Will metastatic cancer be a curable disease ? · • Analysis of tumor volume and animal survival...
Transcript of Will metastatic cancer be a curable disease ? · • Analysis of tumor volume and animal survival...
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Will metastatic cancer be a curable disease ?
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Cancer Treatment is not a success (so far..)
Overall cancer mortality, Age standardized ratio by age class in 19
western countries
MEN WOMEN
Summa et al. Submited
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Age standardized ratio by cancer site in 19 countries
0
100
200
300
400
500
600
700
800
900
1961 1966 1971 1976 1981 1986 1991 1996 2001
ASR
Years
ASR Stomach cancer (male)
ASR Lung cancer (male)
ASR Breast cancer ( female)
ASR Prostate cancer (male)
ASR Lung cancer (female)
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What is Cancer?
Cancer phenotype: Invariants
1- Increased pressure
2- Fractal shape
3- Increased glucose uptake
4- Intracellular alkalosis
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What is Cancer?
Cancer phenotype: 1 - Increased pressure
Measured Interstitial Pressures
Interstitial Pressures compared to
vascular pressures
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What is Cancer?
Cancer phenotype: 2 – Fractal shape
Fleury et al., « Fractal » 2003
Fractal image of a breast carcinoma
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What is Cancer?
Cancer phenotype: 3 – Increased glucose uptake
Pet Scan
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8Hematoxylin and eosin stains are a pH based phenomenon
Cancer phenotype: 4 – Intracellular alkalosis
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Cancer : between glycolysis and physical constraints.
L. Schwartz Springer 2004
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Cell Mitosis
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The cell is an electrical machine
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Bioenergetics of Cell Metabolism
Adenosine triphosphate (ATP) : the energetic currency exchange
Wikipedia_image
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Bioenergetics of Cell Metabolism
ATP hydrolysis is the molecular motor of Life.
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Glycolysis vs. Oxidative phosphorylation
Modified from Diaz-Moralli et al. (2013)
The central carbon metabolism (CCM) oscillates between biomass and energy synthesis
and times cell division.
BIOMASSGLYCOLYSIS
OXPHOS
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Glycolysis vs. Oxidative phosphorylation
Modified from Diaz-Moralli et al. (2013)
The central carbon metabolism (CCM) oscillates between biomass and energy synthesis
and times cell division.
ATPOXPHOS
GLYCOLYSIS
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Differentiated Cells
Differentiated cells have an oxidative metabolism based on mitochondrial respiration and energy synthesis (ATP)
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Differentiated Cells
Differentiated cells have an oxidative metabolism based on mitochondrial respiration and energy
synthesis (ATP)
• ATP = 9 pmol
• Acidic pH = 6.8
• NAD+/NADH ratio = 8-10
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Proliferating Cells
Rapidly proliferating cells have a glycolytic metabolism based on glucose fermentation and biomass synthesis
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Intertwined redox oscillators
In the case of normal cells
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1
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6
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10
pm
ole
s
[ATP]
G0 SG1 MG2 G0 0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
rati
o N
AD
H/N
AD
+
NADH/NAD+
MG0 G1 S G2 G0
0
2E-08
4E-08
6E-08
8E-08
0.0000001
1.2E-07
1.4E-07
1.6E-07
1.8E-07
mo
l/L
[H+]
G0 G1 S G2 M G0
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3. pHi Oscillation Regulates Cell Cycle
RNA polymerase [4]
Chromatin
decondensation
[1-3]
DNA polymerase [4]Chromatin
condensation
[3]
1. Lois et al. (1983)
2. Allfrey et al. (1962)
3. Guo et al. (1989)
4. Grainger et al. (1979)
5. McBrian et al. (2013)
6. Kurdistani (2014)
Histone acetylation [5-
6]
Histone deacetylation [5-6]
6.6
6.7
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
pH
i
pHi oscillation during cell cycle
G2 Early MitosisG1 S G1
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CANCER : A DECREASE IN ENERGY YELD
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Mitochondria are not functional in cancer
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Warburg Effect : Reduced Energy Efficiency
Heiden et al. (2010)
PPP
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Cancer Cells are ATP-deprived
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4
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Normal Cancer Normal Cancer Normal Cancer Normal Cancer Normal Cancer
Pro-G1 Late G1-S Early G2 Late G2-Early M M/G0
pm
ole
s/µ
g p
rot.
