In vivo ALK Inhibitor Efficacy

To test the effectiveness of ALK inhibition in vivo, 6-week-old CD1 mice were intracranially allografted with 5 × 10⁵ mouse PPP1CB–ALK tumor cells (see above) to give a more standardized latency of tumor formation and to avoid having to administer treatment to very young animals. The chosen inhibitor was lorlatinib based on the in vitro results, as well as HCl and temozolomide as vehicle control and standard of care, respectively. Dosing and treatment schedules were described previously (66 (link)). Tumor growth was monitored using BLI on an IVIS imager (PerkinElmer). The tumors were allowed to develop for two weeks before animals were stratified into three treatment groups based on their luciferase signal (rank 1, 4, 7, etc., being assigned to lorlatinib, rank 2, 5, 8, etc., to temozolomide, and rank 3, 6, 9, etc., to vehicle control). Animals were monitored daily for symptoms or abnormal behavior and weighed three times a week, and were sacrificed upon first signs of tumor-related symptoms according to humane endpoint criteria.

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Clarke M., Mackay A., Ismer B., Pickles J.C., Tatevossian R.G., Newman S., Bale T.A., Stoler I., Izquierdo E., Temelso S., Carvalho D.M., Molinari V., Burford A., Howell L., Virasami A., Fairchild A.R., Avery A., Chalker J., Kristiansen M., Haupfear K., Dalton J.D., Orisme W., Wen J., Hubank M., Kurian K.M., Rowe C., Maybury M., Crosier S., Knipstein J., Schüller U., Kordes U., Kram D.E., Snuderl M., Bridges L., Martin A.J., Doey L.J., Al-Sarraj S., Chandler C., Zebian B., Cairns C., Natrajan R., Boult J.K., Robinson S.P., Sill M., Dunkel I.J., Gilheeney S.W., Rosenblum M.K., Hughes D., Proszek P.Z., Macdonald T.J., Preusser M., Haberler C., Slavc I., Packer R., Ng H.K., Caspi S., Popović M., Kotnik B.F., Wood M.D., Baird L., Davare M.A., Solomon D.A., Olsen T.K., Brandal P., Farrell M., Cryan J.B., Capra M., Karremann M., Schittenhelm J., Schuhmann M.U., Ebinger M., Dinjens W.N., Kerl K., Hettmer S., Pietsch T., Andreiuolo F., Driever P.H., Korshunov A., Hiddingh L., Worst B.C., Sturm D., Zuckermann M., Witt O., Bloom T., Mitchell C., Miele E., Colafati G.S., Diomedi-Camassei F., Bailey S., Moore A.S., Hassall T.E., Lowis S.P., Tsoli M., Cowley M.J., Ziegler D.S., Karajannis M.A., Aquilina K., Hargrave D.R., Carceller F., Marshall L.V., von Deimling A., Kramm C.M., Pfister S.M., Sahm F., Baker S.J., Mastronuzzi A., Carai A., Vinci M., Capper D., Popov S., Ellison D.W., Jacques T.S., Jones D.T, & Jones C. (2020). Infant high grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer discovery, 10(7), 942-963.

Publication 2020

IVIS imager

Abnormal behavior Alk 5 Animals Cells Inhibition Lorlatinib Luciferase Mouse Signs symptoms Temozolomide Treatment schedules Tumor

Corresponding Organization :

Other organizations : Institute of Cancer Research, Hopp Children's Cancer Center Heidelberg, German Cancer Research Center, Great Ormond Street Hospital, University College London, St. Jude Children's Research Hospital, Memorial Sloan Kettering Cancer Center, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Royal Marsden Hospital, University of Bristol, Brain Tumour Research, University of Queensland, Queensland Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Medical College of Wisconsin, Kinderkrebs-Zentrum Hamburg, Universität Hamburg, University Medical Center Hamburg-Eppendorf, Wake Forest University, NYU Langone Health, St George's Hospital, King's College Hospital, Breast Cancer Now, Center for Cancer and Blood Disorders, Emory University, Comprehensive Cancer Center Vienna, Medical University of Vienna, Children's National, Chinese University of Hong Kong, Sheba Medical Center, University of Ljubljana, Ljubljana University Medical Centre, Oregon Health & Science University, University of California, San Francisco, Karolinska Institutet, Oslo University Hospital, Beaumont Hospital, Our Lady's Hospital, University Medical Centre Mannheim, University Hospital Heidelberg, University Children's Hospital Tübingen, Erasmus MC, University Hospital Münster, University Medical Center Freiburg, University of Bonn, University of Southampton, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Queensland University of Technology, Sydney Children's Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, University Hospital of Wales, University of Wales

Top 5 similar protocols

Variable analysis

independent variables

Lorlatinib (ALK inhibitor)
HCl (vehicle control)
Temozolomide (standard of care)

dependent variables

Tumor growth monitored using BLI on an IVIS imager

control variables

6-week-old CD1 mice
Intracranially allografted with 5 × 10^5 mouse PPP1CB–ALK tumor cells
Tumor development allowed for two weeks before treatment
Animals monitored daily for symptoms or abnormal behavior and weighed three times a week
Animals sacrificed upon first signs of tumor-related symptoms according to humane endpoint criteria

positive controls

Temozolomide (standard of care)

negative controls

HCl (vehicle control)

Annotations

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