towards the utilization of cannabinoids as anti-cancer...

Towards the utilization of cannabinoids as anti-cancer

agentsagents

Guillermo Velasco

Sestri Levante September 2015

Anti-cancer activity of cannabinoids

Munson Munson et al.et al. (1975) (1975) Antineoplastic activity of cannabinoidsAntineoplastic activity of cannabinoidsJ. Natl. Cancer Inst. 55, 597J. Natl. Cancer Inst. 55, 597--602602J. Natl. Cancer Inst. 55, 597J. Natl. Cancer Inst. 55, 597 602602

VehIcle THC Before THC After THC

Galve-Roperh et. al. Nat. Med. 2000

Cannabinoids exhibit anti-tumor activity in many differentanimal models of cancer

Glioma

animal models of cancer

MelanomaSkin carcinomaSkin carcinoma Lung cancer

Hepatocellular carcinomaBreast cancer

Pancreatic adenocarcinoma

Prostate cancer

Leukaemia

Antitumoral action of cannabinoids

Velasco et al. Nat Rev Cancer (2012)

Selectivity of cannabinoid anticancer action

Veh Cannabinoid

PancreasVeh Cannabinoid

s

TP PP

Nuc

leos

Normal cell Tumor cell T

TP P P

Normal cell Tumor cell

TUN

ELSupervival

T

Carracedo et al. Cancer Res (2006)

Potential clinical application

A 1st Pilot Clinical trialA 1st Pilot Clinical trial (2003-2006)

Glioblastoma (GBM)

GBMdiagnosis

(n=9)

Infusion catheter(Pre-treatmenttumour biopsy)( )

1st Surgery Radiotherapy±Chemotherapy

Relapse

p y)

THC treatmentPost-treatmenttumour biopsy Decease

EXPERIMENTAL PERIOD SURVIVAL

THC activates the autophagy-mediated cell deathpath a in h man glioblastoma samples

Cell proliferation (Ki67) Angiogenesis (CD31)

pathway in human glioblastoma samples

Pre-THC Post-THCPost-THCPre-THC

Apoptosis (caspase 3)Autophagy (LC3) Apoptosis (caspase 3)Autophagy (LC3)

Pre-THC Post-THC Pre-THC Post-THC

Survival of patientsp

n

1.0

0 5 frac

tion

Median survival = 24 wk(95% CI: 15-33)

Si il h d ( TMZ)0.5

urvi

ving

Similar to other drugs (e.g. TMZ)

0

Su

0

Time after THC (wk)

0 20 40 60

Strategies aimed at optimisingStrategies aimed at optimising cannabinoid anticancer activity

1) Increasing our knowledge on the molecular mechanisms1) 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 therapiescombinational therapies

Antitumoral action of cannabinoids

Velasco et al. Nat Rev Cancer (2012)

CBD and other phytocannabinoids

?CBD

TRPVsOth t ?

CB1, CB2

ROS

Other receptors?

ROSAdditional mechanisms

AutophagyApoptosis Cancer cell deathApoptosis Cancer cell death


1) Increasing our knowledge on the molecular mechanisms1) 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 therapiescombinational therapies

Predictor of resistance to cannabinoid ti ti itanticancer activity

Primary cultures of human glioma cells

**THC 6 μM

100120140160

from

Veh

icle

)

ALDH2IGFBP5MDKve

ls (a

.u.)

0.5

1

020406080

100

ell v

iabi

lity

(%

PDGFRACSF1GBP2UPP1ID3m

RN

A le

v

PDGFRA

CSF1

GBP2

UPP1

ID3

0

0

Ce

ALDH2

IGFBP5

MDK


1) Increasing our knowledge on the molecular mechanisms involved in cannabinoid anticancer action

2) Identifying the molecular factors associated with cell2) 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?GBM patients?

Standard GBM therapyGBM

diagnosisSurgery Radiotherapy

TMZ

Relapse2nd line

therapies+TMZ?

TMZ Decease

NEWLY-DIAGNOSED GBM RECURRENT GBM

GBM

Cannabinoids enhance TMZ anticancer activity inGBM li i l d lGBM preclinical models

U87 MG astrocytoma cells

8

10

VEH

y 1)

U87MGVeh


M ± S E M

THC+TMZ

4

6

THC 15 mg/KgTMZ 5 mg/Kg

olum

e (%

day

THC

Mean ± S.E.MVehicle 9.2±0.6THC 5.1±0.4

TMZ 3.2±0.4,

****

2

4

Tum

or v

o

TMZTMZ 3.2±0.4

TMZ+THC 0.4±0.0## ΩΩ**

01 3 5 7 9 11 13 15

Days of treatment

THC+TMZ

Similar effect on cannabinoid and TMZ-resistant tumors

Selecting the appropriate cannabinoids for anticancer therapies

- CBD has anticancer activity by itself

THC CBD

CB1/CB2 agonists ?

