Targeting Hypoxic Signaling in Pheochromocytoma

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Targeting Hypoxic Signaling in Pheochromocytoma

• Karl Zawadzki

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Pheochromocytoma

• rare neuroendocrine cancer of epinephrine and
  norepinephrine producing cells (chromaffin cells)
• usually found in the adrenal medulla
• symptoms
• headaches
• sweating
• rapid heartbeat
• hypertension
• anxiety

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Hypoxia as an Tumour-Initiating Event
Ub
VEGF
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Hypoxic Signalling

• Tumours lacking VHL or SDH subunits have
  constitutive hypoxic signalling
• In small studies, tumours caused by RET mutations
  also usually lost pVHL function
• LOH data show a chromosomal region containing the
  SDHD gene is often lost during tumour
  progression, except in VHL tumours
• extensive vascularization
• of all tumours suggests
• angiogenic signalling

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Hypoxia Inducible Factor 1a

• HIF-1a is degraded by VHL-mediated ubiquitination
  in the presence of oxygen
• in low oxygen or the absence of VHL HIF-1a is
  stable
• binds to HIF-1ß to activate hypoxia-regulated
  genes
• potential drug targets
• HIF-1a transcription (some drugs in development)
• HIF-1a DNA binding
• HIF-1a/HIF-1ß interaction

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Preliminary Compound Screen

• use a VHL deficient cell line with a HIF-1a
  dependent reporter, a constitutive reporter, and
  a reporter with the hif-1a regulatory region to
  screen a compound library

possible post-transcriptional inhibitor
possible inhibitor of transcription
no effect
RFP
GFP
RFP, GFP, YFP
GFP, YFP
GFP
YFP

• further verify compound family with biochemical,
  cell-based, and in vivo assays

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Potential Uses of a HIF-1a Inhibitor

• Applications
• All hypoxia-driven tumours (Pheochromocytomas,
  other VHL syndromes)
• All tumours oxygen-starved tumours
• Limitations
• Overexpression or mutation of HIF-1a will thwart
  therapy
• Positives
• Targeting protein-protein interaction surfaces or
  DNA binding regions may make compensatory
  mutations difficult