New therapies for pancreatic cancer treatment:

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1 New therapies for pancreatic cancer treatment:! Targeting of surface proteins! Development of nanoparticles CRRET laboratory Growth factors and angiogenesis School of Sciences and Technologies University of Paris Est

2 Lessons form 30 years of cancer research:! As normal cells evolve progressively to a neoplastic state, they acquire a succession of at least six identified hallmarks of cancer.! Tumours are more than insular masses of proliferating cells. Instead they are complex tissues composed of multiple distinc cell type that participate in heterotypic interactions with one another. Hanahan and Weinberg, Cell 2011

3 Hanahan and Weinberg, Cell 2011 The hallmarks of cancer

4 Lessons form 30 years of cancer research:! As normal cells evolve progressively to a neoplastic state, they acquire a succession of at least six identified hallmarks of cancer.! Tumours are more than insular masses of proliferating cells. Instead they are complex tissues composed of multiple distinc cell type that participate in heterotypic interactions with one another. Hanahan and Weinberg, Cell 2011

5 The cells of the tumour microenvironnement Hanahan and Weinberg, Cell 2011

6 Treating cancer today! Targeting the hallmarks of cancer! Developping targeting ability and specificity! Improving efficiency " New molecular targets " The combined versus single treatment

7 Multitargeting of the hallmarks of cancer Hanahan and Weinberg, Cell 2011

8 Treating cancer today! Targeting the hallmarks of cancer! Developping targeting ability and specificity! Improving efficiency " New molecular targets " The combined versus single treatment Targeting cancer cell New delivery strategies

9 The importance of targeting specifically tumour cells

10 Pancreatic ductal adenocarcinoma The pancreas is a secretory structure with an internal hormonal role (endocrine) and an external digestive role (exocrine). It has two main ducts, the main pancreatic duct, and the accessory pancreatic duct. These drain enzymes through the ampulla of Vater into the duodenum.

11 Hypotheses for pancreatic ductal adenocarcinoma (PDAC) development Modified by Neuzillet, Pharmacology and Therapeutics 2015

12 Standard treatment of PDAC

13 Selected completed and ongoing adjuvant trials in pancreatic cancer Garrido-Laguna, I. & Hidalgo, M. (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies Nat. Rev. Clin. Oncol. doi: /nrclinonc

14 Pancreatic ductal adenocarcinoma It is one of the five most lethal malignancies into the world compared to other cancers American cancer society, 2012

15 Projecting pancreas cancer deaths to 2030

16 The pancreatic cancer microenvironnement Highly fibrotic Stroma rich in SPARC Poorly angiogenic PDAC

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18 Specificities of PDAC! Resistance to treatment! Poor efficiency of delivery " New molecular targets " The combined versus single treatment New delivery strategies

19 Novel therapies and targets in pancreatic cancer Garrido-Laguna, I. & Hidalgo, M. (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies Nat. Rev. Clin. Oncol. doi: /nrclinonc

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21 Nanomedicine to improve drug efficiency and delivery

22 Cancer nanotechnology: without specific molecular target! New mode for chemotherapeutic drug delivery, the unique phsysicochemical properties of nanomaterials can be exploited for targeting cancer cells: # tunable surface charge to promote electrostatic interaction with the negatively charged cancer cell surface or tumour endothelial cell surface in order to stimulate endocytosis; # tunable hydrophilic surface with stealth properties to prevent phagocytosis! Passive action: Nanomaterials can escape through the leaky vasculature and can be trapped within the tumour due to the dysfunctional lymphatic drainage system.

23 Cancer nanotechnology: without specific molecular target! New mode for chemotherapeutic drug delivery, the unique phsysicochemical properties of nanomaterials can be exploited for targeting cancer cells: # tunable surface charge to promote electrostatic interaction with the negatively charged cancer cell surface or tumour endothelial cell surface in order to stimulate endocytosis; # tunable hydrophilic surface with stealth properties to prevent phagocytosis! Passive action: Nanomaterials can escape through the leaky vasculature and can be trapped within the tumour due to the dysfunctional lymphatic drainage system.

