Urologic Oncology: Seminars and Original Investigations
Original articlesComplete radiological and metabolic response of metastatic renal cell carcinoma to SU5416 (semaxanib) in a patient with probable von Hippel-Lindau syndrome
Introduction
Solid tumors require the development of new blood vessels in order to grow beyond 1–2 mm3. The angiogenic factor VEGF is secreted by many tumors and plays an important role in the induction of tumor neoangiogenesis. VEGF exerts its effects by activating the tyrosine kinase receptors VEGFR-1/Flt-1 and VEGFR-2/Flk-1/KDR on endothelial cells [1], [2]. These receptors are important for the growth of a diverse range of solid tumors including RCC [3], [4], [5].
VHL is a rare autosomal dominant familial cancer syndrome caused by germline deletions or mutations in the VHL tumor suppressor gene located on chromosome 3p25. Approximately 20% of cases result from de novo germline mutations. VHL is characterized by abnormal vascular proliferation and a substantially increased risk of developing clear cell RCC, central nervous system hemangioblastomas, retinal angiomas, pheochromocytomas and neuroendocrine pancreatic tumors [6], [7]. Inactivation of the VHL gene appears to be a critical event in renal clear cell tumorigenesis, as the majority of sporadic cases of RCC display loss of heterozygosity of the VHL gene locus and either intragenic mutation or promoter hypermethylation [8], [9].
The VHL protein forms part of a complex that targets proteins such as hypoxia-inducible factor 1α and 2α for degradation [10]. These transcription factors are important for the activation of hypoxia inducible genes such as VEGF. Thus, VHL plays an important role in modulating VEGF expression, although it may have other tumor suppressor functions.
Because the hypoxia response pathway and VEGF overexpression are critical components of RCC, VEGF receptor inhibition represents a novel therapeutic target. SU5416 (semaxanib) is a selective tyrosine kinase inhibitor of VEGF-2 (Flk-1/KDR), expressed on the cell surface of endothelial cells [11], [12]. SU5416 also inhibits the platelet derived growth factor (PDGF)-receptor and c-kit activation, although its anti-angiogenic activity is largely a result of VEGF receptor inhibition. In murine xenograft models, SU5416 has been shown to inhibit growth of a variety of different tumor types [11].
Here we report a case of a 56 year old male with presumed de novo VHL syndrome and RCC, clear cell type, with widespread metastases on baseline CT and F-18 FDG PET scans. He was treated with SU5416 (semaxanib), 145 mg/m2 IV twice-weekly for 11 doses as part of a phase II trial evaluating the early assessment of response to this agent by FDG PET.
Section snippets
Case report
A 56 year old male with no significant past medical or family history presented initially with a parietal capillary hemangioblastoma, which was completely resected. He subsequently underwent a staging CT and ophthalmological examination to exclude the possibility of de novo VHL syndrome. His eye examination showed no angiomata, however, abdominal CT scan revealed an 8 cm left renal mass, which was subsequently resected with incomplete surgical margins. Histological examination demonstrated
Discussion
The role of VEGF overexpression in VHL syndrome has been previously documented in a number of studies, and is thought to be particularly important in the development of angiomas and hemangioblastomas [13], [14]. A case report of a patient with VHL syndrome with visual impairment secondary to an optic nerve head hemangioblastoma had rapid, extensive and durable recovery following administration of SU5416 [15]. A clinical trial has been proposed using SU5416 in patients with VHL syndrome to
Acknowledgements
We thank Dr. R.J.M. Gardner for his helpful advice. There was no external funding for the production of this paper. None of the authors have any financial relationships with Sugen or Pfizer.
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