Pediatric Blood & Cancer: Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models

Abhik Bandyopadhyay 1Edward Favours 1Doris A Phelps 1Vanessa Del Pozo 1Samson Ghilu 1Dias Kurmashev 1Joel Michalek 2Aron Trevino 2Denis Guttridge 3Cheryl London 4Kenji Hirotani 5Ling Zhang 5Raushan T Kurmasheva 1Peter J Houghton 1

Abstract

Background: Integrating molecularly targeted agents with cytotoxic drugs used in the curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents.

Procedures: Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program.

Results: Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit the growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E.

Conclusions: P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.

Keywords: developmental therapeutics; pediatric oncology; sarcomas.

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