24 Cancer nanotechnology: targeting molecules! Conjugation of biomolecules to the surface of nanomaterial system. The best targets are specific cancer surface molecules that are not expressed in other cell types.! Surface-active biomolecules can bind either non internalising target molecules Or endocytosis-active molecules. In the former case, the nanoparticule is not engulfed but resides on the surface of the cells (generally they are tumour vessels targeting molecules), the drug loaded can then release with higher local concentration near the target site. In the latter case a broad range of chemiotherapeutic agents can be delivered including sirna or DNA binding drugs.! Exemple of selective surface markers: -Folate receptors -Transferrin -Growth factor receptors overexpression (EGFR, HER-2) -Tissue marker (PSA for prostate tumour cells, HER-2 and LHRH for bresat tumour cells,

25 Abraxane: The first nanodrug approved by the FDA

26 Nanoparticle albumin bound (nab) technology : A nanotechnology platform for biologically interactive drug delivery and targeting Neil P. Desai, PhD Vice President, Research and Development Abraxis BioScience, Inc

27 Abraxane (nab-paclitaxel) is a solvent-free nano version of Taxol (cremophor-based paclitaxel) Abraxane Abraxane received FDA Approval January, 2005 for metastatic breast cancer Taxol Contents: 100 mg paclitaxel 900 mg albumin No Surfactants/Solvents Contents: Paclitaxel 6 mg/ml Cremophor 537 mg/ml Ethanol 396 mg/ml

28 Nanoparticle Albumin-bound (nab) platform technology Albumin Active drug in nanoparticle is in non-crystalline, amorphous, readily bioavailable state cryo-tem Mean size = nm Hydrophobic drugs, e.g.,paclitaxel, docetaxel, rapamycin etc. Concentration dependent dissociation into individual drug-bound albumin molecules

29 Recommendations for revising current definitions of size range/function for nanotechnology drug products Function: Must provide special characteristics e.g., novel physical characteristics, unique delivery, cellular penetration, receptor binding, targeting etc. Suggested size cutoff equivalent to pore size of sterile filter (220 nm) : 220 nm or 0.22 um is relevant size cutoff for sterile filtration to ensure that injectable pharmaceutical nanotechnology products are sterile Below about 220 nm, we are outside the visible range of an optical microscope and special techniques are required to characterize these structures. Establish a committee to determine cut off size for nanotechnology definition

30 A key aspect of nanoparticle stability of nab-paclitaxel is size and zeta potential Reproducible, narrow size distribution by Laser Light Scattering Negatively charged nanoparticles resist agglomeration 25.0 Volume Percent Mean Particle Diameter ~ 130 nm Negatively Charged Albumin Particle Diameter (nm) nab nanoparticles are physically stable for several days in suspension

31 Rapid Tumor Accumulation of nab-paclitaxel in tumor Fluorescent nab-paclitaxel Nanoparticles* in Syringe injected via tail vein 1 min after I.V. injection Imaged Tumor MOUSE TUMOR MODEL Imaging under Hg-lamp with nm bandpass excitation; *nab-paclitaxel containing 0.3% Fluorescent Marker ABI, data on file and Desai N, et al. Clin Cancer Res 2006;12(4), min after I.V. injection 33% higher tumor accumulation of paclitaxel over 24 hr confirmed with radiolabelled nab-paclitaxel as compared to Taxol (p<0.0001)

32 Abraxane approved by FDA with about twice the response rate of Taxol in metastatic breast cancer Source: Abraxane Package Insert

33 Abraxane increases the overall survival of PDAC patients

34 Nab-platform utilizes endogenous albumin pathways of endothelial transcytosis (gp60) and intratumoral binding of SPARC gp60 receptor Tumor endothelial cell Red Blood cell Albumin-Bound Drug Gp60 Receptor Albumin-drug complex gp60/alb-drug complex TUMOR BLOOD VESSEL Caveolae TUMOR INTERSTITIUM SPARC on Tumor cell surface Alb-drug complex transcytosed by gp60 Surface SPARC bound to Alb-drug complex SPARC Internalized SPARC/Alb-drug complex Tumor cells Albumin-Drug Accumulation

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36 CRRET laboratory Growth factors and angiogenesis School of Sciences and Technologies University of Paris Est Team leader Courty José DR CNRS Cascone Ilaria MC Destouches Damien MC Carpentier Gilles IGE Haber Damien T Vallé Benoit IGE Claire Houppe, T Marie Darche, IGE Mélissande Cossutta D Matteo Ponzo, D Fabio Raineri T