Dataset Information

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing.

ABSTRACT: Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the drugs that can be repurposed to specifically target the inflammatory pathway of NSCLC utilizing its well-defined inflammatory tumor microenvironment. Continuous inflammatory conditions are responsible to induce DNA damage and enhance cell division rate in lung tissues. There are existing anti-inflammatory drugs which were found suitable for repurposing in non-small cell lung carcinoma (NSCLC) treatment and drug modification for delivery via inhalation. Repurposing anti-inflammatory drugs and their delivery through the airway is a promising strategy to treat NSCLC. In this review, suitable drug candidates that can be repurposed to treat inflammation-mediated NSCLC will be comprehensively discussed together with their administration via inhalation from physico-chemical and nanocarrier perspectives.

SUBMITTER: Rajasegaran T

PROVIDER: S-EPMC10051080 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing.

Rajasegaran Thiviyadarshini T How Chee Wun CW Saud Anoosha A Ali Azhar A Lim Jonathan Chee Woei JCW

Pharmaceuticals (Basel, Switzerland) 20230316 3

Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the ...[more]

PMID: 36986550

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Project description:PurposeSystemic treatments given to patients with non-small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.Experimental designPDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome sequencing, and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential gene expression analysis identified drug-repurposing targets. Validations were performed with internal/external data sets of patients with NSCLC. NSCLC cell lines were used for aldo-keto reductase 1B10 (AKR1B10) knockdown studies and xenograft models to determine the intratumoral bioavailability of epalrestat.ResultsPDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.ConclusionsPDTOs are efficient preclinical models recapitulating the tumor characteristics and are suitable for drug testing. AKR1B10 can be targeted by repurposing epalrestat to overcome chemoresistance in NSCLC. Epalrestat has the potential to advance to clinical trials in patients with drug-resistant NSCLC due to favorable toxicity, pharmacological profile, and bioavailability.

Dataset Information

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing.

Publications

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing.

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