Validation of therapeutic agents in an immunocompetent glioblastoma model

Scientific leader: Carles Arús
Scientific Coordinator: Ana Paula Candiota

Industrial problem/gap covered

This service allows for selection from a panoply of therapeutic agentsfor gliblastoma, to ensure that only the best ones will reach the most advanced phases.

Description

This service offered by NANBIOSIS allows a path for analysis of potential therapeutic agents to be used in glioblastoma. It is a preliminary effectiveness assessment of new therapeutic agents in an immunocompetent preclinical glioblastoma model. It includes in vitro effects over GL261 cultured cells (e.g. EC50 calculation), target validation (e.g. protein kinase CK2 inhibition when using CK2 inhibitors), preliminary studies of 1-month toxicity and maximum tolerated doses, as well as complete in vivostudies for adjusting doses and periodicity for administration. These would allow estimation of classical survival (endpoint validation) and the evaluation of biomarkers of therapy response, either by MRI (RANO, RECIST) or by surrogate biomarkers detected by magnetic resonance spectroscopic imaging. For this, an immunocompetent murine model of glioblastoma will be used( GL261 tumorsgrowing in C57BL/6background).

Ref: Ferrer-Font L, Villamañan L, Arias-Ramos N, Vilardell J, Plana M, Ruzzene M, Pinna LA, Itarte E, Arús C, Candiota AP (2017) Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice. Pharmaceuticals 10 (1):24

Services involved:

• In vitro studies in cultured cells (EC50 calculation) (U25)with target validation, if applicable.
• Cell target validation after finishing the protocol (U25)
• Tolerability and maximum tolerated dose studies in a murine model (U25)
• Adjustment of dose and administration protocol in the preclinical glioblastoma model (GL261). Comparison of overall survival and progression free survival obtained with commercially available therapeutic agents being used in preclinical or clinical practice.
• Combined therapy: in vitro studies in cultured cells with evaluation of synergy or antagonism with Chou-Talalay method(1) .
  (1)Chou, T.C., Drug combination studies and their synergy quantification using the Chou-Talalay method.Cancer Res, 2010.70(2): p. 440-6
• Combined therapy: in vivo evaluation (e.g. comparison with the performance of each agent separately)
• In vivo study with MRI/MRSI follow-up and assessment of response biomarkers, either MRI-based (RANO(2) or RECIST(3) traditional criteria or new paradigms related to immunotherapy(4) ) or MRSI-based (surrogate biomarkers of therapy response(5) ). Analysis of the overall survival in comparison with control mice.
  (1)Vogelbaum, M.A., et al., Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group.Neurosurgery, 2012. 70(1): p. 234-43
  (1)Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer, 2009. 45(2): p. 228-47
  (1)Qin, L., et al., Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma.Neuroradiology, 2017. doi: 10.1007/s00234-016
  (1)Delgado-Goñi, T., et al., MRSI-based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis.NMR Biomed, 2016. 29(6): p. 732-743.
• Possibility of necropsy analysis after protocol finalization, as well as histopathological validation (e.g. Ki67 analysis in the target tissue)

• U25

Figure U25 (1): Biospec 7T scanner, in which MR proposed studies will be performed, with the mouse bed assembly.

Figura U25 (2): Kaplan-Meier survival curve with temozolomide (TMZ) treated and control mice, showing clear difference, statistically significant, between groups.