Anti-Human VHL monoclonal antibody

BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 {64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

The immunomodulatory effects of gamma-aminobutyric acid (GABA) on renal disease were investigated using conditional von Hippel-Lindau gene-knockout C57BL/6 mice (Vhlh(del/del) mice), which spontaneously develop fibrosis, inflammation, and hyperplastic clear-cell lesions in the kidneys. Diets containing either GABA rice or pure GABA significantly extended the life span of Vhlh(del/del) mice, with decreasing levels of urinary kidney injury molecule (KIM)-1 and renal clear cell formation, which are the typical markers of renal damage. Levels of serum inflammatory markers such as interleukin (IL)-6, renal monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-beta, IL-17A, C-C chemokine receptor type 2 (CCR2), and macrophage infiltration were significantly decreased in GABA-fed mice. Further, induction of monocyte migration was significantly suppressed in GABA-treated VHL-silenced HK-2 cells, suggesting that GABA has protective effects against renal injury by disrupting the MCP-1/CCR2 axis and thus macrophage infiltration.