Abstract A80: Modified dosing schedules with the EGFr inhibitors gefitinib and lapatinib in rodent models of mammary and urinary bladder cancer: Preventive and therapeutic effects.

Abstract

Abstract The EGFR inhibitors are approved for treatment of lung and pancreatic cancers (Erlotinib, Gefitinib) and Neu overexpressing breast cancer (Lapatinib) in humans; as well as preventing multiple cancers in animal models. However, the development of toxicities (Iressa, skin rashes; Lapatinib, diarrhea) limit their potential use in prevention; and perhaps even in an adjuvant setting. We examined whether alternative dosing regimens which might reduce toxicity would still achieve preventive and therapeutic efficacy. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. In a prevention study, MNU treated rats administered Gefitinib daily (10 mg/kg BW/day, 7×/week) or Gefitinib (70 mg/kg BW, 1×/week) beginning 5 days after MNU resulted in 94 and 75% reductions, respectively, in cancer multiplicity. Simultaneous measurements of tumor load (number of tumors × tumor weight) showed that both regimens resulted in greater than a 90% decrease. In the therapeutic study (initiating treatment when animals developed a small palpable cancer), both regimens were again highly effective. A prevention study was also performed with Lapatinib (75 mg/kg BW/day, 7×/week or 525 mg/kg BW, 1×/week). While the daily dose reduced cancer multiplicity 90%, the weekly dose caused a 70% reduction. Finally, we examined the effects of daily or weekly dosing with Iressa (100 mg/kg BW/day, 5×/week or 500 or 250 mg/kg BW, 1×/week) in an ER− mouse model (using MMTV/Neu; p53+/− mice). This study showed that while daily dosing with Iressa decreased tumor multiplicity approximately 80%, weekly dosing at either dose caused roughly a 50% decrease. These data show that even a significant alteration in the dosing of Gefitinib (EGFR 1) or Lapatinib (EGFR 2/1) still resulted in a large reduction in mammary cancers. We similarly tested Lapatinib (weekly, 525 mg; or daily, 75 mg/kg/day) in a delayed preventive/therapeutic setting in an OH-BBN model of urinary bladder cancer. We found that although daily dosing was most effective weekly dosing was still relatively effective. The important clinical question will be whether this altered dosing will diminish the toxicities associated with these agents. We cannot determine this in animal models since, at the effective doses employed, the typical toxicities observed in humans are not observed. Supported by NCI contract number HHSN261200433001C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A80.