Abstract
We present a novel approach to a personalized therapeutic concept for solid tumors. We illustrate this on a rare childhood tumor for which only a generalized treatment concept exists using carbonic anhydrase IX and aquaporin 1 inhibitors. The use of microcalorimetry as a refined in vitro method for evaluation of drug susceptibility in organotypic slice culture has not previously been established. Rapid microcalorimetric drug response assessment can refine a general treatment concept when it is applied in cases in which tumors do not respond to conventional chemo-radiation treatment. For solid tumors, which do not respond to classical treatment, and especially for rare tumors without an established protocol rapid microcalorimetric drug response testing presents an elegant novel approach to test alternative therapeutic approaches. While improved treatment concepts have led to improved outcome over the past decades, the prognosis of high risk disease is still poor and rethinking of clinical trial design is necessary. A small patient population combined with the necessity to assess experimental therapies for rare solid tumors rather at the time of diagnosis than in relapsed or refractory patients provides great challenges. The possibility to rapidly compare established protocols with innovative therapeutics presents an elegant novel approach to refine and personalize treatment.
Highlights
Isothermal microcalorimetry allows real-time monitoring of metabolic activity of living organisms
We have previously studied the role of several hypoxia-dependent factors in esophageal carcinoma and neuroblastoma [15,16], two tumor entities with poor prognosis in advanced stages of disease
We have previously investigated the role of the hypoxia-dependent enzyme carbonic anhydrase IX (CAIX), which is modulated by HIF-1α and up-regulated in the hypoxic microenvironment, in esophageal carcinoma and neuroblastoma
Summary
Isothermal microcalorimetry allows real-time monitoring of metabolic activity of living organisms. Use of isothermal microcalorimetry measurements to evaluate treatment response in tumor slice cultures has not been described. Expression of aquaporin 1 (AQP1), the first molecular water channel described [19], has been reported to be associated with a poor prognosis, especially in later stages of several solid tumors [20], when one can assume that hypoxia within the tumor is increasing This would suggest that AQP1 is regulated by mechanisms within the hypoxic tumor microenvironment. Using microcalorimetric assessment the heat flow of slice cultures could be significantly modulated by treatment with specific inhibitors of the target enzyme CAIX using three different substances. But still impressively, the AQP1 inhibitor TEA decreased heat flow of the slice culture This was consistent in all samples within the treatment groups. FC12-520A leads to the strongest response amongst the CAIX inhibitors all CAIX inhibitors show a heat flow reduction in a similar range, demonstrating consistency of CAIX inhibition
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