[ATP] in normal and cancer cells
(n=8)
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Intertwined redox oscillators
In the case of cancer cells
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0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
pm
ole
s
[ATP]
0
1E-08
2E-08
3E-08
4E-08
5E-08
6E-08
7E-08
mo
l/L
[H+]0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
rati
o N
AD
H/N
AD
+
NADH/NAD+
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
rati
o N
AD
PH
/NA
DP
+
NADPH/NADP+
G0G1 S G2G0 M
G0
G0
G0G1
G1
G1S
S
SG2
G2
G2M
M
M G0
G0
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Cancer Drugs Change Cancer Metabolism
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PET SCAN
Chemotherapy normalizes the radioactive glucose uptake
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Can we do better than chemotherapy?
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Our approach
Data-base
Individual screening• 5 cancer cell types
• proliferation and MTT test
• 1, 3, 5 days cultures
Combination screening(same experimental conditions)
Literature screening• Metabolic activity
• Well-known molecules
• Data on human toxicity
28 molecules
7 molecules
7 combinations
Results• High clinical efficiency
• Universal and simple mechanisms
• Low regulatory risk and low cost
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Literature screening
Drugs Mechanism of action
Acetazolamide Anhydrase carbonic inhibition
Albendazole PEP carboxykinase inhibition
Amobarbital NADH dehydrogenase
Amrinone PDE-3 inhibition
Betaine lipotropic factor
Capsaicin NADH dehydrogenase
Dfructose 1,6 biphosphate PKM2 activation
Dichloroacetate PDHK1 inhibition
Dimercaprol PDH activation
Farnesol phospholipase D inhibition
Genistein Phospholipase Cgamma inhibition
Gossypol LDH inhibition
Hydrazine sulfate PEP carboxykinase inhibition
Hydroxycitrate ATP citrate lyase
Ketoconazole Cyt. P450 demethylase inhibition
Lipoic acid PDHK1 inhibition
Lithium chloride PEPCK inhibition
Lonidamine Hexokinase inhibition
Metformine AMPK activation
Miltefosine Choline kinase inhibition
Niacine Lipolysis inhibition
Quinacrine Phospholipase A2 inhibition
Quinine Phospholipase A2 inhibition
Silibinine IGFBP activation
Simvastatine Lipolysis inhibition
Suramine Citrate synthase inhibition
Tolbutamide Potassium channel blocker
Xylitol PP2A
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METABLOC 1
Aim:
Identify a combination of two drugs active
against altered cancer cell metabolism
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In vivo validation
Experiments
• Three syngeneic cancer models
– MBT-2 bladder carcinoma
– B16-F10 melanoma
– LL/2 lung carcinoma
• Analysis of tumor volume and animal survival
METABLOC 1
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0
500
1000
1500
2000
2500
3000
3500
10 20 30 40 50 60 70 80 90 100 110 120 130
Saline 5-FU Ethanol
Contrôle DMSO I33 seul K11/A44
K11/N83 I33/ V25 I33/ A44
V25 / A44 K11 / N83 / B29 I33/V25 Low
I33/A44 Low K11/A44 K11/N83 V25/A44
Combination of molecules in bladder cancer
Vt
(mm
3)
Tumor volume evolution in bladder carcinoma model (MBT-2).
Time since
implantation (days)
Treatment Treatment
METABLOC 1
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0
12
34
56
78
910
11
19 29 39 49 59 69 79 89 99 109 119 129 139
ALA/HCA in bladder carcinoma (MBT-2)
Time since
implantation (days)Nu
mb
er o
f al
ive
mic
e (n
=1
8)
Survival. Saline Ethanol
5-FU ALA/ HCA
Treatment Treatment
The ALA/HCA combination reduces tumor development rate
and doubles survival time as compared to untreated mice.
METABLOC 1
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0
1
2
3
4
5
6
7
8
9
10
18 28 38 48 58 68 78 88 98 108 118
ALA/HCA in melanoma (B16-F10)
Time since
implantation (days)
Treatment
Survival.
