Therapeutic Potential Of A Novel Small Molecule, Prlx 93936, In Models Of Pancreatic Cancer

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO PRLX 93936 displays robust activity in a diverse array of in vitro and in vivo tumor models including pancreatic cancer. Developed and characterized at Prolexys Pharmaceuticals in cell-based assays, PRLX 93936 is a product of extensive SAR work originating from a molecule identified in a screen against isogenic cell lines engineered to differentially express several genes including activated RasV12 (Dolma et.al, Cancer Cell 3: 285-296, 2003). Structural analogs were evaluated for tumor-specific activity against a panel of normal and tumor cell lines to identify a family of biologically active molecules with enhanced pharmacologic and pharmacokinetic properties. PRLX 93936 displayed potent and selective activity against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. Except for MiaPaca2, in vitro testing of PRLX 93936 indicated that all tested pancreatic lines were sensitive to PRLX 93936 including: AsPc1, BxPc3, CAPAN1, CAPAN2, CFPAC1, HS766t, Su86.86 and Panc1. Similarly, in animals bearing MiaPaca2 derived xenografts, IP administration of PRLX93936 produced little tumor growth inhibition, however, as a single agent against PANC-1 derived xenografts, PRLX 93936 produced complete and durable tumor regressions with IP, PO or IV dosing. In vivo administration of low-dose PRLX 93936 in conjunction with standard of care agents identified complementary combinations. PET imaging studies in HT1080 tumor bearing animals indicated that glucose uptake is elevated during initial treatment with PRLX 93936 then decreases significantly concomitant with cell death and tumor shrinkage. Correlation of compound sensitivity with genotype has not been determined, however, COMPARE analysis of PRLX 93936 in the NCI 60 panel of cell lines indicated that it is functionally unique among the agents tested. Characterization of treated cells demonstrated that activation of select MAPK and JNK pathway members is correlated with compound sensitivity. Hit profiling studies examining PRLX 93936 binding or inhibition of enzyme activity against CYP450 enzymes, cell surface receptors and action potential mediating cardiac ion channels showed little response. Kinase profiling of PRLX 93936 against evolutionarily diverse enzymes revealed no significant inhibitory activity. The biological effects of PRLX 93936 treatment of sensitive cells have been characterized to include altered ion flux, cell cycle arrest, mitochondrial membrane depolarization and caspase dependent apoptosis. Mass spectrometry-based proteomics experiments indicate that both PRLX 93936 and its parent compound can bind to a mitochondrial protein VDAC (Voltage Dependent Anion Channel) which may be a molecular target Yagoda et al., Nature. Jun 14;447(7146):864-8. Phase I studies with PRLX 93936 in patients with advanced solid tumors are ongoing (initiated Aug. 20007). Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4694.