biomaven with aria news today and this abstract anymore comments on this. i know its early but it definatly seems exciting for aria going forward.
From: Biomaven 2/27/2011 11:18:32 PM
of 1738
Just one indication of pona's activity outside CML:
Presentation Title: Ponatinib (AP24534), a potent pan-FGFR inhibitor with activity in multiple FGFR-driven cancer models
Presentation Time: Tuesday, Apr 05, 2011, 8:00 AM -12:00 PM
Location: Exhibit Hall A4-C, Poster Section 28
Poster Section: 28
Poster Board Number: 7
Author Block: Joseph M. Gozgit, Matthew J. Wong, Lauren Moran, Scott Wardwell, Qurish K. Mohemmad, Narayana I. Narasimhan, William C. Shakespeare, Frank Wang, Tim Clackson, Victor M. Rivera. Ariad Pharmaceuticals, Cambridge, MA
Abstract Body: Background: Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) with potent activity against BCR-ABL being investigated in a pivotal phase 2 trial in patients with chronic myeloid leukemia (CML). Previously, ponatinib has been shown to potently inhibit FGFR1-4 kinase activity. Here the activity of ponatinib is explored against FGFR1-4 activated via multiple discrete mechanisms in a variety of cancer types in vitro and in vivo.
Results: The cellular activity of ponatinib was first examined in Ba/F3 cells engineered to express activated FGFRs. Ponatinib selectively inhibited viability of cells expressing FGFR1-4, with IC50s of 8 to 34 nM, while having no effect on viability of parental Ba/F3 cells (IC50 >1000 nM). Likewise, ponatinib inhibited phosphorylation of FGFR1-4 with IC50s of 29 to 39 nM. Four other TKIs in clinical development that have been reported to have anti-FGFR activity were substantially less potent: dovitinib (IC50: 34 to 235 nM), cediranib (54 to >1000 nM), BIBF 1120 (214 to >1000 nM) and brivanib (503 to >1000 nM). Next the activity of ponatinib was examined in a panel of cell lines representing multiple tumor types and containing FGFRs dysregulated by a variety of mechanisms. Ponatinib potently inhibited growth of breast cancer cells containing amplified FGFR1 or FGFR2 (GI50: 14-69 nM) and of gastric cancer cells with amplified FGFR2 (GI50: 10-25 nM). In endometrial cancer cells with an activating mutation in the kinase domain of FGFR2 (N549K), or a mutation that increases ligand binding (S252W), ponatinib inhibited growth with GI50s of 14-61 nM. In bladder cancer cells with a mutation in FGFR3 that causes constitutive dimerization (S249C), ponatinib inhibited growth with GI50s of 103-181 nM. In all cell lines, the effects on cell growth were accompanied by inhibition of FGFR or FRS2a phosphorylation. In comparison, ponatinib was less potent in a panel of cell lines lacking expression of activated FGFRs (GI50: 372 nM to >1 uM). The 4 other TKIs examined were less active compared to ponatinib in all FGFR mutant cell lines examined. Daily oral dosing of ponatinib (30 mg/kg) to mice reduced growth of FGFR2N549K endometrial and FGFR3S249C bladder tumor xenografts by approximately 80% and induced regression of gastric tumors expressing amplified FGFR2 by 50%. In all 3 models, dose-dependent inhibition of FGFR phosphorylation in the tumor was demonstrated.
Conclusion: Ponatinib exhibits potent, pan-FGFR inhibitory activity that compares favorably to dovitinib, cediranib, BIBF 1120 and brivanib. These results provide a strong rationale for clinical evaluation of ponatinib in FGFR-driven cancers.
AI