+ (1:1) - CBD attenuates the psychoactive effects of THC

- Wide experience in the use THC and CBD (Sativex) CB1/CB2 agonists ?

FAAH/MAGL inhibitors?

p ( )

Other phytocannabinoids?

Cannabinoids enhance TMZ anticancer activity


12VEH

SAT (7 5 /k THC BDS 7 5 /k CBD BDS))

Peritumoral administration

8

10SAT (7.5 mg/kg THC-BDS + 7,5 mg/kg CBD-BDS)

TMZ (5 mg/kg)

SAT + TMZ

THC (15 mg/kg) Mean ± S.E.M

VEH 10.3 ± 0.4

SAT 6.2 ± 0.3 ∗∗

d fr

om d

ay 1

)

6

THC (15 mg/kg) + TMZ THC (15 mg/kg) 5.8 ± 0.5

TMZ (5 mg/kg) 4.1 ± 0.4

SAT ∗∗

∗∗

SAT + TMZ 2.6 ± 0.3∗∗ΣΣ ΩΩ

volu

me

(fold

2

4THC + TMZ 2.4 ± 0.3

SAT TMZ 2.6 ± 0.3##∗∗ ΩΩ

Tum

or v

0 2 4 6 8 10 12 14 16

0

Time ( days)Time ( days)

Cannabinoids + temozolomide therapy for GBM patientsCannabinoids temozolomide therapy for GBM patients

Second line study (started)

GBMdiagnosis Relapse Sativex

y ( )

diagnosisSurgery Radiotherapy

+TMZ?TMZ

p

Decease

Sativex+ TMZ

NEWLY-DIAGNOSED GBM RECURRENT GBMRelapse

Do MK levels predict resistance to Sativex + TMZ therapy?

Clinical Trial (ongoing) Primary objectivesTo determine the safety profile of- To determine the safety profile of

Sativex® in combination with TMZ- To provide preliminary evidence of anti-tumoural activity for this drug combinationtumoural activity for this drug combination(comparison with a high-dense regime of temozolomide)

Other clinical studies with CBs as anti-cancer agentsOther clinical studies with CBs as anti cancer agents

Future clinical studiesFuture clinical studies

Selecting the appropriate cannabinoids for anticancer therapies

THC CBD+(1:1)Other ratios THC:CBD

CB1/CB2 agonists ?


Optimizing delivery methods/via of administration


Other phytocannabinoids?

Marijuana Sativex(THC/CBD)

Marinol(THC)

Cesamet(Nabilone)

Which cancer types?

Glioma

Cancer types lacking effective treatments

Melanoma

Pancreatic adenocarcinoma

Which cancer types?Subtypes of cancer that do not respond to current therapies

Breast cancer

Prostate cancer

Combinational therapies?

CombinationalCBs + Classic anticancer treatments (ChT and RT)

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

THC 6 μM**

140160

m V

ehic

le)

THC 6 μM

ALDH2s (a

.u.) 1

20406080

100120

iabi

lity

(% fr

om IGFBP5MDKPDGFRACSF1GBP2UPP1m

RN

A le

vels

CSF1

GBP2

UPP1

ID3

0

0.5

020

Cel

l vi

ID3mALDH2

IGFBP5

MDK

PDGFRA

CSF1

It is essential to identify the molecular factors associated with the resistance/sensitivity to cannabinoid anticancer action in clinical studiesresistance/sensitivity to cannabinoid anticancer action in clinical studies

U624 INSERM (Marsella)

AcknowledgementsHospital 12 de Octubre U624 INSERM (Marsella)

J.L. Iovanna

Manuel Guzmán CIB (Madrid)Patricia BoyaHospital Clínico San Carlos

Hospital 12 de Octubre(Madrid)

Juan SepúlvedaAurelio Hernández Laín

David Dávilay

IRCCS 'L. Spallanzani‘(Roma)

Mauro PiacentiniFrancesco Cecconi

Hospital Clínico San Carlos(Madrid)

Juan BarciaPedro Pérez Segura

Eva Resel

Elena G Taboada

Mar Lorente

Israel López Valero

José González Francesco CecconiHospital Virgen de la Salud

(Toledo)Bárbara MeléndezManuela Mollejo

María Salazar

Sonia HernándezCristina Sánchez

U Sheffield (Sheffield, UK)E. Kiss-Toth

f

Alba Orea Ismael Galve-Roperh

Hospital Universitario(Tenerife)

L González-FeriaSofía Torres

María Salazar

Fátima Rodríguez

Iñi S l

Center for Cancer Research(Copenhagen)

M, Jaattela

U Newcastle (Newcastle UK)

Arkaitz Carracedo

MRC PPU (Dundee)Dario Alessi

Iñigo Salanueva

Ainara Egia

U. Newcastle (Newcastle, UK)P. Lovat

ISCiii (Madrid)Pilar Sánchez

Dario Alessi

CSIC(Barcelona)

G Fabrias

UPV(Bilbao)F Goñi

J Casas A AlonsoR Montes

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