Towards the utilization of cannabinoids as anti

Towards the utilization of
cannabinoids as anti-cancer
agents
Guillermo Velasco
Sestri Levante September 2015
Anti-cancer activity of cannabinoids
Munson et al. (1975) Antineoplastic activity of cannabinoids
J. Natl. Cancer Inst. 55, 597597-602
VehIcle
THC
Before THC
After THC
Galve-Roperh et. al. Nat. Med. 2000
Cannabinoids exhibit anti-tumor activity in many different
animal models of cancer
Glioma
Melanoma
Skin carcinoma
Breast cancer
Lung cancer
Hepatocellular carcinoma
Pancreatic adenocarcinoma
Leukaemia
Prostate cancer
Antitumoral action of cannabinoids
Velasco et al. Nat Rev Cancer (2012)
Selectivity of cannabinoid anticancer action
Pancreas
Veh
T
P
P
Nucleoss
P
Cannabinoid
Normal cell
Tumor cell
T
Supervival
T
P
P
TUNEL
P
T
Carracedo et al. Cancer Res (2006)
Potential clinical application
A 1st Pilot Clinical trial
(2003-2006)
Glioblastoma (GBM)
GBM
diagnosis
((n=9))
1st Surgery
Infusion catheter
(Pre-treatment
p y)
tumour biopsy)
Radiotherapy
±Chemotherapy
Relapse
THC treatment
Post-treatment
tumour biopsy
Decease
EXPERIMENTAL PERIOD SURVIVAL
THC activates the autophagy-mediated cell death
path a in human
pathway
h man glioblastoma samples
Cell proliferation (Ki67)
Pre-THC
Post-THC
Autophagy (LC3)
Pre-THC
Post-THC
Angiogenesis (CD31)
Pre-THC
Post-THC
Apoptosis (caspase 3)
Pre-THC
Post-THC
Survival of patients
p
Su
urviving fraction
n
1.0
Median survival = 24 wk
(95% CI: 15-33)
Si il to other
Similar
h d
drugs ((e.g. TMZ)
05
0.5
0
0
20
40
Time after THC (wk)
60
Strategies aimed at optimising
cannabinoid anticancer activity
1) Increasing our knowledge on the molecular mechanisms
involved in cannabinoid anticancer action
2) Identifying the molecular factors associated with cell
resistance to cannabinoid anticancer action
3) Designing the most appropriate cannabinoid-based
combinational therapies
Antitumoral action of cannabinoids
Velasco et al. Nat Rev Cancer (2012)
CBD and other phytocannabinoids
?
CBD
CB1, CB2 TRPVs
Oth receptors?
Other
t ?
ROS
Additional mechanisms
Autophagy
Apoptosis
Cancer cell death
Strategies aimed at optimising
cannabinoid anticancer activity
1) Increasing our knowledge on the molecular mechanisms
involved in cannabinoid anticancer action
2) Identifying the molecular factors associated with cell
resistance to cannabinoid anticancer action
3) Designing the most appropriate cannabinoid-based
combinational therapies
Predictor of resistance to cannabinoid
anticancer
ti
activity
ti it
Primary cultures of human glioma cells
160
140
120
100
80
60
40
20
0
**
mRNA lev
vels (a.u.)
Ce
ell viability (% from Vehicle)
THC 6 μM
1
ALDH2
IGFBP5
MDK
0.5
ID3
UPP1
0
GBP2
CSF1
PDGFRA
MDK
IGFBP5
ALDH2
PDGFRA
CSF1
GBP2
UPP1
ID3
Strategies aimed at optimising
cannabinoid anticancer activity
1) Increasing our knowledge on the molecular mechanisms
involved in cannabinoid anticancer action
2) Identifying the molecular factors associated with cell
resistance to cannabinoid anticancer action
3) Designing the most appropriate cannabinoid-based
combinational therapies
Cannabinoid-based combinational therapies for
GBM patients?
Cannabinoid-based combinational therapies for
GBM patients?
Standard GBM therapy
GBM
diagnosis
Relapse
Surgery Radiotherapy
+TMZ
TMZ?
TMZ
NEWLY-DIAGNOSED GBM
GBM
2nd line
therapies
Decease
RECURRENT GBM
Cannabinoids enhance TMZ anticancer activity in
GBM preclinical
li i l models
d l
U87 MG astrocytoma
cells
U87MG
Tumor vo
olume (% dayy 1)
10
Veh
8
VEH
THC 15 mg/Kg
TMZ 5 mg/Kg
6
M
Mean
± S.E.M
SEM
THC
THC+TMZ
4
TMZ
Vehicle
9.2±0.6
THC
5.1±0.4 **
TMZ
,
TMZ+THC
0.4±0.0 **
2
THC+TMZ
0
1
3
5
7
9
11
13
15
Days of treatment
Similar effect on cannabinoid and TMZ-resistant tumors
3.2±0.4 **
## ΩΩ
Selecting the appropriate cannabinoids for
anticancer therapies
- CBD has anticancer activity by itself
THC + CBD
(1:1)
CB1/CB2 agonists ?
