Abstract
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.
Highlights
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive embryonal brain tumor among infants and young children
We have developed a large panel of patient-derived orthotopic xenograft (PDOX) mouse models using patient tumors and patient-tumor-derived cell lines of ATRT (Figs. 1a, S1A,B)
The most aggressive ATRT tumor model we have developed was invariably lethal in all mice within ~ 1 month of tumor implantation, across multiple reproducible cohorts of mouse xenografts (Figs. 1a, S1B)
Summary
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive embryonal brain tumor among infants and young children. Post-operative recovery after orthotopic brain tumor implantation requires 10–14 days[1], which leaves a narrow time window to administer the drugs and the consequent challenge to achieve sufficient drug doses within the remaining 14–20 days of murine laboratory life-span of this aggressive PDOX model to induce a tumor resolution. Which in this case, renders majority of these aggressive preclinical models not useful to be employed in the laboratory. Our goal is to allow mouse models bearing the most aggressive tumor spectrum to undergo preclinical testing in order to identify effective drugs against the most aggressive tumor on the spectrum, to translate to patient care and impact the survival of these patients who are failing current standard therapy
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