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Harnessing DLL3 inhibition: From old promises to new therapeutic horizons
Diego Luigi Cortinovis1,2, Francesca Colonese1, Maria Ida Abbate1
1Department of Medical Oncology, San Gerardo Hospital, Monza, Italy.
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.
Insights
Small-cell lung cancer (SCLC) has limited options. Delta-like canonical Notch ligand 3 (DLL3) is a promising target, with new antibody-drug conjugates (ADCs) showing potential beyond older treatments.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis and limited targeted therapies.
- Current treatments like chemotherapy and immune-checkpoint inhibitors show promise but lack predictive biomarkers for patient selection.
- Unlike non-small cell lung cancer (NSCLC), SCLC has historically lacked specific molecular targets for treatment.
Purpose of the Study:
- To critically review the efficacy and activity of existing and novel Delta-like canonical Notch ligand 3 (DLL3) inhibitors.
- To explore the potential of DLL3 as a therapeutic target in high-grade neuroendocrine lung cancer.
- To discuss the application of new DLL3-targeting compounds in clinical practice, considering SCLC molecular classification.
Main Methods:
- Literature review of studies on DLL3 inhibitors, including antibody-drug conjugates (ADCs).
- Analysis of clinical data and preclinical findings related to DLL3-targeting therapies.
- Examination of emerging molecular classifications of SCLC.
Main Results:
- Older DLL3 inhibitor antibody-drug conjugates (ADCs) have shown limited success.
- Newer DLL3-targeting compounds demonstrate improved activity and potential efficacy.
- DLL3 is a validated target in SCLC, offering a new avenue for treatment.
Conclusions:
- DLL3 represents a significant therapeutic target for SCLC.
- Novel DLL3 inhibitors, particularly ADCs, offer a promising future for SCLC treatment.
- Further research into DLL3-targeting agents and SCLC molecular subtypes is warranted.
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