CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy

Abstract

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC.

Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance

“…In a phase I and II study, pamrevlumab, enhanced gemcitabine activity in locally advanced pancreatic cancer patients ( 102 ). Similarly, another study also demonstrated the use of peptides targeting CTGF alone and in combination with gemcitabine in reducing tumor size ( 103 ).…”

Nanomedicine Strategies to Enhance Tumor Drug Penetration in Pancreatic Cancer

“…65 These promising results have also granted this regimen for the Phase III clinical trial recently. 65 A study from Resov et al 66 investigated two synthetic peptides targeting CTGF and showed an increased tumor inhibition when administered in combination with gemcitabine. It is worthy to note that the peptide did not improve the gemcitabine level in the PDAC tumor model.…”

Reconstructing co-dependent cellular crosstalk in lung adenocarcinoma using REMI

“…We focused on the mixed-prognostic interactions because these interactions may be involved interactions, we highlight the LR interaction, CTGF:LRP6, due to the increasing interest in anti-CTGF therapy (Fig 5b) (29,30). CTGF is inferred to be secreted not only from M(2), but also iFibs from within the same scREMI-LUAD community (p-val < 0.1)(Fig 5c and Supp Fig 5a-b).…”