Nuclear-Cytoplasmic Transfer Experiments (mutations ≠ origin)
• No detectable mutations in tumor tissues
• Mutations in oncogenes/tumor suppressor genes in normal tissues

9. Seyfried et al. "Can the mitochondrial metabolic theory explain
better the origin and management of cancer than can the
somatic mutation theory?" Metabolites 11.9 (2021): 572.

10. Defective respiration: chronic
damage to mitochondrial
structure, composition,
morphology, function,
number, remodeling...
Seyfried et al. "Can the mitochondrial metabolic theory explain
better the origin and management of cancer than can the
somatic mutation theory?" Metabolites 11.9 (2021): 572.

11. Substrate-level
phosphorylation
(fermentation) of glucose
and glutamine,
regardless of the
presence of oxygen.
Evolution: prokaryotic
SLP (hypoxic)
organisms = genetic
program: unbridled
proliferation
Seyfried et al. "Can the mitochondrial metabolic theory explain
better the origin and management of cancer than can the
somatic mutation theory?" Metabolites 11.9 (2021): 572.
Chondriome: a balance
between damaged and
functional mitochondria

12. OCR ≠ ATP
Seyfried et al. "Can the mitochondrial metabolic theory explain
better the origin and management of cancer than can the
somatic mutation theory?" Metabolites 11.9 (2021): 572.
The genome is metabolically
determined.

13. Good mitochondrial health: prevention vs treatment
Adapted from Loomans-Kropp et al. (2019). Cancer prevention and screening: the next step
in the era of precision medicine. NPJ precision oncology, 3(1), 1-8.
Big picture prevention interventions:
• “Anti-inflammatory diet” – health
biomarkers are objectively favorable
(no overload of nutrient sensing, no
insulin resistance, no inflammation,
redox balance)
• Exercise (strength training and
aerobic threshold)
• Fasting (IF and long-term)
• -> HORMESIS
• Supplementation for mitochondrial
health
In the MMT,
„carcinogen“ is
mitochondrial
damage

14. Three levels of intervention
1. Learn as much as
possible about the
cancer
2. Strict lifestyle
interventions
3. Pharmacology
Individual, patient-level Medical guidance
Metabolic therapy in cancer

15. Three levels of intervention
1. Learn as much as possible about
the cancer
• Absolute knowledge about
what to expect from SOC
(surgery, chemo/radio
protocols, targeted,
immunotherapy) – gold
standard, efficacy well
known – read the studies
• Anatomical and metabolic
imaging (18FDG-PET, novel
glutamine tracers)
• Tumor biomarkers
• Biopsy – when justified
• Genetic screening
• Systematic evaluation of
response
• General bloodwork prior
and during treatment (liver,
kidney function)
2. Strict lifestyle interventions 3. Pharmacology
Individual, patient-level Medical guidance

16. Three levels of intervention
1. Learn as much as possible about
the cancer
• Absolute knowledge about
what to expect from SOC
(surgery, chemo/radio
protocols, targeted,
immunotherapy) – gold
standard, efficacy well
known – read the studies
• Anatomical and metabolic
imaging (18FDG-PET, novel
glutamine tracers)
• Tumor biomarkers
• Biopsy – when justified
• Genetic screening
• Systematic evaluation of
response
• General bloodwork prior
and during treatment (liver,
kidney function)
2. Strict lifestyle interventions
• Ketogenic diet (for cancer*)
• Prolonged fasting (e.g., 5-7
days or more, depending on
weight)
• Exercise (muscle mass
maintenance)
• Advanced
supplementation: cancer
metabolism inflammation,
angiogenesis, immune
system, autophagy, redox
balance.
• Enhance mitochondrial
health in normal cells.
• Synergistic opportunities
with SOC (low-grade or
advanced cancers)
3. Pharmacology
Individual, patient-level Medical guidance

