%0 Journal Article
%T Targeted therapy in small cell lung cancer: can DLL3 notch up a victory?
%A Jonathan M. Lehman
%A Leora Horn
%J SCIE-indexed Journal
%D 2017
%R 10.21037/13271
%X Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma, responsible for ~13¨C18% of lung cancer death with no appreciable improvements in outcomes or treatment options for the last 30 years. The clinical behavior of SCLC is tailor made for nihilism with excellent initial overall response rates transforming to inevitable chemotherapy resistant recurrence in the majority of patients. Targeted therapies to date have failed with little to no efficacy in unselected populations. Naturally, this state of affairs has led to an underfunded SCLC research community, and historical pharmaceutical disinterest in this ¡°graveyard of drug development¡±. The National Cancer Institute (NCI) and worldwide refocus upon ¡°recalcitrant¡± carcinomas has led to renewed interest in SCLC making this the perfect opportunity to consider how and why targeted therapy in unselected SCLC has failed so consistently. The critical factors are both biological factors and structural limitations to previous targeted therapy studies in SCLC. (I) The rapid recurrence after initial response to chemotherapy of SCLC is suggestive of biological features consistent with stem cell biology. This strongly suggests a stem cell like phenotype, or a resistant subclonal expansion (1). Stem cell signaling is complex and redundant which limits signaling interference as a monotherapy; (II) the lack of mutational drivers and the mutational signature of SCLC appears to be principally driven by changes in tumor suppressor or transcription factors. These targets are challenging to drug and this has hampered targeted therapy options; (III) the related issue of inadequate biomarkers for the delineation of SCLC subpopulations. SCLC has long been known to be a heterogeneous disease (2), but previously the tools were unavailable to further characterize potential subpopulations by single cell based methods. The study ¡°Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a £¿rst-in-human, £¿rst-in-class, open-label, phase 1 study¡± recently published in Lancet Oncology constitutes an attempt to address these critical factors in SCLC biology: stem cell targeting, lack of a novel druggable target, and biomarker driven clinical trials. This study is a promising theoretical approach using an antibody drug conjugate (ADC) to target DLL3 labeled putative stem cell populations in SCLC and incorporates an intrinsic biomarker of response
%U http://tcr.amegroups.com/article/view/13271/html