Atypical
teratoid rhabdoid tumor (ATRT) is an aggressive embryonal
brain tumor among infants and young children. Two challenges exist for preclinical testing in ATRT. First, genetically quiet, ATRT is a difficult
tumor to target molecularly.
Tumor cells need to divide to propagate
tumor growth-intercepting the common crossroads in cell cycle progression is a feasible strategy. KIF11 is needed for bipolar spindle formation in metaphase. We identified KIF11 as a universal target of all ATRT-molecular-subtypes.
Ispinesib, a KIF11-inhibitor, effectively inhibited
tumor proliferation in all seven cell lines. A second challenge-a major challenge in preclinical
drug testing in-vivo among aggressive
tumor models, is the narrow therapeutic window to administer drugs within the limited murine lifespan. Our most aggressive ATRT
tumor model was lethal in all mice within ~ 1 month of
tumor implantation. Such short-surviving mouse models are difficult to employ for preclinical
drug testing due to the narrow time window to administer drugs. To overcome this time restriction, we developed a clinical staging system which allowed physically-fit mice to continue treatment, in contrast to the conventional method of fixed
drug-dose-duration regimen in preclinical testing which will not be feasible in such short-surviving mouse models. We validated this approach in a second embryonal
brain tumor,
medulloblastoma. This is a clinically relevant, cost-efficient approach in preclinical testing for
cancer and non-
cancer disease phenotypes. Widely used preclinical mouse models are not the most accurate and lack the aggressive
tumor spectrum found within a single
tumor type. Mice bearing the most aggressive
tumor spectrum progress rapidly in the limited murine life-span, resulting in a narrow therapeutic window to administer drugs, and are thus difficult to employ in preclinical testing. Our approach overcomes this challenge. We discovered
ispinesib is efficacious against two embryonal
brain tumor types.