Harnessing DLL3 inhibition: From old promises to new therapeutic horizons

Abstract

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. The combination of chemotherapy and immune-checkpoint inhibitors brings a new therapeutic era, although the lack of predictive biomarkers of response reduces the efficacy of applying the treatment to the entire population of patients with SCLC. The lack of treatments able to bind to a specific target has always been a substantial difference to the non-small cell lung cancer (NSCLC) counterpart. Delta-like canonical Notch ligand 3 is a protein frequently overexpressed in SCLC and is therefore being explored as a potentially promising therapeutic target in high-grade neuroendocrine lung cancer. In this article, we critically review the activity and efficacy of old DLL3 inhibitors antibody-drug conjugate (ADC) and their failures through new compounds and their possible applications in clinical practice, with a focus on new molecular classification of SCLC.

Prognostic significance of circulating tumor cells and tumor related transcripts in small cell lung cancer: A step further to clinical implementation

“…Furthermore, DLL3 can be used as a target for antitumor drugs. 34 In previous clinical studies, the antibody-drug conjugate ROVA-T was evaluated. 35,36 Despite of the negative results of these studies, extensive further research has been undertaken to develop novel targeted therapies, for example CAR-T cells against DLL3, 37 photo-, 38 and radioimmunotherapy.…”

“…DLL3 is part of the NOTCH signaling pathway and is an optimal CTC biomarker as it is not expressed in normal lung tissue. Furthermore, DLL3 can be used as a target for antitumor drugs 34 . In previous clinical studies, the antibody‐drug conjugate ROVA‐T was evaluated 35,36 .…”

Manuscript title: Activating invasion and metastasis in small cell lung cancer

“…DLL3 is a ligand of the Notch signalling pathway, and is expressed in over 80% of SCLC surfaces, while being minimally expressed on healthy lung tissues. 27 Nuclear expression of Snail occurs in 31% of SCLC, which represents the highest of all lung cancer subtypes. 28 Furuta et al demonstrated DLL3 to be an in vitro inducer of Snail expression in SCLC.…”

Edaravone: A Novel Possible Drug for Cancer Treatment?

“…Targeted therapy involves developing drugs that inhibit cancer proliferation, promote cell cycle regulation, induce apoptosis or autophagy, or deliver harmful substances only to cancer cells to eliminate them [72]. Oral small-molecule drugs or monoclonal antibodies are used in targeted cancer therapy [73,74]. This treatment can improve overall survival and progression-free survival.…”