Parastou Foroutan, PhD
A novel imaging technology was able to determine four days after treatment that experimental therapies for sarcoma were fighting the cancer in xenograft models, a study has demonstrated.
In the study published in the journal PLOS One
, Foroutan et al, of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, used diffusion-weighted magnetic resonance imaging (MRI) to evaluate the activity of gemcitabine and Wee-1 cell cycle checkpoint inhibitor MK1775 in an osteosarcoma xenotransplant model soon after treatment.
Previous studies had found that standard techniques for volumetric analysis, including more conventional forms of MRI, could not accurately assess changes to tumor biology in sarcoma. The newer technology measures water mobility in biological tissue, quantified as Apparent Diffusion Coefficients (ADC); a rising ADC just after treatment may signify cancer cell death, the authors wrote. This application of the technology has not previously been investigated or reported, they added.
The authors embarked on the investigation because novel therapies to replace surgical resection followed by chemotherapy are critically needed in sarcoma, where progress has been hampered by the disease’s heterogeneity, and cure rates have not improved much in the last decade. In previous studies, gemcitabine and MK1775 demonstrated an ability to kill cancer cells, but a better way to measure their activity, particularly soon after treatment, was needed, the authors wrote.
For the study, tissue was harvested during an initial core biopsy of a distal femur osteosarcoma that was metastatic to the lungs. The osteosarcoma patient was chemotherapy-naïve at the time of biopsy. The harvested tissue was subcutaneously transplanted into both flanks of 16 six-week old female SHO/SCID athymic mice. When the tumors reached 500 mm3
, the mice were randomly assigned to four treatment groups: a control group; a group receiving oral MK1775; a cohort receiving gemcitabine by intraperitoneal injection; and a group taking both MK1775 and gemcitabine. Each mouse had two implanted tumors, so there were 8 tumors per treatment group.
The investigators examined multiple descriptors of ADC parameters in the mice at baseline, 24 hours after each drug administration, and at day 14. They observed reduced cellularity and larger ranges in cell sizes for treated groups by day 4 of treatment.
Specifically, the researchers found that gemcitabine, with or without MK1775, significantly slowed tumor growth by day 4 after treatment; this response was heralded 24 hours after treatment by significant elevations in mean tumor ADC, ADC distribution, and entropy. Gemcitabine sparked apoptosis, and the increased ADC values that investigators observed correlated with that activity.
Further, the authors found, when tumor control happened slowly with MK1775 monotherapy, there were no significant changes in ADC or ADC distribution, indicating that therapy-induced edema can be absorbed faster than it is created. Since the MRI technology tested in the study was only able to measure apoptosis that occurred very rapidly, it could be useful in the assessment of the most active new agents, the authors suggested.