Dr Thomas Seyfried Boston College Auteur du livre "Cancer as a metabolic disease"

1. Cancer: A Metabolic Disease with Metabolic
Solutions
Thomas N. Seyfried
Boston College

2. Is the “War on Cancer”going well?
Data from American Cancer Society

3. Is cancer a nuclear
genetic disease or a
mitochondrial metabolic
disease?
Provocative Question

4. Current Dogma:
Cancer is a Genetic Disease
Cancer cells are the foundation of the disease; they
initiate tumors and drive tumor progression forward,
carrying the oncogenic and tumor suppressor mutations
that define cancer as a “Genetic Disease”.
Cell 144, March 4, 2011

5. Evidence that challenges the
somatic mutation theory of cancer

6. Darlington, Brit. J. Cancer, 1948
“There can be no doubt that the cancer determinants arise as
mutant particles in the cytoplasm--that is, as plasmagenes.”
Findings are incompatible with the somatic
mutation theory of cancer

7. Tadpole cloned from nucleus
of frog
renal cell tumor
McKinnell et al Science 1969
Findings are incompatible
with the somatic mutation
theory of cancer

8. The capacity of embryonal carcinoma cells to form normally functioning adult
tissues demonstrates that conversion to neoplasia does not involve structural
changes in the nuclear genome.
Findings are incompatible with the somatic mutation
theory of cancer

9. Findings are
incompatible with the
somatic mutation
theory of cancer.
“Although medulloblastoma-
derived embryos aborted,
none exhibited uncontrolled
proliferation resembling
tumorigenesis”.

10. The presence of trisomy 8 and trisomy 11 in
embryonic mice cloned from a tumor
cell nucleus provide unequivocal genomic
evidence that the R545-1 NT ES cell was cloned
from a tumorigenic nucleus of the R545
tumor cell line.
Genes Dev. 2004 18: 1875-1885
Findings are incompatible
with the somatic mutation
theory of cancer

11. Role of the nucleus and mitochondria
in the origin of tumors
Seyfried, Cancer as a Metabolic Disease, 2012 John Wiley Press; Seyfried et al., 2014, Carcinogenesis

12. Microarray analysis showed that several oncogenic pathways observed
in cybrids with cancer mitochondria are inhibited in cybrids with
non-cancerous mitochondria.
Findings are incompatible with the somatic mutation
theory of cancer

13. If somatic mutations are not the origin of
cancer, then how do cancer cells arise?

14. Warburg Theory of Cancer
1. Cancer arises from damage to cellular
respiration.
2. Energy through fermentation gradually
compensates for insufficient respiration.
3. Cancer cells continue to ferment lactate in the
presence of oxygen (Warburg effect).
4. Enhanced fermentation is the signature
metabolic malady of all cancer cells.
Otto Warburg (Science, 24 February,1956)

15. Cellular Energy Metabolism
Glucose Glutamine

16. Mitochondrial Morphology
Arismendi-Morillo Int J Biochem Cell Biol 41, 2062-68, 2009
cristolysis

17. Cancer as a Mitochondrial Metabolic Disease
Seyfried, Cancer as a Metabolic Disease, 2012 John Wiley Press; Seyfried et al., 2014, Carcinogenesis

18. If all cancers are a type of mitochondrial
metabolic disease, then what therapies
might be effective for managing tumors?

19. Calorie Restriction (CR): A Metabolic Cancer
Intervention
• Involves a total dietary restriction
• Differs from starvation
• Maintains minerals and nutrients
• Enhances mitochondrial biogenesis & OxPhos
• CR in mice mimics water-only therapeutic
fasting in humans

20. β-Hydroxybutyrate
(β-OHB)
AcetoneAcetoacetate
2. Elevated Blood Ketone Bodies
Biomarkers for Calorie Restriction
1. Reduced Blood Glucose

21. bnormal Energy Metabolism in Brain Tumor
X
X
Seyfried and Mukherjee, 2005, Nutrition & Metabolism

22. Calorie restriction reduces intracerebral growth
of the CT-2A astrocytoma
AL CR
40% CR initiated 3 days post-inoculation

23. 1. Anti-angiogenic
Mukherjee et al., Clin. Cancer Res., 2004
2.Anti-inflammatory
Mulrooney et al., PLOS One, 2011
3.Pro-apoptotic
Mukherjee et al., Brit. J. Cancer 2002
Anti-Tumor Effects of
Calorie Restriction

24. AL
CR
CR is anti-angiogenic in the CT-2A astrocytoma
Mukherjee et al, BJC
0
10
20
30
AL CR
Vessels/hpf
*
200 x
Factor VIII microvessels

25. CR is pro-apoptotic in the CT-2A astrocytoma
AL
CR 0
2.5
5
7.5
10
12.5
AL CR
ApoptoticIndex(%)
Mukherjee et al, BJC
*
400 x
*
TUNEL Staining

26. AL CR
Nuclear p-NF-κB (p65) (S-536)
Nuclear Histone H2B
AL
RelativeNuclearp-NF-κB
expression
CR
0.0
0.5
1.0
1.5
*
Calorie restriction targets NF-κB-mediated
inflammation
Mulrooney et al., PLoS One (2011)
CT-2A astrocytoma

27. Glucose (mmol/L)
0
0.5
1
1.5
2
2.5
3
0 5 10 15 20
r2 = 0.598
0
50
100
150
0 5 10 15 20
r2 = 0.643
ß-OHB(mmol/L)
Tumorweight(mg)
Glucose (mmol/L)
Plasma glucose predicts ketone body levels and
CT-2A tumor growth
Seyfried et al, Brit. J. Cancer, 2003

28. Glucose (mmol/L)
IGF-1(ng/ml)
Plasma glucose predicts serum IGF-1 levels
in tumor-bearing mice
Seyfried et al, Brit. J. Cancer, 2003

29. Can CR influence invasion in the VM
mouse model of GBM?
Research Question

30. H
TT
H
AL CR
250 µm 250 µm
CR reduces the invasive growth of the
VM-M3 mouse model of GBM
T, Tumor
H, Hippocampus
Shelton et al., ASNNeuro, 2010

31. Can a restricted ketogenic diet manage
brain cancer in mice?
Research Question

32. Composition (%) of the standard diet
(SD) and the ketogenic diet (KD)
* The ketogenic diet should always be consumed in restricted amounts!