Nu
mb
er o
f al
ive
mic
e (n
=1
0)
Saline Ethanol
Cisplatin ALA/ HCA
The ALA/HCA combination reduces tumor development rate
and doubles survival time as compared to untreated mice.
METABLOC 1
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LLC tumor model
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Well-known molecules
Name
Indications
Toxicity
Lipoic acid Calcium hydroxycitrate
• Anti-oxidant
• Dietary supplement
• Diabetic neuropathy
• No toxicity at
1200mg/day during 2 years
• No mutagenic or
genotoxic activity
Weight loss agent
• No toxicity at 5g/day
during 8 weeks
• No mutagenic or
genotoxic activity
ALA HCA
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0
500
1000
1500
2000
2500
3000
3500
4000
10 15 20 25 30 35 40 45 50 55 60 65
Enhanced efficacy of chemotherapy
Vt
(mm
3)
Treatment
Tumor volume.
Addition of ALA/HCA enhanced the efficiency of
cisplatin treatment (LLC model).
Saline Ethanol Cisplatin
ALA/ HCA CIS/ ALA/ HCA
Time since
implantation (days)
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In vivo screeningsDrugs Mechanism of action6-diazo-5-oxo-L-norleucine Glutaminase inhibition
Agmatine Polyamine synthesis inhibition
Alpha cetoglutarate Citrate synthase inhibition
Amiloride Na+/H+ antiport inhibition
Apigenine IGFBP activation
Bicalutamide IGFBP activation
Bromocriptine Hypothalamic D2 receptor agonist
Butyrate sodium HDAC inhibition
Chitosan PK-M2 inhibition
Choline Chloride lipotropic factor
Citrate Citrate synthase inhibition
Cryogenine PEP carboxykinase inhibition
Curcumin AID inhibition
D-alanine Alanine transaminase inhibition
Epigallocatechin gallate PK-M1/M2 splicing regulation
Fluoxetine Serotonine reabsorption inhibition
Ibuprofen NSAIDS
Indole 3 carbinol Triglycerides reduction
Ketoconazole Cyt. P450 demethylase inhibition
Lactoferine Oxydative stress reduction
Letrozole Aromatase inhibition
L-norvaline Arginase inhibition
Melatonine anti-oxydant, anti-proliferative
Menadione Tyr kinase receptor inhibition
Oméprazole IGFBP activation
Oxythiamine Transketolase inhibition
PEG8000 PK activation
Pegvisomant GH receptor inhibition
Pralidoxime Alanine transaminase inhibition
Retinoic acid Cellular differentiation activation
Sulpiride GH secretion inhibition
Suramine Citrate synthase inhibition
Valproate sodium HDAC inhibition
Vitamine B12 lipotropic factor
METABLOC 2
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0
500
1000
1500
2000
2500
3000
3500
4000
4500
15 25 35 45 55
Vt
(mm
3)
Treatment
Tumor volume (LLC).
Time since
implantation (days)
Screening of 19 combinations
ALA/HCA/OCT
CisplatinALA/ HCA
Vehicles
METABLOC 2
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Combination of ALA/ HCA/ OCT/ CAP
METABLOC 1
First report of tumor regression with a metabolic treatment Schwartz L. Invest New Drugs. 2013 Apr;31(2):256-64.
