Therapy response and resistance
Pre-clinical in vivo evaluation of tumour interventions
Research group leader:
Our ultimate goal is to achieve significant predictability of clinical performance from second or third line therapy in patients with recurrent or refractory disease.
The project evaluates a physiological in vivo model for added relevance of a human homologous, or alternatively autologous microenvironment, regarding predictions of patient cellular sensitivity/resistance following radiation, chemo- or targeted tumour therapies. The work plan concerns the visualization and quantification of tumour cell impairment, i.e., histopathology in combination with a high throughput, high content, single tumour cell analysis, including also in vivo assessment of neurotoxic effects on human non-tumour neurons.
We have demonstrated that mature benign PSCT induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process [Gertow et al 2004, 2011]. Under standardized conditions PSCT consists of a reproducible microenvironment with a rich blend of embryonic tissues including early organoid development, as well as immature neural components. These benign immature components exhibit strong morphological resemblance with tumours of embryonic neuroectodermal origin, and when similar histopathology is present in patient samples they are considered potentially malignant.
Nevertheless, in the embryonic model such findings are part of early development and the shared histology inspired us to study neuroectodermal tumours implanted into matching PSCT microenvironments.
We have recently reached a proof of concept for engraftment of child tumours into PSCT [Jamil et al 2013]. The histology revealed a specific advantage over xenotransplantation showing a strict tropism with non-random integration into morphologically identifiable tissues, and tumour growth recuperating the patient tumour histology [Jamil et al 2013, 2014].
Recently we have also demonstrated quantitative effects of therapy in this human in vivo model [Hultman et al unpublished]. Our findings are now translated into the clinical situation by comparing therapy outcome parameters from similar therapeutic interventions in the patient and the model, this way assessing the accuracy of its predictions in the individual patient.
Members in the group
Evelina Blomberg, Biomed. stud