Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine

Abstract

First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy.

Prostate Cancer Metastases Are Strongly Inhibited by Agonistic Epha2 Ligands in an Orthotopic Mouse Model

“…While both agents seemed very active, ephrinA1-Fc caused a more sustained and extensive decrease in EphA2 levels even at day 3 after treatment, compared to prostate cancer cells treated with 135H12, where EphA2 levels returned after 2 days of treatment ( Figure 2 b). These observations have been made several times with similar agents and a variety of cell lines [ 14 , 15 , 17 , 18 , 21 ], including PC-3 [ 19 , 20 , 24 ], for example reported in Supplementary Figure S1 . While generally we observed that 135H12 has agonistic activity in the low-to sub-micromolar range [ 14 , 15 ], we tested it at 10 μM against PC-3 to assess the ability of the agent to cause a sustained internalization of the receptor over longer periods of time ( Figure 2 ), in view of its anticipated use in vivo.…”

“…Recently, we reported that the dimeric version of 135H11 can efficiently suppress cell migration of pancreatic cancer cells [ 14 , 15 ]. In addition, we also reported previously that earlier generations of agonistic EphA2-targeting-peptide mimetics can be used as carriers for targeted delivery of chemotherapy to breast [ 17 ], pancreatic [ 15 , 18 ], and prostate cancer [ 19 , 20 , 21 ]. In the present study, we aimed at further evaluating the therapeutic potential of targeting EphA2 by agonistic agents 135H12 and ephrinA1-Fc to suppress tumor metastasis in an orthotopic nude-mouse model of prostate cancer.…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…In a recent study, Wang et al developed a peptide-drug conjugate (PDCs) using EphA2 agonists, YSA peptide or its enhanced version, 123B9. Their studies suggested that YSA-and 123B9-drug conjugates could selectively transport cytotoxic drugs to cancer cells in vivo [166,167].…”

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits pancreatic cancer cell proliferation and induces apoptosis via the EGFR pathway and caspase signaling

“…Gemzar (gemcitabine) single-agent chemotherapy is the standard treatment for metastatic or locally advanced pancreatic cancer, but it has a modest survival benefit [5,6]. FOLFIRINOX, a combination of chemotherapeutic agents (folinic acid, fluorouracil, irinotecan, and oxaliplatin), was recently shown to nearly double the median survival of pancreatic ductal adenocarcinoma (PDAC) patients compared to gemcitabine (11.1 vs. 6.8 months).…”