Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model

Abstract

Despite frequent overexpression of numerous growth factor receptors by pancreatic ductal adenocarcinomas (PDAC), such as EGFR, therapeutic antibodies have not proven effective. Desmoplasia, hypovascularity, and hypoperfusion create a functional drug delivery barrier that contributes to treatment resistance. Drug combinations that target tumor/stroma interactions could enhance tumor deposition of therapeutic antibodies, although clinical trials have yet to support this strategy. We hypothesize that macromolecular or nanoparticulate therapeutic agents may best exploit stroma-targeting "tumor priming" strategies, based on the fundamental principles of the Enhanced Permeability and Retention phenomenon. Therefore, we investigated the molecular and pharmacologic tumor responses to NVP-LDE225, an SMO inhibitor of sonic hedgehog signaling (sHHI), of patient-derived xenograft models that recapitulate the desmoplasia and drug delivery barrier properties of PDAC. Short-term sHHI exposure mediated dose-and time-dependent changes in tumor microvessel patency, extracellular matrix architecture, and interstitial pressure, which waned with prolonged sHHI exposure, and increased nanoparticulate permeability probe deposition in multiple PDAC patient-derived xenograft isolates. During sHHI-mediated priming, deposition and intratumor distribution of both a nontargeted mAb and a mAb targeting EGFR, cetuximab, were enhanced. Sequencing the sHH inhibitor with cetuximab administration resulted in marked tumor growth inhibition compared with cetuximab alone. These studies suggest that PDAC drug delivery barriers confound efforts to employ mAb against targets in PDAC, and that shortterm, intermittent exposure to stromal modulators can increase tumor cell exposure to therapeutic antibodies, improving their efficacy, and potentially minimize adverse effects that may accompany longer-term, continuous sHHI treatment.

Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma

“…There obviously exist certain CAF subtypes, some of which with protumorigenic features, whereas others—at least SHH-dependent, α-SMA-positive CAFs, or a subfraction of CAFs fulfilling these criteria—may have antitumorigenic properties restraining PDAC growth. In addition, as the function of the stroma is dynamic during disease progression and its cellular and noncellular components coevolve with the changes of the genetic landscape of cancer cells, also the timing of intervention matters [ 100 ].…”

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

“…Moreover, deletion of the Col1a1 gene, which encodes for the alpha 1 subunit of collagen type I, in α-SMA positive CAFs led to a significant decrease in total stromal collagen type I deposition which results in acceleration of disease and reduced overall survival due to the suppression of CD8 + T cells ( Chen et al, 2021 ). In addition, inhibition of a G-protein coupled receptor, smoothened (SMO), in the hedgehog signaling cascade in PDAC tumors led to reduced desmoplasia, decreased collagen type I content, and a transient increase in vascularization that improved the delivery of chemotherapy and immunotherapy to the tumors resulting in longer median survival in genetically engineered animal models of PDAC ( Olive et al, 2009 ) ( Wang et al, 2019 ). On the other hand, despite the ability of Sonic hedgehog (SHH) to drive the formation of a CAF-rich stroma, its deletion also leads to low-stroma containing tumors that are more aggressive, have more undifferentiated histology, enhanced vascularity, and higher proliferation ( Rhim et al, 2014 ).…”

Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

“…This allowed for the expansion of regulatory T cells, thereby increasing immunosuppression in the TME [ 128 ]. Conversely, in PDX models, short-term hedgehog signaling inhibition mediated dose-dependent alterations in vasculature patency, ECM architecture and IFP, increasing the permeability of nanoparticle deposition [ 129 ]. These studies suggest that short-term or transient treatment schedules using anti-fibrotic agents could potentially increase the efficiency of subsequent therapeutic agents [ 88 , 129 ], while minimizing the adverse effects of chronic long-term treatment, which have also previously been described in genetic studies of stromal ablation [ 35 , 36 ].…”