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Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma.

Publication ,  Journal Article
Dodd, RD; Scherer, A; Huang, W; McGivney, GR; Gutierrez, WR; Laverty, EA; Ashcraft, KA; Stephens, VR; Yousefpour, P; Saha, S; Knepper-Adrian, V ...
Published in: Clin Cancer Res
September 15, 2020

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2020

Volume

26

Issue

18

Start / End Page

5036 / 5047

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Sarcoma
  • Peptides
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Nerve Sheath Neoplasms
  • Nanoparticles
  • Micelles
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Dodd, R. D., Scherer, A., Huang, W., McGivney, G. R., Gutierrez, W. R., Laverty, E. A., … Kirsch, D. G. (2020). Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma. Clin Cancer Res, 26(18), 5036–5047. https://doi.org/10.1158/1078-0432.CCR-19-2597
Dodd, Rebecca D., Amanda Scherer, Wesley Huang, Gavin R. McGivney, Wade R. Gutierrez, Emily A. Laverty, Kathleen A. Ashcraft, et al. “Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma.Clin Cancer Res 26, no. 18 (September 15, 2020): 5036–47. https://doi.org/10.1158/1078-0432.CCR-19-2597.
Dodd RD, Scherer A, Huang W, McGivney GR, Gutierrez WR, Laverty EA, et al. Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma. Clin Cancer Res. 2020 Sep 15;26(18):5036–47.
Dodd, Rebecca D., et al. “Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma.Clin Cancer Res, vol. 26, no. 18, Sept. 2020, pp. 5036–47. Pubmed, doi:10.1158/1078-0432.CCR-19-2597.
Dodd RD, Scherer A, Huang W, McGivney GR, Gutierrez WR, Laverty EA, Ashcraft KA, Stephens VR, Yousefpour P, Saha S, Knepper-Adrian V, Floyd W, Chen M, Ma Y, Mastria EM, Cardona DM, Eward WC, Chilkoti A, Kirsch DG. Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in Pten-deleted Mouse Models of Sarcoma. Clin Cancer Res. 2020 Sep 15;26(18):5036–5047.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 15, 2020

Volume

26

Issue

18

Start / End Page

5036 / 5047

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Sarcoma
  • Peptides
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Nerve Sheath Neoplasms
  • Nanoparticles
  • Micelles
  • Mice, Knockout
  • Mice