Cancer et fonctions cognitives

Cancer et fonctions cognitives
Programme Phare Axe 4
Présenté par Pr F Joly, Caen
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Is cancer and cognition a real problem nowadays?
For the patients : definitely yes
North West Canceropole survey
• 551 French and Belgium Patients
(2010)
• 41% complain of cognitive disorders
with chemo
• 72% consider it a major side effect
(Survey, Lefel at al, Submitted)
Fatigue (62%)
Treatment (45%)
Hurricane Voice Breast Cancer Survey
(2007)
More than 2/3rds complain of cognitive
disorders
Memory dysfonction
during and after CT
98%
Negative impact on day to
day lives
62%
Anxiety, stress
26%
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Is cancer and cognition a real problem, nowadays?
For the research scientific community
180
160
140
120
100
80
60
40
20
0
num
publications
20022007
20082009
20102012
Pubmed : 302 Abstracts selected on words “cognition
and cancer” in title and abstract between 2002-2012
definitely yes
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Is cancer and cognition a real problem, nowadays ?
For medical oncologists
Yes, but until now, not definitely yes
Why?
Some doubts on the reality of “chemobrain” and the
impact on the quality of life of their patients
They don’t have clear explanations on the mechanisms
and which drugs may be involved
Neuropsychological tests are difficult to organize in routine
They have no solution to prevent and/or treat cognitive
decline of their patients or to help them to cope with
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
What we already know
Chemofog is a reality for breast cancer patients
But not for all patients
Incidence : 30% (20 to 70)
Moderate or subtle troubles (in most cases)
Main domains impaired
Memory, concentration, information processing speed
and executive functions
No relationship between objective and subjective disorders
Chemotherapy agents implicated : MTX, 5FU and
Alkylating agents
Hormonotherapy : controversal results
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
What we do not know (1)
Breast cancer
Which groups of patients are at risk?
Do cognitive disorders improve over time?
What are the main biological mechanisms involved?
What about patients with other cancers?
Affect of the cancer itself on cognitive function?
How to integrate all the different factors implicated
(age, co- morbidities, other medications……)
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
What we do not know (2)
Impact of other chemotherapy agents, new
generations of hormonotherapy or new targeted
therapies?
How to treat the cognitive problems and how to help
patients to cope with them?
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Complexity of the process with multiple etiologies
Multidisciplinary approach
Inflammation Metabolism
Vascular damage
Hormones
Neurotransmitters
Neurogenesis
Cognitive dysfunctions
Anemia
Chemotherapy
Other medications
Genes
Emotional status
Cancer
Neuropsychological tests
Neuro-imaging
ICCTF International Cognition and Cancer Task Force Conference
Animals models
March 1515-17
th
2012 – PARIS - FRANCE
COGNITIVE FUNCTION
AND CANCER
A
Clinical research
- Cognitive
function
- Fatigue
- Quality of life
C
Experience of family
and friends
Longitudinal Studies
North West Canceropole Axe 4 :
multidisciplinary approach (since 2008)
B
Memory impairment
Functional Imaging
D
Physiopathology
Behavioural animal
model
Topics : Age, Chemotherapy, targeted therapies, compliance to oral treatment
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
1
2012 – PARIS - FRANCE
Cognition Studies – Axe 4
COG-AGE : Impact of adjuvant
chemo in elderly patients
COG-OBS : Impact of cognitive function
on observance of oral cancer therapies
COG-ANGIO : Impact of targeted
therapies in metastatic kidney
cancer
COG-REDUC : Impact of memory
rehabilitation on patients with cognitive
dysfunctions
CANMEM : Neuropsychological
assessment and fonctionnal MRI
of elderly patients with adjuvant
chemo
Animal models
chemotherapy
targeted therapies
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Multidisciplinary program on CANCER AND
ADJUVANT CHEMOTHERAPY among elderly patients
A
Clinical Research
- Cognitive
function
- Fatigue
- Quality of life
Oncology teams
Oncogeriatric teams
Longitudinal studies
COG-AGE : Patients over 65 treated with adjuvant chemotherapy
for breast cancer
ICCTF International Cognition and Cancer Task Force Conference
B
Neuropsychological
Evaluations
C
Animal models
March 1515-17
th
1
2012 – PARIS - FRANCE
150 participants (ICCTF, Paris, 2012)
USA
France
Netherlands
Canada
Belgium
UK
Australia
Denmark
Singapore
Spain
Germany
Norway
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Developments at the ICCTF meeting in Paris
Improvement of well designed clinical trials
Increase of clinical and research teams who work on the
topic (75 abstracts)
Well designed studies with longitudinal assessment and
control groups
Neuropsychological clinical trials
Data on other tumor sites
Colorectal, Hematology, Prostate, Head & neck,
Kidney cancers, ….
