Background: MPC-3100 is a fully synthetic, orally bioavailable, investigational Hsp90 inhibitor in clinical studies. It is active against many cancer types in xenograft models including colon, gastric, ovary, prostate, breast, lung and myeloid leukemia, when administered on a once a day schedule. We explored alternate dosing schedules, the sensitivity of additional tumor types and compared activity with marketed therapies. We also demonstrated induction of Hsp70 RNA, a biomarker for Hsp90 inhibition, in tumor tissue following a single dose.

Methods: Pharmacokinetic studies were conducted in mice or rats following oral administration. One to ten million cells, depending on cell-type, were implanted subcutaneously into athymic mice (nu/nu) for tumor studies. Dosing was initiated when median tumor volume was >100 mm3. The NCI-N87 (Her2+) gastric cancer xenograft model was used to evaluate dosing schedules. MPC-3100 was dosed at 200 mg/kg daily, once every other day, twice weekly or at 400 mg/kg twice weekly for three weeks. Tumor growth inhibition (TGI) was monitored up to Day 39. For Hsp70 induction studies, RNA was isolated from mouse liver and tumor tissue following a single dose (200 mg/kg). Hsp70 levels were determined by qRT-PCR.

Results: MPC-3100 dosed at 200 mg/kg was effective when dosed either daily (40% regression), once every other day (7% regression), twice weekly (89% TGI) or at 400 mg/kg twice weekly (87% TGI) for three weeks. Although the 200 mg/kg daily schedule was significantly more effective (p<0.03) than all other schedules at the end of dosing on Day 21, there was no significant difference in TGI (79 to 87%) between the various schedules at the end of the study on Day 39. Pharmacokinetic studies in rats comparing once and twice a day (bid) dosing indicated that effective plasma concentrations of compound were maintained with bid dosing.

The anti-tumor activity of MPC-3100 was compared with erlotinib in a lung cancer (A549) xenograft model sensitive to EGFR inhibition. MPC-3100 dosed daily for 21 days at 150 or 200 mg/kg inhibited tumor growth by 88% or resulted in tumor regression by 16%, respectively, and was as effective as erlotinib at its maximum tolerated dose of 100 mg/kg daily (88% TGI). MPC-3100 was also active in a pancreatic cancer (MIA PaCa-2) xenograft, showing 67% and 95% TGI when dosed at 150 mg/kg or 200 mg/kg for 15 days. Tumor growth inhibition observed with MPC-3100 compared favorably to that observed with 5-fluorouracil (5-FU).

Hsp70 mRNA, was induced by ∼70- and ∼110-fold in mouse liver and tumor tissue, respectively, 4 hours after an oral dose of 200 mg/kg. Hsp90 inhibition occurred rapidly in vivo as the Hsp70 induction reverted back to baseline in 12 hours.

Conclusions: MPC-3100 is active against a broad range of cancer cell types and is efficacious in xenograft models with multiple dosing schedules. The anti-tumor activity of MPC-3100 compares favorably to 5-FU and erlotinib.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2635.

©2010 American Association for Cancer Research
2010