17. Three levels of intervention
1. Learn as much as possible about
the cancer
• Absolute knowledge about
what to expect from SOC
(surgery, chemo/radio
protocols, targeted,
immunotherapy) – gold
standard, efficacy well
known – read the studies
• Anatomical and metabolic
imaging (18FDG-PET, novel
glutamine tracers)
• Tumor biomarkers
• Biopsy – when justified
• Genetic screening
• Systematic evaluation of
response
• General bloodwork prior
and during treatment (liver,
kidney function)
2. Strict lifestyle interventions
• Ketogenic diet (for cancer*)
• Prolonged fasting (e.g., 5-7
days or more, depending on
weight)
• Exercise (muscle mass
maintenance)
• Advanced supplementation:
cancer metabolism,
inflammation, angiogenesis,
immune system, autophagy,
redox balance.
• Enhance mitochondrial
health in normal cells.
• Synergistic opportunities
with SOC (low-grade or
advanced cancers)
3. Pharmacology
• Repurposed drugs and
novel agents in clinical
trials
• Metabolism
• Inflammation
• Angiogenesis
• Autophagy
• Immune system
• Redox balance
• Complementary systemic
or local therapies:
• HBOT
• O3
• ROS balance
• Hyperthermia
• Others (do they make
biological sense?)
Individual, patient-level Medical guidance

18. Ketogenic metabolic
therapy (KMT) – a
special form of the KD
• CR-KD and fasting as a first-
order approximation
• Diet composition is
“inconsequential” – it must
achieve specific measurable
parameters – insulin, glucose,
BHB levels, inflammation,
reduced tumor growth,
reduced tumor biomarkers.
• Sine qua non for all
subsequent metabolic
treatments and even SOC
Winter et al. (2017). Role of ketogenic metabolic therapy in malignant glioma:
a systematic review. Critical reviews in oncology/hematology, 112, 41-58.

19. Glucose/ketone index (GKI): easy to measure... But what is the optimal number?
8mM glucose – 8mM BHB
GKI = 1 (low carb + ketone esters)
5mM glucose – 5 mM BHB
GKI = 1 (ad lib KD)
3mM glucose – 3 mM BHB
GKI = 1 (CR-KD + fasting)
2mM glucose – 5mM BHB
GKI = 0.5 (fasting + supplements)
Meidenbauer, J. J., Mukherjee, P., & Seyfried, T. N. (2015). The glucose ketone index calculator: a simple tool to
monitor therapeutic efficacy for metabolic management of brain cancer. Nutrition & metabolism, 12(1), 1-7.
SOC: corticosteroids,
chemoradiotherapy,
stress, lack of sleep...
Lower* – fasting, supplementation,
pharmacology.
Is it necessary? How aggressive is the
tumor?
CR-KD/fasting allows for stable
levels.

20. Supplementation
• Endless list of supplements:
Berberine, HCA, Melatonin, EPA/DHA, Vitamin D3, Quercetin, Fisetin, Luteolin,
Boswellia, Vitamin C, Curcumin, Ashwaganda, Rhodiola, ALA, Se-methylselenocysteine,
Genistein, Astragalus, CoQ10, Silybum, Resveratrol, Vitamin A, Sulphorafane, Apigenin,
Artemisinin, Gingerols, Echinacea, Polypodium leucotomos, Ganoderma lucidum,
Lentinula edodes AHCC, Andrographis paniculata, Eleutherococcus senticosus,
Tinospora cordifolia, Pelargonium sidoides, NAC, Garlic extract, Gamma E Tocotrienol,
Honokiol, Agaricus blazei, Artemisin, Thymoquinone...
• Nutrition + supplementation -> target cancer and optimize mitochondrial health in
normal cells (also, limit SOC toxicity)
• Personalize each case:
E.g., 14 day fasting + CR-KD + 20 supplements for low-grade cancer after surgery
vs.
ad lib unrestricted KD (high GKI) + few general supplements for metastatic cancer

