Alessandro Leonetti1,2, Francesco Facchinetti3,4, Roberta Minari3, Alessio Cortellini5, Christian D Rolfo6, Elisa Giovannetti7,8, Marcello Tiseo3,9. 1. Medical Oncology Unit, University Hospital of Parma, 43126, Parma, Italy. alessandroleonetti@hotmail.com. 2. Department of Medical Oncology, VU University Medical Center, Amsterdam, 1081, HV, The Netherlands. alessandroleonetti@hotmail.com. 3. Medical Oncology Unit, University Hospital of Parma, 43126, Parma, Italy. 4. INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France. 5. Medical Oncology, St. Salvatore Hospital, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy. 6. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, 21220, USA. 7. Department of Medical Oncology, VU University Medical Center, Amsterdam, 1081, HV, The Netherlands. 8. Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, 56124, Pisa, Italy. 9. Department of Medicine and Surgery, University of Parma, Parma, Italy.
Abstract
BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients' prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. CONCLUSIONS: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.
BACKGROUND:Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients' prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. CONCLUSIONS: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.
Entities:
Keywords:
DLL3; Notch pathway; Rovalpituzumab tesirine; Small cell lung cancer (SCLC)
Authors: Camille Tlemsani; Lorinc Pongor; Fathi Elloumi; Luc Girard; Kenneth E Huffman; Nitin Roper; Sudhir Varma; Augustin Luna; Vinodh N Rajapakse; Robin Sebastian; Kurt W Kohn; Julia Krushkal; Mirit I Aladjem; Beverly A Teicher; Paul S Meltzer; William C Reinhold; John D Minna; Anish Thomas; Yves Pommier Journal: Cell Rep Date: 2020-10-20 Impact factor: 9.423