Intratumoral expression profiling of genes involved in angiogenesis in colorectal cancer patients treated with chemotherapy plus the VEGFR inhibitor PTK787/ZK 222584 (vatalanib)

Abstract

The phase III CONFIRM clinical trials demonstrated that metastatic colorectal cancer patients with elevated serum lactate dehydrogenase (LDH) had improved outcome when the vascular endothelial growth factor receptor (VEGFR) inhibitor PTK/ZK (Vatalanib) was added to FOLFOX4 chemotherapy. We investigated the hypothesis that high intratumoral expression of genes regulated by hypoxia-inducible factor-1 alpha (HIF1α), namely LDHA, glucose transporter-1 (GLUT-1), VEGFA, VEGFR1, and VEGFR2, were predictive of outcome in CONFIRM-1. Tumor tissue was isolated by laser-capture microdissection from 85 CONFIRM-1 tumor specimens; FOLFOX4/placebo n=42, FOLFOX4/PTK/ZK n=43. Gene expression was analyzed using quantitative RT-PCR. In univariate analyses, elevated mRNA expression of LDHA, GLUT-1, and VEGFR1 were associated with response to FOLFOX4/PTK/ZK. In univariate and multivariate analyses, elevated LDHA and VEGFR1 mRNA levels were associated with improved progression-free survival in FOLFOX4/PTK/ZK patients. Furthermore, increased HIF1α and VEGFR2 mRNA levels were associated with decreased survival in FOLFOX/placebo patients but not in patients who received FOLFOX4/PTK/ZK. These are the first data suggesting intratumoral mRNA expression of genes involved in angiogenesis/HIF pathway may predict outcome to VEGFR-inhibitors. Biomarkers that assist in directing VEGFR-inhibitors toward patients with an increased likelihood of benefit will improve the cost-effectiveness of these promising agents.

Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib

“…We then examined associations between CTC gene expression levels and outcomes. We used the optimal cut‐off value method as previously described . The cut‐off value of 0.05 for EGFR expression at baseline was chosen based on the maximum χ 2 approach.…”

Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent

“…Tumor cells were collected using laser-capture micro-dissection as described recently [24]. In short, three sections, each of 10-um thickness, were dewaxed, re-hydrated and stained with nuclear fast red (American Master Tech Scientific, Lodi, CA, USA).…”

Receptor tyrosine kinase inhibitors: Are they real tumor killers?

“…A phase I dose‐escalation study of patients with metastasized colorectal cancer showed the typical side effects, such as hypertension, with a maximal dose of 1250 mg/day in combination with FOLFOX4 chemotherapy . Intratumor profiling of gene expression revealed that the up‐regulation of the expression of angiogenesis‐associated genes ( e.g., Glut‐1, VEGFR‐1/‐2 and HIF‐1α) and of microvessel density predicted the outcome to antiangiogenic therapy in patients with colorectal cancer. Unfortunately, in a recently published phase III trial that included 855 patients, no significant extension of OS was observed in patients treated with Vatalanib combined with FOLFOX4 compared with the placebo group.…”