Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV‐134

Abstract

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancers. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB /TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer.

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

“…[16–18] Multiple classes of sigma-2 ligands have been pharmacologically characterized as either agonists, partial agonists or antagonists. [19–21] Sigma-2 agonists have been shown to undergo receptor-mediated endocytosis providing a method to deliver therapeutics into cancer cells.…”

“…[19–21] Sigma-2 agonists have been shown to undergo receptor-mediated endocytosis providing a method to deliver therapeutics into cancer cells. [16–18] Subcellular localization studies have shown sigma-2 agonists are trafficked to the mitochondria, a common site of therapeutic target due to the regulatory processes of cell homeostasis and apoptosis. [22] Sigma-2 agonists are capable of activating caspase 3, 8 and 9 and inducing cell death through multiple pathways, and there are established methods of increasing the potency through conjugation with cytotoxic payloads.…”

“…[22] Sigma-2 agonists are capable of activating caspase 3, 8 and 9 and inducing cell death through multiple pathways, and there are established methods of increasing the potency through conjugation with cytotoxic payloads. [16–18, 21, 23, 24] Non-targeted chemotherapeutics rely on high concentrations to penetrate tissues, which can result in detrimental systemic effects. By harnessing the pharmacological properties of sigma-2 agonists and the selective overexpression of sigma-2 receptors in highly proliferative tumor cells, we provide a mechanism to deliver cytotoxic payloads with the benefit of greatly improving the therapeutic potential of conventional chemotherapeutics.…”

“…[26] Through conjugation of SMCs with sigma-2 targeting compounds, there is potential to deliver SMCs to cancer cells enhancing the drug delivery and minimizing potential side effects. [16–18]…”

Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

“…Further interest in the σ 2 receptor has been generated by the evidence that its activation through specific putative σ 2 agents leads to tumor cell death. A few classes of σ 2 ligands endowed with antiproliferative activity have been developed [14] and some encouraging results from in vivo assays are giving impulse to further studies [15][16][17][18]. In our continuous effort to contribute to the σ 2 -receptor research, we conducted several Structure Affinity Relationship studies (SAfiR) on diverse classes of σ receptor ligands [19][20][21][22][23].…”