Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy

Abstract

Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory. In this study, we employed vismodegib to inhibit the sonic-hedgehog pathway with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of sonic-hedgehog inhibitors to breast cancers, and iii) investigate whether sonic-hedgehog inhibition improves not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely Abraxane® and Doxil®. We found that treatment with vismodegib normalizes the tumor microenvironment by reducing the proliferative CAFs and in cases the levels of collagen and hyaluronan. These modulations re-engineered the solid and fluid stresses in the tumors, improving blood vessel functionality. As a result, the delivery and efficacy of chemotherapy was improved in two models of pancreatic cancer. Additionally, vismodegib treatment significantly improved the efficacy of both Abraxane and Doxil in xenograft breast tumors. Our results suggest the use of vismodegib, and sonic hedgehog inhibitors in general, to enhance cancer chemo- and nanotherapy.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…Furthermore, in our model we account indirectly for stroma normalization via targeting of CXCL12/CXCR4 signaling, which results in decreases of stroma components and thus tumor softening. According to previous studies (28,29,53), a dense tumor stroma is associated with high values of elastic modulus and solid stress levels that reduce functional vascular density (82), whereas reduction of stroma decreases the values of the elastic modulus.…”

“…We next performed simulations to investigate the effect of stroma normalization on improving the efficacy of immunotherapy. Reduction of stroma components such as CAFs, collagen, and hyaluronan decreases the elastic modulus and alleviates intratumoral stresses, resulting in a "mechanically softer" tumor (28,29,53). We investigated the effect of varying the tumor elastic modulus within the range of experimentally measured values (28,29,53,54) on the efficacy of immunotherapy.…”

“…Reduction of stroma components such as CAFs, collagen, and hyaluronan decreases the elastic modulus and alleviates intratumoral stresses, resulting in a "mechanically softer" tumor (28,29,53). We investigated the effect of varying the tumor elastic modulus within the range of experimentally measured values (28,29,53,54) on the efficacy of immunotherapy. Low values of the elastic modulus resulted in improved tumor perfusion, increased T-cell infiltration and polarization of TAMs from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype, and thus increased cancer cell killing (SI Appendix, Figs.…”

A multi-scale model for determining the effects of pathophysiology and metabolic disorders on tumor growth

“…8d). These results highlight the importance of only one aspect of desmoplasia -IHC reduction 95 . However, desmoplasia involves other modifications to tissue structure, cell populations and biochemistry, so more detailed information and additional modeling is warranted.…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…In fact, repurposing of common anti-fibrotic drugs to reduce collagen and/or hyaluronan levels when combined with cytotoxic drugs has shown to cause stress alleviation and improve overall survival of mice-bearing tumors [16][17][18]. Similarly, pharmacologic depletion of CAFs has shown to reduce intratumoral stresses, improving perfusion, drug delivery and overall survival in pancreatic and breast tumor models [19,20]. However, genetic deletion of CAFs might enhance tumor progression [21,22].…”