DLL3: an emerging target in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.

Precision medicine for human cancers with Notch signaling dysregulation (Review)

“…Notch signaling dysregulation is involved in a variety of pathologies, including cancer and non-cancerous diseases. Small-molecule inhibitors, antagonistic monoclonal antibodies (mAbs), antibody-drug conjugates (Adcs), bispecific antibodies or biologics (bsAbs) and chimeric antigen receptor-modified T cells (CAR-Ts) targeting Notch signaling components have been developed as investigational anti-cancer drugs (10)(11)(12). The safety, tolerability and anti-tumor effects of these compounds have been studied in clinical trials; however, Notch-targeted therapeutics are not yet approved for the treatment of patients with cancer.…”

“…Recruitment of new patients for the randomized phase III clinical trial of Rova-T in patients with ScLc (registration no. NcT03061812) was halted owing to shorter overall survival times in the Rova-T treatment group than in the topotecan treatment group (12). LoF NOTCH1 mutations that decrease dLL3 dependence to suppress Notch signaling might lead to intrinsic resistance to Rova-T, whereas transdifferentiation from dLL3-high ScLc to dLL3-low ScLc or NScLc might elicit acquired resistance to Rova-T. To enhance the clinical benefits of Rova-T in patients with ScLc, the mechanisms of resistance and biomarkers of responders should be elucidated by monitoring dLL3 expression, NOTCH mutations and tumor phenotypes before, during and after Rova-T therapy.…”

Establishment of novel long-term cultures from EpCAM positive and negative circulating tumour cells from patients with metastatic gastroesophageal cancer

“…Multiple other potential therapeutic targets were identified by RNA expression profiling. UWG02CTC had high expression of EGFR, FGFR2, ERBB2, and JAK/STAT pathway genes, suggesting potential sensitivity to treatments directed at these validated targets, while UWG01CTC had high expression levels of the DLL3 gene, which is proposed as a potentially druggable target 39 . While these data show that CTC derived cell lines can be used to define personalised drug sensitivities for gastric cancer patients, it is important to note the rapid disease progression and clinical decline of the patients that yielded CTC cultures.…”

Small Cell Lung Cancer: Advances in Diagnosis and Management

“…A promising molecular target in SCLC is delta-like ligand 3 (DLL3), an inhibitory Notch pathway ligand that is highly upregulated and aberrantly expressed on the cell surface in SCLC and other high-grade neuroendocrine tumors, but not on normal adult tissues. [110][111][112] Notch signaling is downregulated during neuroendocrine tumor growth and is inhibited by DLL3 expression. DLL3 is expressed in around 83% of SCLC, 113 promoting SCLC migration and invasion.…”

“…Other agents targeting DLL3 remain in active investigation including a bispecific T cell engager (BiTE) and chimeric antigen receptor (CAR) T cell therapy. 112 Another promising target is poly(ADP-ribose) polymerase 1 (PARP), which is highly expressed on SCLC cells. 115 A randomized phase II study of first-line cisplatin and etoposide with either the PARP inhibitor veliparib or placebo showed a trend toward improved PFS among patients with elevated lactate dehydrogenase levels (PFS HR: 0.24, 80% CI: 0.22-0.51), though there was no significant survival difference in the overall study population.…”