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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease
E Jonasch1, I E McCutcheon2, S G Waguespack3
1Departments of Genitourinary Medical Oncology.
Background:
Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.
Methods:
Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).
Results:
Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).
Conclusions:
Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.
Insights
Sunitinib showed acceptable toxicity in Von Hippel-Lindau (VHL) disease patients, with partial response in renal cell carcinoma (RCC) but not hemangioblastomas (HB). Fibroblast growth factor pathway inhibitors may benefit HB.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Von Hippel-Lindau (VHL) disease is characterized by vascular neoplasms.
- Sunitinib is evaluated for safety and efficacy in VHL patients.
- Candidate receptor expression in archived tissues is examined.
Purpose of the Study:
- To assess the safety and efficacy of sunitinib in patients with VHL disease.
- To investigate biomarker expression in VHL-associated tumors.
Main Methods:
- Patients received sunitinib for four 28-day cycles with 14 days off.
- Toxicity and tumor response (modified RECIST) were primary endpoints.
- Laser-scanning cytometry analyzed biomarker expression in renal cell carcinomas (RCCs) and hemangioblastomas (HBs).
Main Results:
- Sunitinib treatment was associated with Grade 3 fatigue in 5/15 patients, requiring dose reductions in 10.
- Partial response was observed in 33% of RCCs, but not in HBs (P=0.014).
- Lower phosphorylated VEGFR-2 and higher pFRS2 levels were found in HB endothelium compared to RCC.
Conclusions:
- Sunitinib demonstrated acceptable toxicity in VHL patients.
- Significant anti-tumor activity was noted in RCC but not HB.
- Elevated pFRS2 in HB suggests potential benefit from fibroblast growth factor pathway inhibitors for HB treatment.
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