Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas

EBioMedicine. 2019 Feb:40:224-230. doi: 10.1016/j.ebiom.2019.01.046. Epub 2019 Jan 31.

Abstract

Background: Olaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS.

Methods: Primary STS were initiated in mice. When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm3, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype.

Findings: RT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09).

Interpretation: 1E10Fc did not act as a radiosensitizer in this primary STS model.

Funding: This study was funded by a research agreement from Eli Lilly and Company.

Keywords: Olaratumab; PDGFRα; Radiation; Soft tissue sarcoma.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Transgenic
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Radiation-Sensitizing Agents / pharmacology*
  • Radiotherapy
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Sarcoma / metabolism*
  • Sarcoma / pathology
  • Sarcoma / therapy
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Protein p53
  • Receptor, Platelet-Derived Growth Factor alpha