Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic

Abstract

Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

“…Our results reiterate the importance of targeting SLC7A11 in both CAFs and PDAC cells.Consistent with this, conditional knockout of SLC7A11 in only the tumour compartment of KPC tumours did not affect mouse survival, but interestingly it did decrease intra-tumoural fibrosis, implying pro-fibrogenic cross-talk between tumour and stromal cells had been disrupted.Notably, these results were reproduced in vitro, whereby SLC7A11 knockdown in isolated CAFs from the KPC mouse tumours significantly reduced their proliferation but had no effect in KPC PDAC cells. Our results are in striking contrast to prior KPC mouse PDAC models in which SLC7A11 was inhibited via a modified form of erastin(20), systemic deletion of SLC7A11 or cysteinase enzyme treatment(21) and significantly reduced tumour growth. What is important to note is that these studies did not selectively target PDAC tumour cells and these mouse models are characterised as having a prominent fibrotic tumour stroma.…”

“…What is important to note is that these studies did not selectively target PDAC tumour cells and these mouse models are characterised as having a prominent fibrotic tumour stroma. Therefore, it is likely that SLC7A11 inhibition would have also affected CAFs pro-tumour/fibrotic activity which would have contributed to the reduced tumour growth.Both prior studies also demonstrated that SLC7A11 inhibition(20) or systemic genetic deletion(21) in the KPC mouse model increased median survival, highlighting the efficacy of SLC7A11 inhibition as a standalone therapeutic approach. To complement this work, we opted for an orthotopic model of PDAC with a defined pre-mortality endpoint.…”

“…They subsequently showed that SLC7A11 inhibitor sulfasalazine (SSZ) significantly reduced subcutaneous PDAC tumour growth (17). Since then, additional studies have demonstrated the therapeutic potential of inhibiting or genetically ablating SLC7A11 in PDAC cells (18)(19)(20)(21)(22).…”

Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors

“…In this cell line, where σ 2 ligands previously displayed promising in vitro and in vivo efficacy [37], we assessed the expression level of P-gp as a mean to determine what role, if any, this efflux pump plays in the context of the cytotoxicity of our drugs. Western blot analysis clearly showed no expression of the efflux pump in KP02 cells, so that activity at the P-gp of these compounds did not seem to be involved in their action in this cell line (Figure S1, Supporting Information).…”

TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death

“…The sigma-2 receptor is a potential target for cancer therapeutics 6,23 . Sigma-2 ligands have been shown to induce cytotoxicity in cancer cells as a single agent, a drug delivery agent 24,25 and a sensitizer to other anticancer drugs in cell culture and in animal models. Sigma-2 ligands trigger cell death by inducing lysosome dysfunction, ROS production, caspase-independent, and caspase-dependent events 26–31 .…”