New data on others drugs (oxaliplatin, docetaxel,targeted
therapies)
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Developments at the ICCTF meeting in Paris
Neuropsychological clinical trials
Influence of factors other than chemotherapy
Cortisol, Co morbidities, age, sleep…..
Cultural representation of cognitive impairment
New concepts (the impact of the cancer itself)
First preliminary trials on cognitive rehabilitation
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Developments at the ICCTF meeting in Paris
Animal models +++ (17 abstracts) and biology
Cancer itself
Memory and age
Mechanisms of brain injuries induced by oxaliplatin,
docetaxel, targeted therapies (antiangiogenic and
Mtor Inhibitors)
Influence of drugs other than chemo on the brain
Corticoids, EPO, fluoxetine, …….
Biology
Cytokines and APOE genotype, …….
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Developments at the ICCTF meeting in Paris
Imaging +++ (14 abstracts)
fRMI
Longitudinal studies,
With control groups
Complex modern functional imaging
Cancer and treatments evaluations
Long term impact of chemotherapy
Pet-FDG
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Participation of Axis 4 to ICCTF 2012 :
9 communications
Oral
Plenary : F Eustache
Self and cancer
Animal session : M Dubois/H Castel
Cerebral plasticity in young and old mouses with 5 Fu and oxaliplatin
Posters
S Noal : Antiangiogenic treatment and cognition
M Lange : Chemo adjuvant and elderly
N Morel : Autobiographic memory before chemo for breast cancer
J Lefel : interest of « memory clinics »
E Peres : EPO and brain tumor
M S Quittet : effect of targeting angiogenesis on cognition in healthy
mouse
M Dubois : impact of everolimus (inh MTor) on cognition
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Aging and cognition
Arti Hurria
Our society is aging
There will be an increase in:
the number of cases of cancer
the number of cases of dementia
The majority of cancer survivors are older adults
Understanding the association between aging, cancer
(and therapy), and cognitive function is critical
ICCTF International Cognition and Cancer Task Force Conference
March 1515-17
th
2012 – PARIS - FRANCE
Potential Trajectories of Cognitive Function
Cognition
No Cancer
Cancer survivor
Phase Shift Hypothesis:
The trajectory of cognitive
dysfunction parallels normal aging
Cancer survivor
Accelerated Aging Hypothesis:
The trajectory of cognitive
dysfunction is accelerated in
comparison to normal aging
Time
Time
Hurria & Ahles 2012
Increased Age and Lower Cognitive Reserve
Associated with Decline in Processing Speed
WRAT-3 Below Median
WRAT-3 Above Median
Ahles et al, J Clin Oncol, 2010
Impact of Age and Cognitive Reserve
Age
Chemotherapy
Cognitive Reserve
Age and baseline cognitive reserve are
predictors of post-treatment cognitive function
in the Processing Speed domain.
Ahles et al, J Clin Oncol, 2010
Are We Missing Key Factors That
Impact Cognitive Function?