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First patient
7/2001: Adenocarcinoma of the colon pT4 N0
10/ 2009 : Peritoneal metastasis
12/2009 : Chemotherapy at Institut Gustave Roussy
(Villejuif)
5-FU, Cisplat, Avastin
12/2009 oral ALA and HCA
3/ 2010 : Avastin discontinued because of poor tolerance
7/ 2010 : abdominal radiotherapy followed by Gemcitabine
7/ 2011: discontinuation of chemotherapy
10/2014: death
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CT of the perirectal mass at the date of discovery (Nov. 2009)
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CT of the same region, on June 2012
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First italian patient
Glioblastoma multiforme started Metabloc in early
2008
Multiple relapses but alive and reasonably well in
5/2015
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In the mean time
Dr Burt Berkson (New Mexico)
10 cases of uncurable advanced cancer :
Long term stabilization with IV Lipoic acidand low dose naltrexone
Number of patients treated not stated
Integrative Cancer Therapies 2009 (4) 416–422
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Compassionate use in desperate patients
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Targeting the Central Carbon Metabolism
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Inclusion criteria
Metastatic carcinoma
Standard chemotherapy failed
Offered only palliative care
Karnofsky status between fifty and eighty
Life expectancy estimated to be between 2 and 6 months
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Chemoresistant advanced metastatic cancer :
• lipoic acid 600 mg IV (Thioctacid® (Meda Pharma)
• hydroxycitrate 500 mg t.i.d (Solgar)
• low-dose naltrexone 5 mg (Revia) at bed time
Treatment Protocol: chemoresistant tumors
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0
1
2
3
4
5
6
7
8
9
10
11
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Month survival
Life expectancy
Clinic results for the first 11 patients
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Advanced metastatic cancer :
• lipoic acid 1, 8gr (Tiobec®)
• hydroxycitrate 500 mg t.i.d (Solgar)
• low-dose naltrexone 5 mg (Revia) at bed time
• In combination with standard chemotherapy
Treatment Protocol: chemosensitive tumors
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Second Series of Clinical treatment
• Group I: Metabolic treatment only (n=17)
• Group II: Metabolic treatment and chemotherapy (n=27)
• 12 months treatment
Months
Pro
port
ion s
urv
ivin
g
Months
Pro
po
rtio
n s
urv
ivin
g
Group IGroup II
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54
Florentine
• 3/2006 Sarcoma of the uterus : surgery + RT + chemotherapy ( TEC)
• 2008 Radiation induced enteritis
• 1/2013 multiple brain metastasis ( N sup 15)
Palliative radiatiotherapy (30gy in 10 fractions)
Sent home to die
• 3/ 2013 start metabloc
• 5/ 2015 NED
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Yun
56 year old lady
• 3/13 Squamous cell carcinoma of the lung with bone and brain metastasis ( N sup 20)
• Treatment gifetinib, partial response
• 2/14 because of tumor progression , continue gifetinib and start metabolic treatment partial response
• 6/14 brain irradiation 30Gy/10 fractions. During radiation acute psychosis, weight loss.
• 8/14 The husband is told that she is going to die
• 9/14 starts Alimta for palliative care and metabolic treatment
• 5/ 15 She lives an almost normal life
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Vincent’s wife
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Marina
• 2/12 Cholangiocarcinoma partial hepatectomy
• 5/12 Lung metastasis
• 5 FU and cisplatin ineffective
Stutent ineffective
Other treatment option sent home to die
• 2/13 start LDN, LA, HCA
Tumor stabilisation for 16 months
• 2/15 Death
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PSA in hormone resistant prostate cancer
0
2
4
6
8
10
12
14
ng/m
L
Dates
PSA concentration (ng/mL)Start metabolic treatment
12/05/11 14/11/12 24/11/13 15/10/14 06/03/15
0
100
200
300
400
500
600
700
800
900
ng/m
L
Dates
PSA concentration (ng/mL)
01/04/1520/12/1329/03/1311/05/12
Start metabolic treatment
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Metastatic colon cancer (3 different lines of chemotherapy)
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Decrease level of tumor markers followed by regrowth
035
287
602
641
214
175
104
159
190
153154157170
184182
237233235
276
327
397
738
701
830
000
100
200
300
400
500
600
700
800
900
0 2 4 6 8
Months of metabolic treatment
Start metabolic treatment
Ca125 (UI/mL)
Add Nivaquine
Glucophage
Death
Gemzar Zocor
Stop Zocor
Ptérostilbène
Cyclosérine
Stop metabolic treatment
Relais Crevel
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61Schwartz and Israel 2005
From:
Israël and Schwartz.
2006
Targets for a combined anti-tumoral therapy
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How to improve METABLOC?
A)Decrease glucose uptake
B)Decrease intracellular pH
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PET scan
Colon carcinoma with
liver metastasis
PET scan
Regular administration
of Metabloc Digoxin
and 5 FU
(2 months later)
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As of september 2015, it is probable that:
1) Cancer is the simple consequence of mitochondrial inactivation.
2) Alzheimer’s disease has a lot of common features with cancer
3) It is a matter of time before effective treatment will reach the market
4) There will be economical/political changes