Release Date: 27-Feb-2023
Neuroendocrine tumors, such as small-cell lung cancer, have a high relapse rate, few treatment options, and a dismal prognosis. Chemotherapy, targeted therapy, and immune therapy are among the available treatments; however due to a lack of diagnostic biomarkers, these alternatives have only been used to treat a tiny subset of patients with neuroendocrine cancers. The Notch signaling pathway has recently been implicated in the formation of neuroendocrine cells and DLL3 has been identified to be an inhibitory ligand of the Notch pathway. DLL3 is undetectable or infrequently expressed on non-cancerous cells but is significantly elevated and aberrantly expressed on the cell surface in high-grade neuroendocrine tumors. Therefore, DLL3 is a promising prospective new target for many neuroendocrine cancers. The clinical and developmental pipelines have been greatly increasing over the years in response to similar research findings, and several candidates are currently in the early stages of studies.
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The role of DLL3, or Delta-like 3, has been implicated in a number of cancers with a neuroendocrine origin like glioblastoma multiforme, small cell bladder cancer, small cell lung cancer and melanoma. When the Notch receptor proteins namely Notch1, Notch2, Notch3, and Notch4, interact with the ligand DLL3, a signaling pathway is initiated that regulates cell proliferation, cell fate, differentiation and cell death in humans. DLL3 was seen to be overexpressed in neuroendocrine carcinomas as compared to normal tissues. The DLL3 modulates the Notch1 and promotes migration and invasion of carcinoma cells. Through various studies, the overexpression of the DLL3 has been associated with several neuroendocrine carcinomas and has a negative effect on the patients’ survival. Additionally, high DLL3 expression is also associated with features of high-grade neuroendocrine carcinomas.
To evaluate the therapeutic potential of DLL3, studies were carried on cancer patients in real time. Lower expression of DLL3 was correlated to longer disease-free survival and longer median overall survival. Subsequently, molecules targeting the DLL3 were developed. Rovalpituzumab tesirine (ROVA-T) was a first-in-class antibody-drug conjugate belonging to the first generation of DLL3 inhibitors. It was developed and clinical tested by AbbVie, who had to stop the further development ROVA-T for its unacceptable toxicities. Consequently, SC-002 was developed to address the problems associated with ROVA-T but its development too was terminated for strategic reasons.
With improvements and advancements in science, many next-generation new candidates have begun entering the clinical pipeline. Some new generation drugs targeting the DLL3 include PT819, HPN328 and Tarlatamab. These are all DLL3-targeting bispecific T cell engagers, and this class of drugs is dominating the global clinical and developmental pipelines. T cell engagers are a novel subclass of immune cell-based engager therapy that has shown promising results in preclinical studies. Tarlatamab (AMG 757) is the first DLL3-targeting bispecific T cell engager. It was developed by Amgen, who is now evaluating it in small cell lung cancer and neuroendocrine prostate cancer. The drug has now progressed to phase II and is a potential first-in-class DLL3-targeting bispecific T cell engager to get FDA approval.
PT217 is another candidate in the pipeline, which is a first-in-class bispecific antibody targeting the DLL3 and CD47 in patients with neuroendocrine cancers. it has been developed by Phanes Therapeutics, who had also developed the above mentioned PT819. PT217 along with Harpoon Therapeutics’ HPN328, has been granted the Orphan Drug Designation by the FDA in 2022 for small cell lung cancer. Both candidates are in their initial phases of clinical trials. Apart from Amgen, Phanes Therapeutics and Harpoon Therapeutics, global pharmaceutical giant Boehringer Ingelheim is another prominent company with a DLL3-targeting candidate in its pipeline.
The clinical pipeline of DLL3 is in its infancy but the involvement of key market players such as Boehringer Ingelheim, Amgen, and Harpoon Therapeutics has helped draw attention to this emerging potential target for cancer therapeutics. DLL3 plays a complex role in cancer progression and a lot of these functions have been revealed, which has highlighted its potential. The developmental pipeline for cancer therapeutics is crowded with drugs targeting immune checkpoints and other signaling proteins, and DLL3 has emerged as a breath of fresh air in the therapeutics pipeline.