NERDG 2026
Poster 19 Abstract
Combinatorial nanomedicine strategy to remodel tumor stroma and degrade BRD4 to treat pancreatic ductal adenocarcinoma
Drishti Rathod, Ketan Patel
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY 11439, USA
Presenting Author: Drishti Rathod
Corresponding Author: Ketan Patel, [email protected]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) will become second leading cause of cancer death by 2030 yet remains untreatable. PDAC's dual resistance mechanisms prove to be an impenetrable fortress where Focal Adhesion Kinase (FAK) driven desmoplastic stroma impedes drug penetration and BRD4 overexpression drives the aggressive tumor growth. This necessitates dual targeting strategies that can simultaneously disrupt the microenvironment and eliminate oncogenic drivers. PROteolysis TArgeting Chimera (PROTAC) have recently gained traction for degrading undruggable targets. To overcome pharmacokinetic barriers, we designed a dual-route nanomedicine platform: oral self-nanoemulsifying PND-1186 (PNDnano, FAK inhibitor) and intravenous albumin-anchored PROTAC (ARV-825) nanoliposomes (AAnano, BRD4 PROTAC). The aims are a) To develop and characterize the nanoformulations of PND and ARV, b) To evaluate their anticancer efficacy in 2D/3D PDAC models, and c) To assess their anticancer efficacy in PDAC xenograft studies. PNDnano was developed by screening different excipients, including oils, surfactants and cosolvents, and the excipients exhibiting superior solubility of PND were selected for developing the SNEDDS. AAnano was developed via modified hydration method using the DGS-NTA-Ni for surface conjugation of histidine-tagged human serum albumin. Successful conjugation of albumin on the liposomal surface was confirmed by polyacrylamide gel electrophoresis and shift in zeta potential. Both the nanoformulations showed 2 to 3-fold higher in-vitro cytotoxic effect in PDAC cells compared to the individual drugs alone. Combenefit analysis revealed robust synergistic cytotoxicity between ARV and PND in PDAC cells, achieving maximum synergy (score = 28) at 0.5 µM ARV and 2 µM PND. Scratch and clonogenic assays depicted that combinatorial nanotherapy markedly suppressed migration and clonogenicity. Three-dimensional spheroid assays showed superior combination efficacy, with ~63% spheroid growth reduction and 4.4-fold invadopodia suppression in PDAC. In-vivo anticancer efficacy of AAnano+PNDnano was evaluated in nude mice bearing PDAC tumors. Combination therapy achieved 56.9% tumor suppression, with reduced growth rates (9.66 vs 19.37 mm³/day) compared to control. All treatment groups maintained stable body weights, indicating excellent tolerability with no systemic toxicity. This first-in-class dual-targeting strategy combining PROTAC with FAK inhibitor demonstrates potent antitumor activity, disrupting tumor stroma, thus eliminating oncogenic drivers of desmoplastic PDAC.
Keywords
Pancreatic ductal adenocarcinoma, Albumin nanoliposomes, PROTAC, FAK inhibition, tumor stromal disruption
Poster 19 Abstract
Combinatorial nanomedicine strategy to remodel tumor stroma and degrade BRD4 to treat pancreatic ductal adenocarcinoma
Drishti Rathod, Ketan Patel
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY 11439, USA
Presenting Author: Drishti Rathod
Corresponding Author: Ketan Patel, [email protected]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) will become second leading cause of cancer death by 2030 yet remains untreatable. PDAC's dual resistance mechanisms prove to be an impenetrable fortress where Focal Adhesion Kinase (FAK) driven desmoplastic stroma impedes drug penetration and BRD4 overexpression drives the aggressive tumor growth. This necessitates dual targeting strategies that can simultaneously disrupt the microenvironment and eliminate oncogenic drivers. PROteolysis TArgeting Chimera (PROTAC) have recently gained traction for degrading undruggable targets. To overcome pharmacokinetic barriers, we designed a dual-route nanomedicine platform: oral self-nanoemulsifying PND-1186 (PNDnano, FAK inhibitor) and intravenous albumin-anchored PROTAC (ARV-825) nanoliposomes (AAnano, BRD4 PROTAC). The aims are a) To develop and characterize the nanoformulations of PND and ARV, b) To evaluate their anticancer efficacy in 2D/3D PDAC models, and c) To assess their anticancer efficacy in PDAC xenograft studies. PNDnano was developed by screening different excipients, including oils, surfactants and cosolvents, and the excipients exhibiting superior solubility of PND were selected for developing the SNEDDS. AAnano was developed via modified hydration method using the DGS-NTA-Ni for surface conjugation of histidine-tagged human serum albumin. Successful conjugation of albumin on the liposomal surface was confirmed by polyacrylamide gel electrophoresis and shift in zeta potential. Both the nanoformulations showed 2 to 3-fold higher in-vitro cytotoxic effect in PDAC cells compared to the individual drugs alone. Combenefit analysis revealed robust synergistic cytotoxicity between ARV and PND in PDAC cells, achieving maximum synergy (score = 28) at 0.5 µM ARV and 2 µM PND. Scratch and clonogenic assays depicted that combinatorial nanotherapy markedly suppressed migration and clonogenicity. Three-dimensional spheroid assays showed superior combination efficacy, with ~63% spheroid growth reduction and 4.4-fold invadopodia suppression in PDAC. In-vivo anticancer efficacy of AAnano+PNDnano was evaluated in nude mice bearing PDAC tumors. Combination therapy achieved 56.9% tumor suppression, with reduced growth rates (9.66 vs 19.37 mm³/day) compared to control. All treatment groups maintained stable body weights, indicating excellent tolerability with no systemic toxicity. This first-in-class dual-targeting strategy combining PROTAC with FAK inhibitor demonstrates potent antitumor activity, disrupting tumor stroma, thus eliminating oncogenic drivers of desmoplastic PDAC.
Keywords
Pancreatic ductal adenocarcinoma, Albumin nanoliposomes, PROTAC, FAK inhibition, tumor stromal disruption
