Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary β2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.

Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors

SummaryThe vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors.

The Impact of VEGF Inhibition on Clinical Outcomes in Patients With Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy: A Retrospective Cohort Study

BackgroundIn recent years, immune checkpoint inhibitors (ICIs) in combination with chemotherapy have increased survival in patients with advanced non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF), which plays a key role in tumor angiogenesis, is an immunological modulator; therefore, it is expected that anti-VEGF therapy in combination with ICIs enhances the antitumor effect of ICIs. In the present study, we investigated the impact of VEGF inhibition on clinical outcomes of NSCLC patients, including the efficacy of ICI treatment.MethodsA total of 105 patients with advanced NSCLC who had been treated with ICIs were retrospectively analyzed to examine the relationship between the history of treatment with anti-VEGF agents and the clinical outcomes with ICI monotherapy.ResultsPatients who had received anti-VEGF therapy prior to ICIs showed shortened progression-free survival of ICI treatment and a decreased overall response rate to ICI treatment. By contrast, anti-VEGF therapy after ICI treatment was associated with increased survival, especially in patients who had also received anti-VEGF therapy prior to ICI therapy.ConclusionsThese retrospective observations suggest that anti-VEGF therapy prior to ICIs might be a negative predictor of response to ICIs. The sequence of anti-VEGF therapy might play a role in its ability to predict survival in NSCLC patients. Further investigation is warranted to identify the role of VEGF inhibition in altering clinical outcomes after immunotherapy.

Phase I/II study of nivolumab plus vorolanib in patients with thoracic malignancies: Interim efficacy of the SCLC and primary refractory NSCLC cohorts, and safety data across all cohorts.

2578 Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086.

Angiotensin-Converting Enzyme 2 Activator Ameliorates Severe Pulmonary Hypertension in a Rat Model of Left Pneumonectomy Combined With VEGF Inhibition

Background: Pulmonary arterial hypertension (PAH) is a life-threatening and deteriorating disease with no promising therapy available currently due to its diversity and complexity. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism of PAH. Angiotensin-converting enzyme 2 (ACE2), which catalyzes the hydrolysis of the vasoconstrictor angiotensin (Ang) II into the vasodilator Ang-(1-7), has been shown to be an important regulator of blood pressure and cardiovascular diseases. Herein we hypothesized diminazene aceturate (DIZE), an ACE2 activator, could ameliorate the development of PAH and pulmonary vascular remodeling.Methods: A murine model of PAH was established using left pneumonectomy (PNx) on day 0 followed by injection of a single dose of the VEGF receptor-2 inhibitor SU5416 (25 mg/kg) subcutaneously on day 1. All hemodynamic and biochemical measurements were done at the end of the study on day 42. Animals were divided into 4 groups (n = 6–8/group): (1) sham-operated group, (2) vehicle-treatment group (SuPNx42), (3) early treatment group (SuPNx42/DIZE1−42) with DIZE at 15 mg/kg/day, subcutaneously from day 1 to day 42, and (4) late treatment group (SuPNx42/DIZE29−42) with DIZE from days 29–42.Results: In both the early and late treatment groups, DIZE significantly attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, and right ventricle brain natriuretic peptide (BNP), as well as reversed the overexpression of ACE while up-regulating the expression of Ang-(1-7) when compared with the vehicle-treatment group. In addition, the early treatment group also significantly decreased plasma BNP and increased the expression of eNOS.Conclusions: ACE2 activator has therapeutic potentials for preventing and attenuating the development of PAH in an animal model of left pneumonectomy combined with VEGF inhibition. Activation of ACE2 may thus be a useful therapeutic strategy for the treatment of human PAH.

Vascular Endothelial Growth Factor Inhibits Phagocytosis of Apoptotic Cells by Airway Epithelial Cells

Professional phagocytes such as dendritic cells and macrophages can ingest particles larger than 0.5 μm in diameter. Epithelial cells are nonprofessional phagocytes that cannot ingest pathogenic microorganisms, but they can ingest apoptotic cells. Inhibition of the engulfment of apoptotic cells by the airway epithelium can cause severe airway inflammation. Vascular endothelial growth factor (VEGF) is an angiogenesis-promoting factor that can mediate allergic airway inflammation and can promote airway epithelial cells (AECs) proliferation, but it is not clear whether it affects the engulfment of apoptotic cells by AECs. In the present study, VEGF inhibited engulfment of apoptotic cells by AECs via binding to VEGF receptor(R)2. This inhibitory effect of VEGF was not influenced by masking of phosphatidylserine (PS) on the surface of apoptotic cells and was partially mediated by the PI3K-Akt signaling pathway. VEGF inhibition of phagocytosis involved polymerization of actin and downregulation of the expression of the phagocytic-associated protein Beclin-1 in AECs. Since engulfment of apoptotic cells by AECs is an important mechanism for airway inflammation regression, VEGF inhibition of the engulfment of apoptotic cells by airway epithelial cells may be important for mediating allergic airway inflammation.