NSCLC is the form of lung cancer most commonly referred to as "lung cancer," accounting for about 90% of cases. Early detection tools for this cancer type are still lacking.
ION CHANNELS AS TUMOR BIOMARKERS ?
Many cancers, and NSCLC in particular, are associated with disruptions in the mechanisms controlling ionic homeostasis. This is largely due to dysfunction and/or overexpression of several ion channels, such as specific sodium, calcium, and potassium channel subtypes, pH-sensitive ion channels (ASICs), or nicotinic acetylcholine receptors. Activation of these channels is known to play a key role in cancer cell aggressiveness and tumor invasion.
Despite the availability of several imaging techniques (X-ray, CT, MRI, PET) commonly used to assess the anatomical and metabolic features of NSCLC, their limitations highlight the need for new imaging probes that can more specifically target molecular markers overexpressed in lung adenocarcinomas. Among the ion channels altered in this cancer, some appear to be promising candidates as tumor biomarkers. This is the case for the voltage-gated sodium channel subtype 1.7 (hNaV1.7), which is overexpressed in NSCLC, the challenge being to detect and quantify it as early as possible.
PEPTIDE TOXINS AS TARGETING TOOLS ?
THE EXAMPLE OF HUWENTOXIN-IV
Ion channels have long been known as targets of the thousands of peptide neurotoxins found in animal venoms, which have been characterized over the past 40 years. Among these natural molecules, Huwentoxin-IV (HwTx-IV), a neurotoxin derived from the venom of Cyriopagopus schmidti, a spider native to southern China, strongly inhibits the voltage-gated sodium channel subtype hNaV1.7.
In this study, the researchers investigated the ability of chemically synthesized HwTx-IV to bind to hNaV1.7 channels expressed in NSCLC cell lines. They also synthesized a fluorescently labeled version of the peptide, HwTx-IV conjugated to cyanine 5 (HwTx-IV-Cy5). Overexpression of hNaV1.7 channels was observed in various NSCLC cell lines, including a metastatic one, but not in healthy lung cells. Electrophysiological recordings confirmed the presence of functional hNaV1.7 channels in the metastatic line, but not in non-metastatic or healthy NSCLC cell lines. The sodium current recorded in the metastatic line was completely inhibited by 100 nM of HwTx-IV and HwTx-IV-Cy5. Finally, confocal microscopy experiments using HwTx-IV-Cy5 localized hNaV1.7 at the plasma membranes of NSCLC cells.
Together, these results open the way for the use of HwTx-IV-Cy5 as an imaging agent for NSCLC detection in preclinical models and suggest that a radiolabeled version of the peptide (18F-HwTx-IV) could be used in PET imaging to confirm the potential of this peptide as a tool for early diagnosis of NSCLC.
Joliot contact : Denis Servent (denis.servent@cea.fr)