Journal article
Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma
Clinical cancer research, Vol.26(18), pp.5036-5047
09/15/2020
DOI: 10.1158/1078-0432.CCR-19-2597
PMCID: PMC7641033
PMID: 32718998
Abstract
Purpose: Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant 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 nanoscale micelle formulation, in comparison with 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 with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, 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.
Details
- Title: Subtitle
- Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma
- Creators
- Rebecca D. Dodd - University of IowaAmanda Scherer - University of IowaWesley Huang - Duke UniversityGavin R. McGivney - University of IowaWade R. Gutierrez - University of IowaEmily A. Laverty - University of IowaKathleen A. Ashcraft - Duke UniversityVictoria R. Stephens - University of IowaParisa Yousefpour - Duke UniversitySoumen Saha - Duke UniversityVickie Knepper-Adrian - University of IowaWarren Floyd - Duke UniversityMark Chen - Duke Medical CenterYan Ma - Duke UniversityEric M. Mastria - University of California San Francisco Medical CenterDiana M. Cardona - Duke UniversityWilliam C. Eward - Duke UniversityAshutosh Chilkoti - Duke UniversityDavid G. Kirsch - Duke University
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.26(18), pp.5036-5047
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1078-0432.CCR-19-2597
- PMID
- 32718998
- PMCID
- PMC7641033
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Number of pages
- 12
- Grant note
- R35CA197616; F30CA206424; T32GM007171; T32GM0677954; T32GM007337 / Department of Defense CDMRP NF1 New Investigator Award; United States Department of Defense P30 CA086862 / NCI Core Grant
- Language
- English
- Date published
- 09/15/2020
- Academic Unit
- Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359948702771
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