- CBD attenuates the psychoactive effects of THC
- Wide experience
p
in the use THC and CBD ((Sativex))
FAAH/MAGL inhibitors?
Other phytocannabinoids?
Cannabinoids enhance TMZ anticancer activity
U87 MG astrocytoma cells
Peritumoral administration
12
Tumor v
volume (fold
d from day 1))
VEH
SAT (7.5
(7 5 mg/kg
/k THC
THC-BDS
BDS + 7,5
7 5 mg/kg
/k CBD
CBD-BDS)
BDS)
10
Mean ± S.E.M
THC (15 mg/kg)
TMZ (5 mg/kg)
8
SAT + TMZ
THC (15 mg/kg) + TMZ
6
4
2
0
0
2
4
6
8
Time ( days)
10
12
14
16
VEH
10.3 ± 0.4
SAT
6.2 ± 0.3
THC (15 mg/kg)
5.8 ± 0.5
TMZ (5 mg/kg)
4.1 ± 0.4
SAT + TMZ
2.6 ± 0.3
THC + TMZ
2.4 ± 0.3
∗∗
∗∗
∗∗
∗∗ ΣΣ ΩΩ
∗∗ ## ΩΩ
Cannabinoids + temozolomide therapy for GBM patients
Second line study
y ((started))
GBM
diagnosis
Relapse
p
Surgery Radiotherapy
+TMZ?
TMZ
NEWLY-DIAGNOSED GBM
Sativex
+ TMZ
Decease
RECURRENT GBM
Relapse
Do MK levels predict resistance to Sativex + TMZ therapy?
Clinical Trial (ongoing)
Primary objectives
- To determine the safety profile of
Sativex® in combination with TMZ
- To provide preliminary evidence of antitumoural activity for this drug combination
(comparison with a high-dense regime of
temozolomide)
Other clinical studies with CBs as anti
anti-cancer
cancer agents
Future clinical studies
Selecting the appropriate cannabinoids for
anticancer therapies
THC + CBD
(1:1)
Other ratios THC:CBD
Optimizing delivery
methods/via of
administration
CB1/CB2 agonists ?
FAAH/MAGL inhibitors?
Other phytocannabinoids?
Marijuana Sativex
(THC/CBD)
Marinol
(THC)
Cesamet
(Nabilone)
Which cancer types?
Cancer types lacking effective treatments
Glioma
Melanoma
Pancreatic adenocarcinoma
Which cancer types?
Subtypes of cancer that do not respond to current therapies
Breast cancer
Prostate cancer
Combinational therapies?
CBs + Classic anticancer treatments (ChT and RT)
Combinational Combinational
therapies
CBs + Targeted therapies
CBs + Classic anticancer treatments (ChT and RT)
+ Targeted therapies
Additional preclinical research is still required
Future of cancer treatment: individualized therapies
160
140
120
100
80
60
40
20
0
**
mRNA levels
m
s (a.u.)
Cell viiability (% from
m Vehicle)
THC 6 μM
1
ALDH2
IGFBP5
MDK
0.5
ID3
UPP1
0
GBP2
CSF1
PDGFRA
CSF1
GBP2
UPP1
ID3
PDGFRA
MDK
IGFBP5
ALDH2
It is essential to identify the molecular factors associated with the
resistance/sensitivity to cannabinoid anticancer action in clinical studies
Acknowledgements
David Dávila
Manuel Guzmán
Israel López Valero
Elena G Taboada
Mar Lorente
Eva Resel
Hospital 12 de Octubre
(Madrid)
Juan Sepúlveda
Aurelio Hernández Laín
U624 INSERM (Marsella)
J.L. Iovanna
Hospital Clínico San Carlos
(Madrid)
Juan Barcia
Pedro Pérez Segura
José González
Sonia Hernández
Alba Orea
Cristina Sánchez
Ismael Galve-Roperh
Hospital Virgen de la Salud
(Toledo)
Bárbara Meléndez
Manuela Mollejo
María Salazar
Sofía Torres
Fátima Rodríguez
Iñi
Iñigo
S l
Salanueva
Arkaitz Carracedo
Ainara Egia
Hospital Universitario
(Tenerife)
L González-Feria
ISCiii (Madrid)
Pilar Sánchez
CIB (Madrid)
Patricia Boya
y
IRCCS 'L. Spallanzani‘
(Roma)
Mauro Piacentini
Francesco Cecconi
U Sheffield (Sheffield, UK)
E. Kiss-Toth
Center for
f Cancer Research
(Copenhagen)
M, Jaattela
U Newcastle (Newcastle,
U.
(Newcastle UK)
P. Lovat
MRC PPU (Dundee)
Dario Alessi
CSIC
(Barcelona)
G Fabrias
J Casas
UPV
(Bilbao)
F Goñi
A Alonso
R Montes