A pharmacokinetic interaction was not observed [7]. Taken together, these results suggest that HFSR and HT may both be related to the activity of anti-VEGF and anti-VEGFR therapy; thus, HT and HFSR may also EPZ-6438 ic50 be markers for a greater degree of response in patients treated with sorafenib and bevacizumab. Inter-individual genetic variation in the VEGF pathway may also alter both the toxicity and response to these agents. The VEGFR2 gene contains two SNPs that are located in exons 7 and 11 and result in nonsynonymous amino acid changes at

residues 297 Val>Ile and 472 His>Gln in the third and fifth immunoglobulin like (Ig-like) domains of VEGFR2 receptor, respectively. The Ig-like domain 3 is critical for binding to the VEGF ligand [8], while domains 4-7 contain structural features that inhibit VEGFR2 signaling in the absence of VEGF [9]. HEK293 s cells that were transfected with VEGFR2 V297I SNP had significantly low VEGF binding efficiency regardless of VEGFR2 H472Q genotype, while variant VEGFR2 H472Q allele had minimal effect on VEGF binding efficiency

[10]. We hypothesize that 1) the development of HT and HFSR following anti-VEGF therapy with bevacizumab and sorafenib is a CP-868596 cell line marker for response to these drugs; 2) that since both toxicities are related to the activity of these agents, the development of a single toxicity (i.e. HT) would increase the risk of GSI-IX developing the other toxicity (i.e. HFSR); and 3) that functional SNPs in VEGFR2 could alter antiangiogenesis treatment response or outcome by affecting the VEGF signalling pathways. To this end, we determined if HT and HFSR were associated with progression free survival or overall survival, and if development of HT increased the risk of developing HFSR in patients with various solid tumors being treated

with sorafenib and/or bevacizumab. We also determined if genetic polymorphisms in the VEGFR2 gene modified the relationship BCKDHA between toxicity and survival endpoints as well as the relationship between coincidence of HT and HFSR. Methods Patients and treatment The analyses were performed on genomic DNA from 178 patients (143 males and 35 females) with solid tumors who received sorafenib (VEGFR2 inhibitor) and/or bevacizumab (anti-VEGF) with or without other agents. These patients were enrolled in six phase I or II clinical trials at the National Cancer Institute (Table 1). Two phase II trials (BAY-CRPC and APC-CRPC; NCT00093431 and NCT00091364 respectively on clinicaltrials.gov) in patients with castrate resistant prostate cancer (CRPC) administered sorafenib 400 mg bid and a combination of thalidomide (200 mg qhs), bevacizumab and docetaxel (15 mg/kg plus 75 mg/m2 day 1, q 21 days), respectively [11, 12].