Cancer Diagnosis &
Cancer Therapeutics
Genetic Variation
- APOE
- ACE Genotype
- UBQLN1 Gene
Lifestyle
- Physical activity
- Diet/Nutrition
- Smoking
- Alcohol
Patient’s
Cognition
Sociodemographics
- Gender
- Race/ethnicity
- Education
Aging
Psychological State
- Anxiety
- Depression
- Fatigue
Comorbidity
- Vascular Risk Factors
- Cardiovascular disease
- Obesity
- Chronic Kidney disease
Co-morbidités (Patel et al)
Significant Differences on Processing Speed
Processing Speed
58
55
52
55.32
54.96
50.75
51.26
49.75
49
No Comorbidity
46
44.47
Comorbidity
43
40
WAIS Processing
Speed
DKEFS Color Word
Reading
Grooved Pegboard
F(1, 142) = 9.30
F(1, 155) = 3.82
F(1, 122) = 6.81
p = .003
p = .05
p = .01
Performance scores presented in T-score measurement (M = 50, SD = 10)
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Comorbidités (Patel et al)
Significant Differences on Executive Functioning
Executive Functioning
12
11.5
11
10.65
10.33
10.5
10
11.12
11.09
10.21
9.35
No Comorbidity
9.5
Comorbidity
9
8.5
8
Trails 4
F(1, 149) = 6.33
p = .01
Inhibition
Inhibition Switching
F(1, 154) = 4.23
F(1, 154) = 4.26
p = .04
p = .041
Performance scores presented in scaled score measurement (M = 10, SD = 3)
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Self - Autobiography memory and cancer
(F Eustache, B Giffard, N Morel)
AM in Cancer patients without stress-related psychiatric disorder
Overgeneral memories in BC patients compared with healthy
controls (Nilsson-Ihrfelt et al, 2004; Bergouignan et al, 2011)
Smaller hippocampal volume (post.)
in BC patients relative to healthy controls
Smaller post Hpc +
deficits of episodic AM:
Reflect the effect of :
-Cumulative stressful
events
-Aggressive treatments
Bergouignan et al, 2011, PlosOne
5èmes
(McDonald et al, 2010; Deprez
et al 2012; de Ruiter et2012–
al – Deauville
Journées Scientifiques – 10 et 11 mai 2012
2011…)
Canmem, preliminary analysis)
*
*
* P<0.05
*
*
*
Active adaptation process in these patients with « fighting spirit »?
Adaptation process different from that used by depressed patients
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
What’s new, in animal models?
The impact of the cancer on cognition? (Fardel et al)
To examine the role of cancer in cognitive decline associated with
docetaxel (DTX) chemotherapy
Using a murine model of ovarian cancer (ID8 cancer cells)
Secondary aims:
Examine the role of ABC transporters (Pgp and mrp7) in brain
exposure to DTX
From Fardell et al
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Docetaxel (DTX) concentrations (24h)
(using HPLC)
Plasma
Brain
12
10
Brain DTX concentration
(ng/g)
Plasma DTX concentration
(ug/ml)
12
8
6
4
2
*
10
8
6
4
2
0
0
Healthy + DTX ID8 + DTX
From Fardell et al
Healthy +
DTX
ID8 + DTX
ID8 : ovarian cancer mouses
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Cancer & DTX affect object recognition (Fardell et al)
Novel object prefence (%)
100
90
80
70
60
50
40
30
20
10
0
Control
Main effect of ID8:
F(1,29)=13.134 p<.05
ID8
ID8 + DTX
DTX
Interaction between ID8 + DTX:
F(1,29)=4.701 p<.05
From Fardell et al
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Gene expression changes
Changes in gene expression (Fardell et al)
300%
Control
ID8
ID8 + DTX
DTX
250%
200%
150%
*
100%
*
50%
*
0%
mrp7
mdr1a
Genes of interest
mdr1b
The presence of cancer downregulates the expression of Pgp genes;
This is associated with
- Greater brain exposure to DTX
- Worse cognitive outcomes
From Fardell et al
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
H Castel and M Dubois
The Morris water maze test
Learning test
1st Day
4th Day
Transfer test
• Aged mice altered in spatial learning and memory,and learning plasticity
• 5-FU altered young and aged behavioral flexibility
Distance (m)
5
Young Saline
Young 5-FU
Aged Saline
Aged 5-FU
Age effect: ***
Day effect: $$$
4
3
2
1
0
1
2
Training days
3
4
R
Retention
Learning plasticity
Distance (m)
Spatial learning and memory
9
8
7
6
5
4
3
2
1
0
Treatment effect: #
Age x trial: ***
1
2
3
4
Trials
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
H Castel and M Dubois
Exploration duration difference (s)
Object recognition memory test
Familiar objects
*
40
Young Saline
Young 5-FU
Aged Saline
Aged 5-FU
#
35
30
25
20
15
10
#
5
0
-5
F
N
Novel object
Novel object exploration duration:
Difference between test and sample session
• Aged mice exhibit deficient recognition memory
• 5-FU provokes hyper-reactivity to novelty in young and aged mice
Spontaneous activity
Nb squares
120
100
80
60
40
Executive functions
20
0
