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Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models
Author(s) -
Bandyopadhyay Abhik,
Favours Edward,
Phelps Doris A.,
Pozo Vanessa Del,
Ghilu Samson,
Kurmashev Dias,
Michalek Joel,
Trevino Aron,
Guttridge Denis,
London Cheryl,
Hirotani Kenji,
Zhang Ling,
Kurmasheva Raushan T.,
Houghton Peter J.
Publication year - 2018
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.26870
Subject(s) - medicine , cytotoxic t cell , cisplatin , cyclophosphamide , vincristine , pharmacology , doxorubicin , erlotinib , cancer research , chemotherapy , oncology , epidermal growth factor receptor , cancer , in vitro , chemistry , biochemistry
Background Integrating molecularly targeted agents with cytotoxic drugs used in 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 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.

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