Unraveling ck2 inhibition and temozolomide contribution to therapy response in preclinical gl261 glioblastoma: immune system implications and magnetic resonance based nosological imaging
- Autores: Lucía Villamañán de Santiago
- Directores de la Tesis: Ana Paula Candiota Silveira (codir. tes.), Maria Plana i Coll (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
- Idioma: español
- Materias:
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- Resumen
Glioblastoma is the most common primary brain tumor in adults with a very poor prognosis, for which urgent improvements in treatment are needed. The aim of this thesis was to unravel the contribution of the CK2 inhibitors and the alkylating agent Temozolomide (TMZ) to therapy response in the preclinical glioblastoma (GB) murine model GL261 using in vitro (GL261 cell line) and in vivo (GL261 tumor bearing mice) approaches.
The enzyme CK2 is a tetramer composed by two catalytic subunits (α/ α') and two regulatory subunits (β). In this Thesis, a differential content of the CK2 α' subunit was observed in highly and slowly proliferating GL261 cells, which could potentially affect the susceptibility of these cells to the treatment with CK2 inhibitors depending on their proliferative status. Moreover, the effect of the dual CK2 and Pim-1 inhibitor TDB was evaluated in the GL261 cell line and in GL261-tumor bearing mice. While TDB showed a potent effect in vitro, we were not able to detect any inhibitory effect on CK2 in the tumor site after administration to tumor-bearing animals, suggesting that changes in the formulation of this drug would be needed to improve bioavailability and performance.
Preliminary results from our group showed an increased survival in GL261-tumor bearing mice when treated in a immune-enhanced metronomic schedule (1 dose every 6 days) with the combination of TMZ and the CK2 inhibitor CX-4945, although other administration schedules did not result in such improvement. In this sense, it has been described that tumor cells treated with certain immunogenic drugs expose and release certain molecules called danger signals, leading to the activation of a potent antitumoral host immune response. We have performed in vitro studies in order to assess danger signals after both treatments alone or in combination. Results showed that TMZ and TMZ+CX-4945 GL261 treated cells expose calreticulin, an early danger signal of the immune cycle cascade. Also, CX-4945 and CX-4945+TMZ has been shown to release ATP, another danger signal that binds to P2 receptors, also contributing to the activation of the immune system.
Moreover, the evolution of GL261-tumor bearing mice treated with TMZ in an immune enhanced metronomic schedule was evaluated using multislice magnetic resonance spectroscopic image (MRSI) based nosological images for noninvasive therapy response follow-up. Our group has described imaging-based biomarkers that are able to distinguish responding and non-responding tumor zones, probably sampling local changes which include host immune system action over the tumor. Results are shown as a color-coded image (the aforementioned nosological image) resulting from machine learning analysis of MRSI data. The follow-up of TMZ treated mice showed an oscillatory behavior in the percentage of tumor area identified as “responding” within the tumor mass during the transient response to therapy. This oscillation period (ca. 6 days) is in agreement with the immune system cycle in mice in response to damage produced after TMZ administration. This information would be helpful in the future for prediction of therapy response/effectiveness and in the development of personalized therapeutic strategies.
In conclusion, the use of non-mutagenic therapies and immune system respectful cycles for therapy administration combined with an accurate therapy response follow-up using non-invasive strategies could help to improve the poor outcome of glioblastoma.
