Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma
Purpose: Pancreatic ductal adenocarcinoma (PDA) is really a deadly cancer that’s broadly chemoresistant, due partly to biophysical qualities of tumor stroma, which works as a barrier to drug delivery for many classical chemotherapeutic drugs. The aim of the work would be to assess the preclinical effectiveness and mechanisms of PTC596, a singular agent with potent anticancer qualities in vitro and desirable pharmacologic qualities in vivo.
Experimental Design: We assessed the pharmacology, mechanism, and preclinical effectiveness of PTC596 in conjunction with standards of care, using multiple preclinical types of PDA.
Results: We discovered that PTC596 has pharmacologic qualities that overcome the barrier to drug delivery in PDA, together with a lengthy circulating half-existence, insufficient P-glycoprotein substrate activity, and systemic tolerability. We discovered that PTC596 combined synergistically with standard clinical regimens to enhance effectiveness in multiple model systems, such as the chemoresistant genetically engineered “KPC” type of PDA. Through mechanistic studies, we found that PTC596 functions like a direct microtubule polymerization inhibitor, yet a previous medical trial discovered that it lacks peripheral neurotoxicity, as opposed to other such agents. Strikingly, we discovered that PTC596 synergized using the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions inside a PDX model. Furthermore, similar effectiveness was achieved in conjunction with nab-paclitaxel alone, highlighting a particular synergistic interaction between two different microtubule-targeted agents within the setting of pancreatic ductal adenocarcinoma.
Conclusions: These data demonstrate obvious rationale to add mass to PTC596 in conjunction with standard-of-care chemotherapy for PDA.