This oral presentation made at ESOC 2016 Marbella by Eric Raymond investigates the role of c-MET and HGF in carcinogenesis and its potential role as a target for novel therapy in various malignancies. The presentation includes an historical overview and updated information on the role of the HGF/MET in resistance to various therapies, including chemotherapy, radiotherapy, targeted agents, antiangiogenics, and immunotherapy.

1. MET/HGF relevance for targeted
therapy malignancies
Eric Raymond MD, PhD
Chair of Medical Oncology
@ Groupe Hospitalier Paris Saint-Joseph - France
eraymond@hpsj.fr

2. Disclosures
– Pfizer
– Novartis
– Eli Lilly
– Ipsen
– Oncoethyx

3. Cellular & Molecular Components of Carcinoma
Microenvironments
Endothelial cells
Pericytes
VEGFR-PDGFR
T cells (CD4-Treg)
CD4:PD1-CTLA4-CD28
Treg: CD73-CD39
Dendritic cells
PDL1-PD1-MSH II-CD80/86
Tumor associated macrophages
CXCR4-TGFβR
Tumor cells
TGFβR-MET-PDL1
Fibroblasts
FGFR
TGFβ HGF
FGF19 IL8 IL10
SDF1/CXCL12

4. MET/HGF Historical Milestones
MET: Mesenchymal to Epithelial Transition factor / HGF: Hepatocyte Growth Factor
1984 1991 1994 1997
Identification of the met oncogene in a chemically transformed
human osteosarcoma cell line (Cooper)
c-met maps to chromosome bands 7q21-31
c-met proto-oncogene was detected on the cell surface and classified as a
growth factor receptor of the tyrosine kinase family
c-met proto-oncogene acts as a transmembrane tyrosine kinase
receptor for a single ligand, HGF (Bottaro)
An autocrine loop of an otherwise unaltered HGF/c-MET pair confers
oncogenic properties (Bellusci)
Identification of germline mutations of the c-met proto-oncogene in
hereditary papillary renal carcinoma and establishment of a genetic
link between c-MET and cancer (Schmidt)
1982
A peptide growth factor, structurally related to plasminogen, was
isolated and characterized as a new substance responsible for liver
regeneration in the serum of partially hepatectomized rats
(Michalopoulos, Nakamura, Michalopoulos, Thaler)
A scatter factor was shown to disrupt intercellular junctions of
epithelial cells, stimulate their migration in a paracrine manner and
promote an invasive phenotype (Stoker, Weidner)
1985
Hepatotropin & hepatopoietin was subsequently purified from the plasma of
patients with fulminant hepatic failure, from rat platelets, normal human plasma,
rabbit serum, and rat liver (Gohda, Nakamura, Zarnegar
Designation of HGF as a mitogen, motogen and morphogen) (Rubin, Montesano, Matsumoto)
Adapted from Petr Szturz et al, in press 2016

5. Structural Determinants of MET/HGF
MET
Adapted from Petr Szturz et al, in press 2016 & Shinya Mizuno & Toshikazu Nakamura Int. J. Mol. Sci. 2013

6. Relevant Docking Sites in Cancer
Adapted from Shinya Mizuno & Toshikazu Nakamura Int. J. Mol. Sci. 2013

7. Cellular Effects of HGF in Various Cellular
Components of the Tumor Microenvironment
Adapted from Shinya Mizuno & Toshikazu Nakamura Int. J. Mol. Sci. 2013

8. HGF/MET Cooperates with HER1-3 to
Develop Aggressive Phenotypes
Adapted from Petr Szturz et al, in press 2016

9. Therapy-Induced HGF Secretion Protects Against
Apoptosis and Confers Resistance to Anticancer Drugs
Hypoxia - Necrosis
Sunitinib
Sorafenib
Adapted from Shinya Mizuno & Toshikazu Nakamura Int. J. Mol. Sci. 2013

10. Senino B, et al. Cancer Discovery 2012 & Faris JE, et al. ASCO 2014
NCT01466036 - Cabozantinib pNET & Carcinoids
Dual VEGFR/C-MET inhibitors may counteract EMT
activation developed under anti-VEGF/VEGFR inhibitors

11. c-MET Dysfunctions Commonly
Observed in Carcinomas
47%
26%
23%
4%
mRNA overexpression
Protein overexpression
Gene amplification
Mutation
Chronic inflammation
Fibrosis
Local immunosuppression
Genuine Hypoxia
Treatment induced hypoxia
(embolization, anti-angiogenic)
Exposure to chemotherapy and
radiotherapy
Random gene mutation

12. Identification of Selective c-Met & EGFR Inhibitors in a Vichem
Compound Library in a 3D Tissue Culture-Based High-Content
Screening Platform (prostate cancer cells)
http://ocello.nl/development-3d-tissue-culture-based-high-content-screening-platform-uses-phenotypic-profiling-discriminate-selective-inhibitors-receptor-tyrosine-kinases/

13. Current MET/HGF Inhibitors
Tepotinib
DARPin MP0250
Adapted from S Peters & A.A. Adjei Nature Reviews Clinical Oncology 9, 314-326 (2012)

14. Potential of MET/HGF Inhibitors in Cancer Therapy
Reduced
angiogenesis
Potentiation of
anti-angiogenic
drugs
Tumor
angiogenesis
Direct inhibition of cancer
cell invasion and metastasis
Restore of DNA damage
induction of apoptosis
Counteract resistance to
EGFR/HER2-3 inhibitors
Tumor cell signaling
Restore the local
inhibition of
dendritic cells &
T-lymphocytes
May potentiate
the effects of
checkpoint
inhibitors
Immune stroma
ç Combinations è

15. Conclusions
• Various components of tumor microenvironment
could be used as targets to control tumor growth
and progression in human carcinoma
• MET/HGF inhibitors appear as promising options for
tumor aggressiveness by inhibiting invasion &
metastases and restore sensitivity to DNA-damaging
agents including radiotherapy, HER-inhibitors, and
antiangiogenics
• Combinations of MET/HGF with therapies known to
induce epithelial-to-mesenchymal-transition offer
promises in sustaining control of tumor progression

16. Thanks for your attention
Eric Raymond MD, PhD
Chair of Medical Oncology
@ Groupe Hospitalier Paris Saint-Joseph
France
eraymond@hpsj.fr