Targeting the seeds of small cell lung cancer

Abstract

The concept of antibody drug conjugates (ADCs), which includes the delivery of cytotoxic drugs to antigen-expressing tumor cells by harnessing the antigen-selectivity of a monoclonal antibody, has the potential to redefine the landscape of translational medicine. With the advent of patient derived xenograft (PDX) models and sophisticated genomic technologies, the identification of a selective antigen can be accurately validated within the appropriate tumor milieu. However, a major biological hurdle in cancer translational medicine is the inherent tumoral heterogeneity, underscoring the importance of targeting the 'right' sub-population of cancer cells. Herein, we review a seminal work highlighting the ability to target a key 'stem-like' cancer sub-population called tumor initiating cells (TICs) using engineered ADCs. While the promise of this approach needs to be validated in the clinical setting, TIC-targeted ADCs offer great hope for circumventing current limitations with conventional ADC therapy.

Keywords: Antibody drug conjugates (ADCs); cancer; stem cells; tumor initiating cells (TICs).

Figure 1

Cartoon depicting TIC targeting antibody therapies in different malignancies. (A) According to the cancer stem cell hypothesis, standard of care (SOC) chemotherapies debulk the tumor. A small population of ‘stem like’ cells (TICs) repopulates the tumor leading to patient relapse; (B) DLL3 targeted ADC may lead to patient response through either debulking of the tumor mass (1^st line therapy) or more specific targeting of TICs in relapsed patients. The level and percentage of TICs that express DLL3 are yet to be determined.