33. The KD-R Reduces Intracerebral Growth of
Mouse and Human Brain Tumors
0
20
40
60
80
100
120
140
1
Wetweight(mg)
SD-UR KD-UR KD-R
CT-2A
*
0
10
20
30
40
50
60
70
80
1
Wetweight(mg)
*
SD-UR KD-UR KD-R
U87-MG
*
n = 11-14 mice/group * P < 0.01
Mouse Brain Tumor Growth Human Brain Tumor Growth
Zhou et al., Nut & Met, 2007

34. Influence of the KD-R on Plasma Glucose
and β-OHB Levels in CT-2A Tumor-Bearing
Mice
Blood
Glucose
Blood β-OHB
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
1
mM
*
*
SD-UR KD-UR KD-R
*
*
0
2
4
6
8
10
12
14
16
1
mM
*
SD-UR KD-UR KD-R
*
n = 11-14 mice/group * P < 0.01
Zhou et al., Nut & Met, 2007

35. Metabolic management of cancer following
changes in plasma glucose & ketones

36. Influence of raw KD-R on mast cell tumor in a dog
July 8, 2013 Sept 28, 2013
April 8, 2014

37. Can the KD-R be effective for the
metabolic management of malignant
brain cancer in patients?
Clinical Question

38. The results showed that a ketogenic diet, which
reduced blood glucose and elevated blood
ketones, could provide long-term management in
two children with recurrent inoperable brain
tumors

39. Patient: Female 65 yrs old, 64 kg (141 lbs)
12/5/08: Progressive memory loss, chronic headaches, nausea

40. Histology showed high cell density, vascularization, and
pseudopalisades
Diagnosis: Glioblastoma Multiforme (GBM).
Histopathology

41. GBM is Responsive
to Metabolic Therapy
The Metabolic
Zone

42. How the standard of care can provoke
GBM growth and recurrence
eyfried et al., Lancet Oncology, 2010; Seyfried et al., Cancer Letters, 2014
Increases
Glutamine!
Increases
Glucose!
HCMV
infection
increases
use of
Glu & Gln

43. Overall survival for GBM using “Standard of Care”
Stupp et al., 2009 Lancet Oncology
A total of only
6 long-term
survivors out
of 532
irradiated
patients = 1.1%!
TMZ increases
Driver
mutations
Johnson et al.,
2014, Science
TMZ + Radiotherapy

44. Glucose (mmol)/Ketone (mmol) = GKI
The Glucose/Ketone Index Calculator:
A simple tool to help manage brain
cancer
Therapeutic efficacy is considered best with
index values approaching 1.0 or below

45. Influence of metabolic therapy alone on the G/K Index
in an adult patient with diffuse, infiltrative brainstem glioma

46. Calorie restriction reduces intracerebral growth
and the GKI in mice with the CT-2A astrocytoma
AL CR
GKI = 15.2 3.7

47. Glucose/Ketone Index
Values =
37.5
1.4

48. The Press-Pulse Paradigm: A Novel
Therapeutic Strategy for the Metabolic
Management of Cancer
1. Cyclic Energy Stress Targets Mutated Tumor Cells:
a. Calorie restricted ketogenic diet.
b. Calorie restricted raw vegan diet.
c. Hyperbaric oxygen therapy.
d. Non-toxic drugs.
Press
Pulse

49. Press-Pulse therapy using the KD-R with
the glycolysis inhibitor 2-DG for managing
n = 3-6/groupDose: 25 mg/kg BW Marsh et al., Nutrition & Met

50. Press-Pulse therapy using the KD with Hyperbaric
Oxygen for Systemic Metastatic Cancer in VM Mice
Poff, A., C. Ari, T. N. Seyfried, and D. P. D’Agostino (PLoS One, 2013)
SD

51. Influence of a restricted ketogenic diet on
brain metastases of the VM-M3 tumor cells:
Preliminary data
SD-UR KD-R (18% BW reduction)

52. Journal of Lipid Research, Sep;55(9):1815-7, 2014

55. Conclusion
1. Preclinical and case report studies indicate
that the restricted ketogenic diet (R-KD) can be
an effective non-toxic “metabolic therapy” for
managing malignant cancers in children and
adults.
2. The therapeutic effects of the R-KD against
cancer can be enhanced when combined with
drugs or HBO2T that also target energy
metabolism.

56. Acknowledgements
Purna Mukherjee, Ph.D.
Michael Kiebish, Ph.D.
Todd Sanderson, MD
Jeremy Marsh, MD
Weihua Zhou, MS
Giulio Zuccoli, MD
Miguel Sena-Esteves, Ph.D.
Laura Shelton, Ph.D.
Richard McGowan, S.J.
Roberto Flores
Angela Poff, Ph.D
Dominic D’agostino, Ph.D.
Linh Ta
Josh Meidenbauer
Tiernan Mulrooney
Joseph Maroon, MD
Funding: Amer. Inst. Cancer Res.,
National Cancer Institute,
Boston College Research
Fund.