21. What about
glutamine
• Non-essential amino acid (conditionally essential)
• Concentrations 0.6 mM serum (less than glucose at ≈ 5
mM), 6 mM cytoplasm, up to 15-50 mM mitochondria
• Glutamine: biosynthesis / ATP (mSLP)
• Cannot be “eliminated” from diet (there is no amino acid
restriction for glutamine)
• Glutamine inhibitors: supplements and pharmacology
• EGCG, hesperedin, urosolic acid, caffeic acid,
curcumin, pterostilbene, apigenin, luteolin, HCA
(supplements have low potency)
• DON, JHU-083, phenylbutyrate, CB-839, BPTES,
GPNA, AOAA, L-asparaginase, V-9302, indirectly by
tamoxifen/raloxifene, etc.
• Clinical trials in monotherapy: what to expect?
Mukherjee et al. (2019). Therapeutic benefit of combining calorie-restricted
ketogenic diet and glutamine targeting in late-stage experimental
glioblastoma. Communications biology, 2(1), 1-14.

22. 3rd level: Pharmacological and systemic therapies
• Guided by results of the first 2 levels. SOC (or if we know it will not work) and level 2: are
tumor biomarkers and size decreasing? Prevention of high-rates of recurrence?
Seek active clinical trials:
monotherapy or multi-
layered approach?

23. 3rd level: Pharmacological and systemic therapies
• Guided by results of the first 2 levels. SOC and level 2: are tumor biomarkers and size
decreasing?
• Evidence based targeting of metabolism (repurposed and novel drugs)
• Metabolism: MBZ, DCA, DON, CB-839 and other glutamine inhibitors, phenylbutyrate, metformin (GKI),
lonidamine, leflunomide, 2-DG, CPI-613, statins, disulfiram, L-asparaginase, CPI-613, AZD3965, TVB-2640,
ADI-PEG 20, etc.
• Other processes: diclofenac, celecoxib, etodolac, doxycycline, ciprofloxacin, rapamycin, itraconazole,
indomethacin, spironolactone, niclosamide, ritonavir, quinacrine, hydroxychloroquine and other
autophagy inhibitors, thiomolybdic acid, etc.
• Examples: CUSP9v3 (Germany) or COC Protocol (UK)
Seek active clinical trials:
monotherapy or multi-
layered approach?

24. Third level: Systemic
therapies
• HBOT
• Ozone therapy
• IV vitamin C (+ curcumin + DCA + HBOT -> ROS)
• Hyperthermia (seems to combine well with SOC)
• Others (are the biological mechanisms sound?)

25. Controversy, skepticism, personal freedom
• Should metabolic therapy be adjuvant or the standard therapy?
• The patient has the ultimate decision power. “Burden of responsibility”. Development of protocols:
each case needs to be individualized.

26. Controversy, skepticism, personal freedom
• Should metabolic therapy be adjuvant or the standard therapy?
• The patient has the ultimate decision power. “Burden of responsibility”. Development of protocols: each
case needs to be individualized.
• Level 1: What can we expect from the gold standard? Are we offered the maximum or the minimum
established in clinical guidelines?
• If SOC is expected to succeed, level 2 might be sufficient.
• If SOC is expected to fail, level 2 and 3 and go down the evidence pyramid: pilot human studies, case
reports, animal studies, molecular mechanisms. Guidance from knowledgeable physician. If not available,
self-education.

27. Controversy, skepticism, personal freedom
• Should metabolic therapy be adjuvant or the standard therapy?
• The patient has the ultimate decision power. “Burden of responsibility”. Development of protocols: each
case needs to be individualized.
• Level 1: What can we expect from the gold standard? Are we offered the maximum or the minimum
established in clinical guidelines?
• If SOC is expected to succeed, level 2 might be sufficient.
• If SOC is expected to fail, level 2 and 3 and go down the evidence pyramid: pilot human studies, case
reports, animal studies, molecular mechanisms. Guidance from knowledgeable physician. If not available,
self-education.
• Skepticism and frustration from oncologists is understandable, refusal to sit down and study the scientific
literature is not. A lot of time must be destined for each patient. What is being offered as an alternative?
• Metabolic therapy -> part of the standard oncology toolbox.

28. Thank you!
Tomás Duraj, M.D., Ph.D.
Dr. Seyfried laboratory
Boston College