Targeting cancer stem cells with a novel virus-like drug conjugate.

Abstract

3084 Background: Belzupacap sarotalocan (bel-sar) is a novel virus like-drug conjugate in clinical stage development for multiple solid tumors. The virus-like particle component of the drug is derived from the papillomavirus and specifically binds to heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) with unique sulfation modifications on the surface of cancer cells. Upon activation with near-infrared light, cell associated bel-sar causes immediate cell death and induces an anti-tumor immune response, with a single administration leading to elimination of solid tumors accompanied by long-term protective immunity in a number of animal tumor models. Cancer stem cells (CSCs) represent a distinct subpopulation of tumor cells that possess stem-like characteristics, including self-renewal. These cells are thought to drive disease persistence and are intrinsically more resistant to conventional cancer treatment, such as chemotherapy, radiotherapy, and immunotherapy. CSC-mediated resistance remains a major obstacle to achieving durable clinical responses and the elimination of this cell population is hypothesized to be essential for long-lasting tumor control. Methods: We developed and characterized a panel of human-derived CSC models (bladder, breast, oropharyngeal, prostate cancers, glioblastoma, uveal melanoma) using a SORE6 lentivirus reporter in which stem-like transcription factors SOX2 and OCT4 drive GFP expression to identify CSC subpopulations. Bel-sar binding and potency was compared between CSC and the more differentiated non-cancer stem cells (nCSC) populations. Additionally, chemotherapy resistant tumor lines were established from the CSC panel and were similarly tested for bel-sar targeting and cytotoxicity. Results: CSC populations were validated by SOX2/OCT4 co-expression, CSC surface marker expression (CD24, CD44, EpCAM-1, CXCR4), ALDH activity, and tumorsphere formation. Bel-sar was capable of binding CSCs with equal or enhanced efficiency as compared to nCSCs through cell surface HSPGs and CSPGs as demonstrated by heparin and chondroitin sulfate inhibition. Additionally, bel-sar was able to kill CSCs and nCSCs with equal efficiency in vitro. Following chemotherapy-induced enrichment of CSCs, bel-sar maintained its therapeutic effect on chemotherapy-resistant CSC populations, reinforcing previous data demonstrating complete responses in animal models. Conclusions: This study highlights bel-sar’s distinctive capacity to target and eradicate CSCs across diverse tumor types. These results support bel-sar’s clinical development for local tumor control and suggest bel-sar treatment may be effective against recurring or chemotherapy-resistant tumors.