Towards the utilization of cannabinoids as anti-cancer
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1 Towards the utilization of cannabinoids as anti-cancer agents Guillermo Velasco Sestri Levante September 2015
2 Anti-cancer activity of cannabinoids Munson et al. (1975) Antineoplastic activity of cannabinoids J. Natl. Cancer Inst. 55,
3 VehIcle THC Before THC After THC Galve-Roperh et. al. Nat. Med. 2000
4 Cannabinoids exhibit anti-tumor activity in many different animal models of cancer Glioma Melanoma Skin carcinoma Lung cancer Breast cancer Hepatocellular carcinoma Pancreatic adenocarcinoma Leukaemia Prostate cancer
5 Antitumoral action of cannabinoids Velasco et al. Nat Rev Cancer (2012)
6 Selectivity of cannabinoid anticancer action Pancreas Veh Cannabinoid P T P P Normal cell Tumor cell Nucleos T P T P P Supervival TUNEL T Carracedo et al. Cancer Res (2006)
7 Potential clinical application
8 Glioblastoma (GBM) A1 st Pilot Clinical trial ( ) GBM diagnosis (n=9) 1st Surgery Radiotherapy ±Chemotherapy Infusion catheter (Pre-treatment tumour biopsy) Relapse THC treatment Post-treatment tumour biopsy Decease EXPERIMENTAL PERIOD SURVIVAL
9 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
10 Survival of patients 1.0 fraction Su urviving Median survival = 24 wk (95% CI: 15-33) Similar il to other drugs (e.g. TMZ) Time after THC (wk)
11 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
12 Antitumoral action of cannabinoids Velasco et al. Nat Rev Cancer (2012)
13 CBD and other phytocannabinoids? CB1, CB2 TRPVs Other receptors? CBD ROS Additional mechanisms Autophagy Apoptosis Cancer cell death
14 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
15 Predictor of resistance to cannabinoid anticancer activity it Primary cultures of human glioma cells THC 6 μm ** from Vehicle) Ce ell viability (% mrna lev vels (a.u.) ID3 UPP1 GBP2 CSF1 PDGFRA MDK ALDH2 IGFBP5 MDK PDGFRA CSF1 GBP2 UPP1 ID3 IGFBP5 ALDH2
16 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
17 Cannabinoid-based combinational therapies for GBM patients?
18 Cannabinoid-based combinational therapies for GBM patients?
19 Standard GBM therapy GBM diagnosis Surgery Radiotherapy +TMZ? TMZ Relapse 2nd line therapies Decease NEWLY-DIAGNOSED GBM RECURRENT GBM GBM
20 Cannabinoids enhance TMZ anticancer activity in GBM preclinical i l models 10 U87 MG astrocytoma cells U87MG Veh Tumor vo olume (% day 1) VEH THC 15 mg/kg TMZ 5 mg/kg THC+TMZ THC TMZ Mean ± SEM S.E.M Vehicle 9.2±0.6 THC 5.1±0.4 TMZ 3.2±0.4 TMZ+THC 0.4±0.0, ** ** ** ## ΩΩ 0 THC+TMZ Days of treatment Similar effect on cannabinoid and TMZ-resistant tumors
21 Selecting the appropriate cannabinoids for anticancer therapies - CBD has anticancer activity by itself THC + CBD (1:1) - CBD attenuates the psychoactive effects of THC CB1/CB2 agonists? - Wide experience in the use THC and CBD (Sativex) FAAH/MAGL inhibitors? Other phytocannabinoids?
22 Cannabinoids enhance TMZ anticancer activity U87 MG astrocytoma cells 12 Peritumoral administration VEH Tumor volume (fold from day 1) SAT (7.5 mg/kg THC-BDS + 7,5 mg/kg CBD-BDS) BDS) THC (15 mg/kg) TMZ (5 mg/kg) SAT + TMZ THC (15 mg/kg) + TMZ Mean ± S.E.M VEH 10.3 ± ± 0.3 SAT THC (15 mg/kg) 5.8 ± 0.5 TMZ (5 mg/kg) 4.1 ± 0.4 SAT + TMZ ΣΣ ΩΩ 2.6 ± 0.3 THC + TMZ ## ΩΩ 2.4 ± Time ( days)
23 Cannabinoids + temozolomide therapy for GBM patients Second line study (started) GBM diagnosis Surgery Radiotherapy +TMZ? TMZ Relapse Sativex + TMZ Decease NEWLY-DIAGNOSED GBM RECURRENT GBM Relapse Do MK levels predict resistance to Sativex + TMZ therapy?
24 Clinical Trial (ongoing) Primary objectives - To determine the safety profile of Sativex in combination with TMZ - To provide preliminary evidence of anti- tumoural activity for this drug combination (comparison with a high-dense regime of temozolomide)
25 Other clinical studies with CBs as anti-cancer agents
26 Future clinical studies
27 Selecting the appropriate cannabinoids for anticancer therapies THC + CBD (1:1) Other ratios THC:CBD CB1/CB2 agonists? FAAH/MAGL inhibitors? Optimizing delivery methods/via of administration Other phytocannabinoids? Marijuana Sativex (THC/CBD) Marinol (THC) Cesamet (Nabilone)
28 Which cancer types? Cancer types lacking effective treatments Glioma Melanoma Pancreatic adenocarcinoma
29 Which cancer types? Subtypes of cancer that do not respond to current therapies Breast cancer Prostate cancer
30 Combinational therapies? Combinational therapies CBs + Classic anticancer treatments (ChT and RT) CBs + Targeted therapies CBs + Classic anticancer treatments (ChT and RT) + Targeted therapies Additional preclinical research is still required
31 Future of cancer treatment: individualized therapies THC 6 μm ** iability (% from Vehicle) Cell vi mrna levels (a.u.) ID3 UPP1 GBP2 CSF1 PDGFRA MDK ALDH2 IGFBP5 MDK PDGFRA CSF1 GBP2 UPP1 ID3 IGFBP5 ALDH2 It is essential to identify the molecular factors associated with the resistance/sensitivity to cannabinoid anticancer action in clinical studies
32 David Dávila Israel López Valero Mar Lorente José González Sonia Hernández Alba Orea María Salazar Sofía Torres Fátima Rodríguez Iñigo Salanueva Arkaitz Carracedo Ainara Egia Manuel Guzmán Elena G Taboada Eva Resel Cristina Sánchez Ismael Galve-Roperh Acknowledgements Hospital 12 de Octubre (Madrid) Juan Sepúlveda Aurelio Hernández Laín Hospital Clínico San Carlos (Madrid) Juan Barcia Pedro Pérez Segura Hospital Virgen de la Salud (Toledo) Bárbara Meléndez Manuela Mollejo Hospital Universitario (Tenerife) L González-Feria ISCiii (Madrid) Pilar Sánchez U624 INSERM (Marsella) J.L. Iovanna CIB (Madrid) Patricia Boya IRCCS 'L. Spallanzani (Roma) Mauro Piacentini Francesco Cecconi U Sheffield (Sheffield, UK) E. Kiss-Toth Center for Cancer Research (Copenhagen) M, Jaattela U. Newcastle (Newcastle, UK) P. Lovat MRC PPU (Dundee) Dario Alessi CSIC (Barcelona) G Fabrias J Casas UPV (Bilbao) F Goñi A Alonso R Montes
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