Development and application of xenograft models to predict the prognosis and study the treatment-driven evolution of pediatric sarcomas
- Autores: Helena Castillo Ecija
- Directores de la Tesis: Angel Montero Carcaboso (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2022
- Idioma: inglés
- Tribunal Calificador de la Tesis: Marçal Pastor Anglada (presid.), Rafael Artuch Iriberri (secret.), Francisco Javier Alonso García de la Rosa (voc.)
- Materias:
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- Resumen
Drug resistance or chemoresistance is present in a small proportion of pediatric cancer patients from diagnosis, while a higher proportion acquires resistance to treatment after chemotherapy. In relapsed patients, the evolution of tumors towards a more resistant and aggressive phenotype could be produced due to acquisition of new mutations, adaptive response and natural selection of a drug-resistant tumor clone population. However, whether the lack of response to therapy of pediatric sarcoma patients is due to drug delivery issues in resistant tumor cells is not completely understood.
The main question addressed in this thesis was whether patients whose tumors stop responding to anticancer medicines show diminished intratumoral drug distribution. One of the principal mechanisms inducing multiple drug resistance in tumor cells is the up-regulation of drug efflux processes. In tumors, multidrug resistance associated proteins mediates the outflow of a range of chemotherapeutic agents such as gemcitabine, doxorubicin, methotrexate, vincristine, etoposide and irinotecan, among others, thereby decreasing the intracellular drug concentration and drug exposure in tumor cells. Despite intense clinical investigation of ABC transporter inhibitors, results of these trials have not shown significant therapeutic activity in cancer patients.
A detailed characterization of the intratumoral drug distribution helps understand the efficacy of anticancer drugs. Microdialysis is a well-validated and minimal invasive technique used for the measurement of the dynamic release and determination of unbound pharmacological agents in the extracellular fluid (ECF) of tissues. Because this experimental procedure was challenging to address in the clinical setting, we needed to generate the adequate laboratory models. Thus, we established PDX models in immunodeficient mice. Patient biopsies for engraftment can be obtained from different tissue locations (e.g., primary tumors vs metastasis) and at different times during the evolution of the disease (e.g., diagnosis vs recurrence). It is rare to obtain more than one sample from the same patient during disease progression. There is compelling evidence suggesting that PDX, at least at initial passages, reproduce the clonal heterogeneity, genetics and histology of several types of cancer. Whether this holds true for pediatric sarcomas was not sufficiently clear. Thus, we embraced this ambitious project to address 1) the identification of clinical and technical factors involved in pediatric sarcoma PDX engraftment, 2) the characterization of the stability of the PDX during initial passages, and 3) the relationship between successful PDX and patient prognosis.
