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5/5/2016
1
Rachel GilesNephrology, University Medical Center Utrecht
VHL Medical Symposium: What’s New?
Transcription of:VEGFOther angiogenic factors
HIF‐
Nucleus
HIF‐
VHL
VEGF = vascular endothelial growth factor; HIF = hypoxia‐inducible factor.
VHL Mutation Mimicsthe Hypoxic State
Eric Jonasch
Sorafenib, SunitinibPazopanib, Axitinib
BevacizumabTemsirolimusEverolimus
Albiges et al. The Oncologist 2012
Targeted therapy for kidney cancer
-CA9
Progression model of ccRCC development in VHL patients
Single cell Multiple cells
Microcyst Simple cyst Atypical cyst
Micro-ccRCC Solid ccRCC
Cystic ccRCC
Biallelic VHL loss
PI3K pathwayLoss of primary cilium Loss of p53
Loss of p53
HIF-1- and HIF-2-dependent cyst and tumour initiation
HIF-1 loss ???
HIF-1 oncogenic HIF-1 tumour suppressiveHIF-2 oncogenic HIF-2 oncogenic
Ian Frew
5/5/2016
2
Kidney tubule Simple cyst Renal cell carcinoma
Cilia loss>48 genes (VHL)
VHL, HIF1a and HIF2a, P53, RB (?PBRM1, SETD2, BAP1, KDM5), ER stress, Replicative stress
Renal Cell RegulationTalks: Ruhe Dere, Ian Frew, Scott Haake , Chan‐Yen Kuo, Othon Iliopoluos
PAS‐A
PAS‐B
bHLH bHLH
PAS‐A
PAS‐B
HIF‐2ARNT
Talk Fraydoon Rastinejad
5 distinct druggable sites
Eijiro Nakamura: inducible pluripotent stem cells
iPS cells
Fibroblasts
differentiation stem cells
Zebrafish with VHL: Othon Iliopoulous and Rachel Giles
Vascular defects, like hemangioblastomasRetinal angiomasPancreasKidneyAdrenal Glands
Drug testing/target discovery
5/5/2016
3
VHL‐ A Regulatory Hub
Li and Kim J Cell Mol Med 2011 Eric Jonasch
VHLHIF
Non HIFProteins
gHIF
Targets
How many metabolites are present, and in what quantities?
Which pathways are active?
How active are the pathways (i.e. how fast are they moving)?
*
*
Ralph Deberardinis
VHL‐specific metabolism: Amato Giaccia
• HIF suppresses PGC‐1α expression via activation of Dec1• PGC‐1α suppression results in decreased OXPHOS activity and promotes clear cell
phenotype• Induction of PGC‐1α inhibits ccRCC tumor growth and suppresses clear cell phenotype• Decreased expression of PGC‐1α is significantly associated with poor clinical outcome
in ccRCC
Puzzle pieces of fundamental biology
• JADE‐1 (Herb Cohen)‐ DNA damage repair• pVHL binds AKT1 (WenYi Wei)• pVHL link to LC3C which acts like a new tumor suppressor in mice (Maria Czyzyk‐Krzeska)
• ZHX2: new pVHL target in kidney cancer (Qing Zhang)
• We have hemangiomblastoma cell lines! (Ana Matelo)
5/5/2016
4
Immunotherapy, Kidney CancerTalks: Gordon Freeman, Marcela Maus
CART‐cell therapyCheckpoint inhibitorsDiscussion about safety for VHL carriers
More Information: 10‐for‐IO.info