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