Stromal barriers, such as the desmoplastic stroma that is characteristic of PDAC, can block the delivery and decrease the tumor-penetrating ability of therapeutics such as TRAIL, which selectively induces cancer cell death, researchers explain in Gut.
Dr. Yunching Chen of National Tsing Hua University in Taiwan and colleagues aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumors, but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.
They theorized that since NO plays a role in preventing tissue desmoplasia, if it could be delivered together with TRAIL, it might improve TRAIL delivery to tumors. After a series of experiments in cells and mice, they constructed nanogels modified with stroma-targeting peptides to co-deliver NO and TRAIL.
Delivering NO with TRAIL to the PDAC tumor stroma resulted in reprogramming of activated pancreatic stellate cells, a reduction in tumor desmoplasia, and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating TRAIL's penetration into the tumor and enhancing TRAIL's antitumor efficacy.
The authors conclude, "The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumor microenvironment and suppresses tumor growth has the potential to be translated into a safe and promising treatment for PDAC."
Dr. Dequan Xiao, Associate Professor of Chemistry and Director of the Center for Integrative Materials at the University of New Haven in Connecticut, commented in an email to Reuters Health, "This is a feasible combination therapy to enhance the anticancer effect of a clinical trial drug for PDAC through the approach of targeted co-delivery of NO to remove a drug penetration barrier, desmoplastic stroma."
"This approach could indeed significantly suppress the pancreatic tumor by reducing the tumor volume to 20%-50% in mice and in a human cancer model," he said.
That said, he noted. "This drug-delivery approach belongs to stromal depletion therapy, which is usually linked to a side effect of cancer metastasis, even though the delivery here is aimed at targeted tissues. Thus, more studies of the long-term metastasis inhibition potential of NO may be needed."
"TRAIL (has) a moderate therapeutic effect in PDAC, even though an enhanced anti-cancer effect was observed here," he noted. "In the future, this therapeutic approach may be combined with more effective drugs than TRAIL to find the ultimate solution for treating PDAC."
"In general, the safety of this approach is good," he added. "A clinical trial may be pursued for this therapy if there are no better chemotherapeutic solutions to treat PDAC," Dr. Xiao concluded.
None of the three corresponding authors responded to requests for a comment.
SOURCE: https://bit.ly/3zaAu1k Gut, online December 17, 2021.
By Marilynn Larkin
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