ABSTRACT
INTRODUCTION: Evidence-based information about cerebrospinal fluid (CSF) levels of biomarkers in patients with amyotrophic lateral sclerosis (ALS) is limited. METHODS: Vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2), optineurin (OPTN), monocyte chemoattractant protein-1 (MCP-1), angiogenin (ANG), and TAR DNA-binding protein (TDP-43) were quantified by enzyme-linked immunoassay in the CSF of 54 patients with sporadic ALS and 32 controls in a case-control study design. RESULTS: CSF levels of VEGF (P = .014) and ANG (P = .009) were decreased, whereas VEGFR2 was higher (P = .002) in patients with ALS than in controls. TDP-43 positively correlated with MCP-1 (P = .003), VEGF (P < .001), and VEGFR2 (P < .001) in patients with ALS. DISCUSSION: Our findings suggest possible utility of VEGF, VEGFR2, and ANG as biomarkers for use in ALS treatment trials.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Cell Cycle Proteins/cerebrospinal fluid , Chemokine CCL2/cerebrospinal fluid , DNA-Binding Proteins/cerebrospinal fluid , Membrane Transport Proteins/cerebrospinal fluid , Ribonuclease, Pancreatic/cerebrospinal fluid , Vascular Endothelial Growth Factor A/cerebrospinal fluid , Vascular Endothelial Growth Factor Receptor-2/cerebrospinal fluid , Adult , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Case-Control Studies , Female , Humans , India , Male , Middle AgedABSTRACT
A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211-ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non-small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose-escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK-positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211-ALK in a patient with LM.
Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Biomarkers, Tumor/cerebrospinal fluid , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Cycle Proteins/cerebrospinal fluid , Gene Rearrangement , Meningeal Carcinomatosis/drug therapy , Microtubule-Associated Proteins/cerebrospinal fluid , Piperidines/therapeutic use , Serine Endopeptidases/cerebrospinal fluid , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/metabolism , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/cerebrospinal fluid , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Proteins/genetics , Female , Humans , Lung Neoplasms/cerebrospinal fluid , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Meningeal Carcinomatosis/cerebrospinal fluid , Meningeal Carcinomatosis/genetics , Meningeal Carcinomatosis/secondary , Microtubule-Associated Proteins/genetics , Middle Aged , Prognosis , Protein Kinase Inhibitors/therapeutic use , Serine Endopeptidases/geneticsABSTRACT
Growth arrest specific 1 (GAS1) is a GPI-anchored protein that inhibits proliferation when overexpressed in tumors but during development it promotes proliferation and survival of different organs and tissues. This dual ability is caused by its capacity to interact both by inhibiting the signaling induced by the glial cell line-derived neurotrophic factor and by facilitating the activity of the sonic hedgehog pathway. GAS1 is expressed as membrane bound in different organs and as a secreted form by glomerular mesangial cells. In the developing central nervous system, GAS1 is found in neural progenitors; however, it continues to be expressed in the adult brain. Here, we demonstrate that soluble GAS1 is present in the cerebrospinal fluid (CSF) and it is expressed in the choroid plexus (CP) of the adult rat, the main producer of CSF. Additionally, we confirm the presence of GAS1 in blood plasma and liver of the adult rat, the principal source of blood plasma proteins. The pattern of expression of GAS1 is perivascular in both the CP and the liver. In vitro studies show that the fibroblast cell line NIH/3T3 expresses one form of GAS1 and releases two soluble forms into the supernatant. Briefly, in the present work, we show the presence of GAS1 in adult rat body fluids focusing in the CSF and the CP, and suggest that secreted GAS1 exists as two different isoforms.