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Cerebellum
Adulte
H Castel and M Dubois
Hippocampus and prefrontal cortex
SVZ-SGZ
RMS
SGZ
Specific link between behavioral
flexibility and neurogenesis
BrdU+ cells nb
NS
2500
2000
NS
#
EPPI/Saline
EPPI/5-FU
1500
Gluc/Saline
1000
Gluc/5-FU
500
0
Neurogenic
niches
Outside SGZ
5-FU
5-FU
Sub-granular zone
BrdU+ cells nb
§
*
1500
#
#
1000
Sub-ventricular zone
500
0
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
H Castel and M Dubois
Young
Young
5-FU/saline
saline
Young
Glu
Young
5-FU/GLU
5-FUFU-37.5 mg/kg
5-FU
Saline
5-FU
Saline
5-FU
Saline
W1
Beginning of behavioral assessment
W2
D0
D7
W6-9
W3-5
D14
D38
BrdU
WFI/Glucose
WFI/Glucose
WFI/Glucose
Exploration duration difference (s)
Glucose abolishes 5-FU-induced hypereactivity to novelty
Object recognition test
30
#
EPPI/Saline
25
EPPI/5-FU
20
Gluc/Saline
Gluc/5-FU
15
10
5
0
F
N
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Imaging : Research
Questions
Potential mechanism = direct neurotoxicity
Possible WM injury?
Changes in WM microstructure measurable
with MRI Diffusion Tensor Imaging (DTI)?
WM : white matter
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Diffusion tensor imaging
diffusion
Visualisation AND quantification of white matter
Fractional
Anisotropy
( ) ( ) ( )
3 λ1 −λ 2 + λ2 −λ 2 + λ3 −λ 2
FA=
2
2
2
2
λ1 +λ2 +λ3
anisotropy
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Diffusion tensor imaging
diffusion
Visualisation AND quantification of white matter
Fractional
Anisotropy
( ) ( ) ( )
3 λ1 −λ 2 + λ2 −λ 2 + λ3 −λ 2
FA=
2
2
2
2
λ1 +λ2 +λ3
anisotropy
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Results (De Ruiter)
De Ruiter et al., 2011
Memory encoding
No sign. group differences in performance at encoding
Chemo group: less activation
Interpretation:
•
•
•
Less allocation of
processing resources
Less focussing of
attention
Less information
transmission
Hypoactivation identified in parahippocampal gyrus (PHG)
and posterior parietal cortex (PPC)
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Results (Silverman et al)
Silverman et al., 2008
Task performance not recorded
Chemo-group: more activation in prefrontal areas
Interpretation (less is more):
Compensatory response
More effortful processing
Chemo
no Chemo
5èmes
Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Results (Deprez)
Main conclusions
Chemotherapy seems to affect WM
microstructure
This decrease in FA could be correlated
with a decrease in performance on
memory and attention tests
DTI WM parameters seem to have the
required sensitivity to quantify
chemotherapy-induced changes
Deprez et al, Journal of Clinical Oncology 2012
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Late impact of adjuvant CMF chemotherapy for
breast cancer on cognition (Koppelmans)
More than 20 years post-tt
associated with:
smaller global gray matter
volume
Furthermore: with increasing time
since treatment white matter
integrity and gray matter volume
decreases independently of age
FA (white matter integrity)
decreases with longer time since treatment
…not associated with:
•focal gray matter density
•global or focal
microstructural white matter
integrity
•total cerebral blood flow or
cerebral perfusion
Koppelmans et al JCO 2012
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
Cytokines et cognitions
Relationship between TNFα-308 SNP &
Self-reported Cognitive Complaints at T1 (P Ganz)
25
GG
GA
AA
7
20
6
15
10
-4
-6
-8
5
MFSI Mental
-2
Squire memory
PAOFI memory severity score
0
5
4
3
2
-10
1
-12
0
0
GG
p=0.02
GA
AA
p=0.06
GG
GA
AA
p=0.008
GG allele associated with greater cognitive complaints on three
independent measures (n=171 at T1)
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
IL6 rs1800795 (c.C-174G) (Merriman et al)
Poor outcomes for carriers of the G allele
Associated with elevated levels of IL6
High levels associated with poor outcomes
Associated with symptoms of sickness
behavior, including difficulty concentrating
Protein Data Bank; Spath-Schwalbe, 1998; DeMichele, 2009; Bull, 2009; Hulkkonen,
2001 Scientifiques – 10 et 11 mai 2012
5èmes Journées
2012–
– Deauville
Targeted therapies : preliminary results
30,0
T0 (n=59)
T0 (n=59)
20,0
15%
15,0
5%
48%
10,0
32%
5,0
0
1
2
3
0,0
verbal episodic
memory
visual episodic
memory
working memory
executive
functions
information
processing
speed
T0
8
7
6
Nb of patients
% impairment
25,0
5
4
3
2
1
0
verbal episodic memory
visual episodic memory
working memory
executive functions
- At baseline, 53% of patients (n=31) had
cognitive disorders.
