Tumor subtype determines therapeutic response to chimeric polypeptide nanoparticle-based chemotherapy in Pten-deleted mouse models of sarcoma

Purpose: Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective anti-tumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemo-resistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.

Experimental design: New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of Pten-deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nano-scale micelle formulation, in comparison to free doxorubicin.

Results: The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison to free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. Additionally, elevation of CD8+ T cells was observed exclusively in CP-Dox-treated MPNSTs, although these cells were not required for full efficacy of the CP-nanoparticle-based chemotherapy.

Conclusions: These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype-dependent nature of therapeutic response.