Utilizing Peptide Ligand GPCRs to Image and Treat Pancreatic Cancer

Abstract

It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 74–75). There is an unmet need for reagents that can reliably identify early cancerous or precancerous lesions through various imaging modalities or could be employed to deliver anticancer treatments specifically to tumor cells. However, to date, many PDAC tumor-targeting strategies lack selectivity and are unable to discriminate between tumor and nontumor cells, causing off-target effects or unclear diagnoses. Although a variety of approaches have been taken to identify tumor-targeting reagents that can effectively direct therapeutics or imaging agents to cancer cells (Liu, D. et al., J. Controlled Release 2015, 219, 632–643), translating these reagents into clinical practice has been limited, and it remains an area open to new methodologies and reagents (O’Connor, J.P. et al., Nat. Rev. Clin. Oncol. 2017, 14, 169–186). G protein–coupled receptors (GPCRs), which are key target proteins for drug discovery and comprise a large proportion of currently marketed therapeutics, hold significant promise for tumor imaging and targeted treatment, particularly for pancreatic cancer.

GPCRomics: An Approach to Discover GPCR Drug Targets

“…GPCRomics may identify GPCRs amenable to such approaches and may help guide appropriate hiPSC-derived models for drug screening and perhaps, cell therapy. Newly recognized GPCRs may also be useful as biomarkers that can be analyzed on circulating (tumor, fetal) cells, exosomes in the blood or urine or as cell surface proteins detectable with antibodies or other probes, perhaps via imaging methods [32,[84][85][86][87][88][89]. Such techniques may further facilitate personalized/precision medicine approaches for GPCR therapeutics: identification of individual and groups of patients who express one or more GPCRs that can be treated with appropriate GPCR-targeted agents and whose response is monitored by biomarker analyses.…”

RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges

“… 40 Therefore, therapeutic strategies involve modulation of receptor dimerization and/or oligomerization. 41 For example, pre-eclampsia is associated with altered GPCR heterodimerization. In patients with pre-eclampsia, significant increase in the formation of the angiotensin II receptor type I (AGT1R)/bradykinin B2 receptor (B2R) heterodimers promotes angiotensin II (Ang II)-stimulated activation of Gαq/11 on the membranes and upregulates Ang II-related hypersensitivity.…”

Antineoplastic Properties of THCV, HHC and their anti-Proliferative effects on HPAF-II, MIA-paca2, Aspc-1, and PANC-1 PDAC Pancreatic Cell Lines

“…Aside from poor prognosis, TME (tumor microenvironment) is characterized by dense desmoplasia and extensive immunosuppression. Extensive desmoplasia results in various cell infiltration, vascularization, and hypoxia, preventing drugs to target such areas specifically [32,34]. PDAC target through this experiment, is through GPCR ligand targeting, as the membrane protein is present it also accounts for 20% of all cancers that contain a mutated GPCR or g-alpha subunits [35].…”