Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.

Determination of a DNA repair-related gene signature with potential implications for prognosis and therapeutic response in pancreatic adenocarcinoma

“…Despite considerable advances in our understanding of the molecular basis of PAAD, little therapeutic progress has been made in this disease, in contrast to the progress that has been made in the treatment of various other cancers in recent decades ( 4 ). During that period, numerous clinical trials of treatments for PAAD have failed, and treatment options remain limited ( 5 ). The molecular and functional heterogeneity of PAAD may partially explain the lack of progress in clinical treatment ( 6 ).…”

Clinical Response to Seribantumab, an Anti–Human Epidermal Growth Factor Receptor-3 Immunoglobulin 2 Monoclonal Antibody, in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma Harboring an NRG1 Fusion

“…1,2,[6][7][8][9][10] Outcomes with PDAC are dismal with high mortality rates and a 5-year survival rate of , 10%. [11][12][13][14] Chemotherapy with gemcitabine-based regimens or folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is recommended for patients with advanced PDAC. [15][16][17] However, these regimens have shown limited efficacy 18,19 and are often associated with toxicities that negatively affect patients' quality of life.…”

“…[15][16][17] However, these regimens have shown limited efficacy 18,19 and are often associated with toxicities that negatively affect patients' quality of life. 11,19,20 The Cancer Molecular Screening and Therapeutics (MoST) program is an Australian precision oncology program using DNA-and RNA-based sequencing to identify targetable genomic alterations in treatmentrefractory advanced cancers. 21,22 Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks the ligand-dependent activation of HER3 and HER3-HER2 dimerization.…”

Microfluidic-Assisted Preparation of Targeted pH-Responsive Polymeric Micelles Improves Gemcitabine Effectiveness in PDAC: In Vitro Insights

“…For this reason, monotherapy or combined therapy with Gem is still the golden standard of current PDAC chemotherapy regimens, even though there is evidence that PDAC cells participate in the pathogenesis of Gem resistance [ 4 , 10 , 11 ]. To overcome resistance, higher doses of Gem are required, which lead to severe systemic toxicity [ 12 , 13 ]. The control of the drug release site and time could improve drug efficacy, with lower doses and toxicity [ 14 , 15 ].…”

“…The nano-system consisted of a mixture of three di-block copolymers, namely the poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG), to confer stealth properties, and the poly(lactic-co-glycolic acid)-poly-L-lysine conjugated to the 2,3-dimethylmaleic anhydride (PLGA-PLL-DMA) as a pH-responsive moiety. In addition, to improve specific targeting to the PDAC, the surface of such micelles was properly functionalized with a selective ligand for uPAR receptor, which is highly expressed in PDAC cells [ 12 , 13 ], such as the peptide AE105 [ 5 ]. The microfluidic technique has already been successfully employed to control the size, shape, and polydispersity of polymeric micelles [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]; however, to the best of our knowledge, there have been few reports on microfluidics-based pH-responsive polymeric micellar delivery systems [ 37 , 38 , 39 ] and no one has applied these to PDAC cancer research.…”