ATRT-06. ISPINESIB IS AN EFFICACIOUS THERAPEUTIC AGENT FOR ATYPICAL TERATOID RHABDOID TUMORS

Abstract BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and deadly embryonal brain tumor in children. KIF11 is needed for formation of the bipolar spindle in metaphase. KIF11 suppression leads to prolonged mitotic arrest and subsequent cell death in mitosis. KIF11 inhibitors are currently in Phase 2 trials for recurrent myeloma. There are >20 high affinity, specific small-molecule KIF11 inhibitors, including ispinesib. Previously, ispinesib was reported to be effective in-vitro on 2 ATRT cell lines from a large screen on different tumor types, however there were no functional studies, nor in-vivo evaluation due to a lack of ATRT animal models. Our group has developed patient-derived orthotopic xenograft (PDOX) mouse models of ATRT in preclinical testing. AIMS: Our objectives were to (1) Evaluate in-vitro and in-vivo efficacy of ispinesib, (2) Investigate the functional mechanisms of ispinesib in ATRT. RESULTS: We discovered KIF11 was upregulated in patient ATRT tumors, compared to normal brain controls. In our cohort of 7 patient-derived tumor cell lines, we found 3 cell lines highly expressing KIF11. Ispinesib effectively inhibited tumor cell proliferation (Day 7 IC50 4nM-533nM) for 7 cell lines. Ispinesib concentration of 215nM demonstrated sustained time-dependent killing-effect on 5/7 cell lines. Ispinesib at only 10nM is highly effective against the most tumorigenic cell line, causing 80% cell death (Day 13) and induced G2/M arrest. In-vivo, this highly aggressive tumor model is lethal in all mice within 1 month of tumor implantation. By Day 29 of tumor implantation, 4/4 untreated mice (control) died. By Day 36, after 1 treatment-cycle (3 doses), 3/5 ispinesib-treated mice died. Two surviving ispinesib-treated mice underwent and completed 2nd treatment cycle (3 doses), these 2 mice died on Day 50 and Day 54. CONCLUSIONS: We are currently elucidating mechanisms of proliferation inhibition and cell death, and further evaluating in-vivo efficacy in our xenografts.