Abstract 3921: The use of a novel in vivo orthotopic imaging model of AML for assessment of drug efficacy.
Authors: Batey Michael A. , Ponthan Frida , Heidenreich Olaf 
Published: August 2014

One of the major challenges facing drug discovery programs is the development and validation of clinically relevant preclinical models to allow meaningful efficacy testing of potentially therapeutic agents. In standard sub cutaneous (s.c.) xenograft studies, engraftment and disease progression is measured using callipers. However, orthotopic and metastatic models, although more clinically relevant, are more difficult to measure in vivo, requiring larger group sizes and additional satellite groups for the study of terminal end points. Classically in non-solid tumours, such as Acute Myeloid Leukaemia (AML), terminal end points such as hind limb paralysis have been used, alongside FACS analysis, to assess leukemic disease burden in animals. However, this type of model does not lend itself to longitudinal study of disease burden and low levels of engraftment are hard to assess. With the use of in vivo optical imaging we can now follow disease progression at orthotopic sites, and in the case of non solid tumours, monitor systemic disease burden in the same animal over time. Here we describe the use of intrafemoral (i.f.) cell transplantation, in which cells are implanted directly into the biological niche of interest, the bone marrow, correlating with the environment in which disease develops in patients. Luciferase labelled KASUMI-1 pHR-SLIEW AML cells were injected into the bone marrow cavity of the femur of severely immunocompromised NOG (NOD/Shi-scid/IL-2Rynull) mice via the knee joint. These animals were monitored over eight weeks from time of initial transplantation, and disease burden followed and quantified using bioluminescent detection. Once engraftment was evident, animals were administered treatment with either vehicle, etoposide, or cytarabine, and progression of disease monitored weekly by optical imaging. The model consistently gave rise to leukemic disease disseminating from the site of initial transplantation. Etoposide or cytarabine were shown to abrogate disease, compared to control, in a dose dependent manner. This orthotopic model has advantages over standard, s.c xenograft models, including the ability to quickly identify engrafted animals and the consistent, predictable development of disease allows for therapeutic intervention at an early stage, extending the treatment window. Disease burden can be measured in each individual animal for the duration of the study and treatment efficacy can be easily followed by optical imaging. This model provides an attractive, clinically relevant option for the preclinical assessment of novel therapeutics and combination treatment regimens.

Citation Format: Michael A. Batey, Frida Ponthan, Olaf Heidenreich. The use of a novel in vivo orthotopic imaging model of AML for assessment of drug efficacy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2013-3921