- Among the 41 patients with T0 & T3
evaluations, 16 (39%) had cognitive impairment
over AA treatment, mainly executive functions
and episodic memory.
T3
Anti-angiogenic agents and metastatic renal cancer, Noal et al
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville
The targeted cancer therapy Everolimus does not alter cognitive function but modifies
metabolic activity in hypothalamichypothalamic-related areas in mice
Martine Dubois1,2,6, Vadim Lejoncour1,2, Nicolas Lapinte1,2, Marie Thérèse Schouft1,2, Marie-Christine Tonon 1,2, Pierrick Gandolfo1,2,6 , Florence Joly 4,5,6, Pascal Hilber3,6 et Hélène Castel1,2,6
Cancer and treatments can induce cognitive impairments. Chemotherapies such as 5-Fluorouracil (5-FU), an anti-metabolite used to treat breast or colon cancers, led frequently to deficits of visual and spatial memories, and slowing of
psychomotor processing, symptoms referred to as “chemofog”. Targeted therapies, such as inhibitors of the mTOR signaling pathway (mammalian target of the rapamycin), represent a new approach for cancer treatment but are commonly
associated to adverse effects such as fatigue. The mTOR pathway plays a crucial role in proliferation, differentiation, migration and cell survival. Everolimus (RAD001 or Afinitor@), an oral derivative of rapamycin, inhibits the mTOR pathway,
and block cell proliferation and neoangiogenesis.
The mTOR pathway is important for synaptic plasticity, in particular in the hippocampus, and participates to long-term memory processes through the protein neosynthesis process. Our study aimed at assessing the direct middle-term effect of
Everolimus on cognitive functions in non-bearing cancer mice, and at assessing its in vivo impact on cerebral plasticity and brain metabolism, and in vitro effects on neural stem or endothelial cells, in order to understand the biological mechanisms
that underlie cognitive adverse effects of targeted therapy particularly deleterious for patients daily quality of life.
D13
Treatment 5 mg/kg
D20
Everolimus
**
*
**
***
***
***
*
**
*
**
***
***
*
* *
Neural stem cells in culture
Vehicle
Everolimus
Sub-granular zone of the dentate gyrus
0
5000
4000
3000
2000
1000
NS
Vehicle
Everolimus
0
10-8 M
10-7 M
10-6 M
10-5 M
10-8 M
10-7 M
10-6 M
10-5 M
Vehicle
T+24h
2
3
4
5
6
7
8
9
10
11
12
13
14
″
17
18
19
″
40
″
45
46
47
48
49
Days
Everolimus
Morris water maze: intact behavioural flexibility
0
Vehicle
Everolimus
Spheres volume
(percent)
3
Trials
Everolimus
4
Exploration
duration (s
+SEM)
Object recognition memory: no deficit
12
10
8
6
4
2
0
**
*
Familiar
Vehicle
Everolimus
Novel
Objects
Number of
branches
IQGAP positive-cell
number
*
100
90
80
70
60
50
40
30
20
10
0
Vehicle
Everolimus
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
***
Everolimus
200
180
160
140
120
100
80
60
40
20
0
***
Vehicle
Length (µm)
Hippocampus vascular niche: altered density
1400
1200
1000
800
600
400
200
0
#
T+24h
0
-8
-7
-6
-5
Concentrations (logM)
T+24h 10-8 M
% of total
2
***
70
60
50
40
30
20
10
0
70
60
50
40
30
20
10
0
0-0.3
0.3-0.7
0.7-1.2
1.2-2.5
