Imaging biomarker development for treatment efficacy for prostate cancer to the bone
Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO showed a reduction in [Tc99m]-bone scan signal suggesting tumor response to treatment. Nevertheless, a return in signal to pre-treatment levels was observed in these patients following therapy completion. It has yet to be determined if the response observed in bone scans results from tumor death, changes in bone metabolism or vascular alterations in the tumor-stromal microenvironment resulting in reduced transport of the imaging tracer. The study objective was to assess tumor and bone response to CABO in an animal model of bone metastasis using a quantitative multi-modal imaging approach.
Twenty-seven male SCID mice were implanted with PC3 cell line in the right tibia. PC3 cells were transfected with a plasmid expressing a bioluminescence imaging (BLI) reporter for measuring apoptosis. When tumor volumes reached 10mm3 by MRI, mice were distributed into 2 groups: CABO at 30 mg/kg (N=13) and vehicle (N=14). Treatments were delivered by oral gavage once a day for three weeks. Starting pre-treatment, MRI and BLI were acquired every third day and CT every week. Tumor and bone volumes were monitored by manually contouring volumes of interest (VOI) on anatomical MRI and CT images, respectively. The apparent diffusion coefficient (ADC), an indirect measure of tumor cellularity, was calculated from diffusion MRI.
Mice treated with CABO were found to have significantly higher ADC values and slower growth profile than controls (p
These are wonderful research pieces, biglabowski.
Please don't mistake my questioning for a bearish take. But the question begs the asking....
We have an approved drug in multiple P3 indications, and a wealth of ongoing human clinical workups in varied stages of mPC to boot. Who in heck is paying for these pre-clinical workups in mouse models...??
Scientifically interesting stuff, but isn't it a bit redundant to the process at this point?
Once you figure out how to bake the cake, is there a need to bake it twice?
"Who in heck is paying for these pre-clinical workups in mouse models...?? " They are both very similar experiments. The first was done by de Bono and his group at the Royal Marsden and the second at Univ. of Michigan. I suspect both were funded by the institutions who did the studies.
"Scientifically interesting stuff, but isn't it a bit redundant to the process at this point?" With understanding comes the promise of being able to better manipulate and improve on the process. This is the type of research that will uncover the means of resistance that eventually develops and may lead to a means of delaying that resistance. From EXEL's prespective, this work will have no effect on the outcome of the pivotal trials. The institutions doing the research have a different set of motivations and they simply want to better understand the process and answer questions that arose from earlier research.
I may be wrong, but without bone biopsy and proved by pathology, the best you can do is: "normalization of bone scan with Cabo/XL-184". The finding of normalized bone scan after Cabo treatment can be due to tumor death; changes in bone metabolism; or vascular alterations in the tumor-stromal microienviroment resulting in reduced transportation of the imaging tracer. The latter two do not support Cabo's efficiency on cancer treatment. This animal study will support the first possibility of tumor death. It could be very difficult to convince terminal stage CRPC patient under go painful bone biopsy to prove Cabo's efficiency.