Abstract

Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated B-cells characterized by both de novo and acquired resistance to presently available cytotoxic therapeutic agents. TAE226 (Novartis) is a potent and specific inhibitor of focal adhesion kinase (FAK) phosphorylation that also has the capacity to inhibit IGF1-R at sub-micromolar concentrations. FAK inhibition has been shown to abrogate intra-cellular phosphorylation of both ERK and AKT and to have anti-tumor effects in murine solid-tumor xenografts. Based on these data we have undertaken a pre-clinical evaluation of TAE226 as a potential therapeutic for MM. Eight genetically heterogeneous human myeloma cell lines (HMCL) (KMS11, KMS12, JIM1, LP-1, U266, RPMI8226, NCI H929, OPM2) were evaluated by MTS assay following exposure to TAE226 at various concentrations for 24 to 72 hours. All HMCL displayed reductions in viability (45% to 100% at 72 hours with 10μM) that were dose and time-dependent, with the range of effective TAE226 concentration being 1 – 10μM depending on cell type. Under standard culture conditions 5μM TAE226 was markedly cytostatic with complete inhibition of cellular proliferation observed over a 72 hour time period and with cell viability at 72 hours based on tryphan blue exclusion in the range of 40 – 90%. Four HMCL with modest (KMS11/U266) or high (LP-&, OPM2) TAE226 sensitivity were further using 5μM TAE226 for 48 hours. AnnexinV expression confirmed apoptosis induction while PhosFlow measurement of p44/42 MAPK confirmed abrogation of intra-cellular ERK phosphorylation - relative reduction following TAE226 compared to untreated controls of 11% KMS-11, 13% U266, 35% OPM2 and 64% LP-1. The induction of synergistic killing of NCI H929 was observed by combining TAE226 (1μM) with sub-lethal concentrations of either bortezomib (5nM) (synergism quotient (SQ) = 1.5) or adriamycin (10μg/ml) (SQ = 1.4) with the scheduling of TAE226 prior to drug partner superior to the reverse order (SQ both = 1.2) of administration. Primary MM cells from patients (n = 7) with advanced relapsed disease were treated after appropriate informed consent. Cell killing as determined by propidium iodide expression varied widely but with a clear dose-dependency – 5μM median 11%, range 0% – 47%; 10μM median 14%, range 1% – 61%; and, 20μM median 31%, range 9% – 67%. Finally, we tested TAE226 in the 5T33 murine model of systemic myelomatosis. C57BL/KaLwRiJ hosts were treated with TAE226 30mg/kg (n = 9) or vehicle (n = 9) for 14 days from day +7. Median time to hind limb paralysis post-treatment was prolonged in the TAE226 group compared to vehicle treated animals, 16 days vs 9 days, respectively (p = 0.06, Log Rank). We conclude based on these encouraging preliminary data that TAE226 warrants further evaluation as a potential therapeutic for MM.

Disclosures: Andrew Spencer - Novartis, Pharmion.; Andrew Spencer - Novartis, Pharmion, Janssen-Cilg.; Andrew Spencer - advisory board - Novartis, Pharmion, Janssen-Cilg.

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