Volumes (106 µm3)
0.3-0.7
0.7-1.2
1.2-2.5
Volumes (106 µm3)
10-11 M
0
10-9 M
10-10 M
10-8 M
10-7 M
0
-8
-7
-6
-5
Concentrations (logM)
70
60
50
40
30
20
10
0
2.5-25
0-3
3-7
7-12
12-25
25-70
7-12
12-25
25-70
Volumes (106 µm3)
T+48h 10-5 M
0-3
3-7
Volumes (106 µm3)
Vehicle
10-7 M
10-6 M
10-5 M
10-6 M
Sub G1 9%
G0/G1 74%
S
9%
G2/M 7%
Sub G1 3%
G0/G1 74%
S
11%
G2/M 10%
Control
10-5 M
Sub G1 8%
G0/G1 74%
S
8%
G2/M 8%
Sub G1 9%
G0/G1 76%
S
7%
G2/M 5%
Sub G1 4%
G0/G1 76%
S
8%
G2/M 11%
Vehicle
T+24h
Everolimus
Everolimus
10-11 M
0
0
#
Neural stem cell cycle
10-8 M
Endothelial cells: reduced survival and proliferation
Vehicle
Everolimus
T+48h
T+48h 10-8 M
70
60
50
40
30
20
10
0
2.5-25
T+24h 10-5 M
0-0.3
14000
12000
10000
8000
6000
4000
2000
***
1
Vehicle
T+48h
% of total
Trial effect :
35
30
25
20
15
10
5
0
***
Latency (s +SEM)
Treatment
Spheres volume
(percent)
1
% of total
0
% of total
Weight gain
(%)
Vehicle
Behavioural tests
Weight gain: delayed reduction
120
115
110
105
100
95
90
Neurogenesis in the hippocampus: no modification
D42
BrdU+ cell
number (+SEM)
D0
10-9 M
10-10 M
10-8 M
10-7 M
10-6 M
10-8M
10-5 M
10-7M
T+48h
10-6M
Sub G1 4%
G0/G1 77%
S
10%
G2/M 8%
Sub G1 3%
G0/G1 76%
S
10%
G2/M 11%
Vehicle
10-5M
Sub G1 4%
G0/G1 79%
S
10%
G2/M 8%
Sub G1 9%
G0/G1 73%
S
10%
G2/M 5%
Cerebral metabolism: selective modifications
###
PrL
Rh
Re
***
***
-5
###
***
-6
###
***
-9
-8
-7
Concentrations (Log M)
###
***
-10
###
*
***
-11
##
*
***
**
*
0
T+48h
120
100
80
60
40
20
0
Ect
VM
EP
Bregma 1.94 mm
Bregma -1.46 mm
0
-11
-10
-9
-8
-7
Concentrations (Log M)
-6
Optic
density
(% +SEM)
##
***
#
Cell number (percent)
Vehicle
Everolimus
T+24h
###
***
###
**
120
100
80
60
40
20
0
***
Cell number (percent)
Everolimus
140
120
100
80
60
40
20
0
*
*
Acb Sh PrL
*
*
LPO
5N
In conclusion, No modification of cognitive functions evaluated with
hippocampal- and frontal-dependent behavioral tasks.
Detrimental effects on neural stem cells and endothelial cells in culture, and
altered hippocampal vascularization and metabolism of brain regions
controlled by the hypothalamic orexin and MCH systems,involved in
fatigue described in patients.
Ect
EP
*
*
*
PSTh
Re
Rh
Sub
*
Vehicle
Everolimus
VM
Brain regions
-5
Learning and memory
modulation
*
*
*
Thalamic nuclei
Arousal
Monoaminergic systems
Preoptic area
Sleep/wake cycle
Orexin and MCH neurons
Reward
Accumbens shell
Motor trigeminal nucleus
Hedonism
Food intake
Blood energy balance signals
Ingestion
Arcuate nucleus
High level mTOR
Everolimus
Hypothalamus
5èmes Journées Scientifiques
– 10 et 11 mai 2012
2012–
– Deauville
Conclusions
Cancer – treatment – cognition : a reality!
Need more research to:
Better understand the mecanisms involved
Animal models
Imaging
Biology
Better evaluate the real impact of cognitive dysorders
on quality of life of patients More trials among specific
groups of patients: elderly
To find strategies to help the patients to improve their
cognitive functions and/or to cope with this side effects
(during and after treatments)
5èmes Journées Scientifiques – 10 et 11 mai 2012
2012–
– Deauville