The treatment of cancer is continually improving due to increasing knowledge in oncogenesis and the development of new targeted compounds. Many candidate compounds for clinical trials are therefore generated each year.
In order to select the potentially most efficient molecules, preclinical investigation of antitumor compounds on tumor models is an important step in the process of drug development. Nevertheless, to obtain preclinical results with high predictive value for clinical trials, the choice of the preclinical tumor models on which new compounds will be evaluated is a crucial point. Human primary xenografts, directly obtained from cancer patients, constitute one main category of preclinical cancer models. Indeed, they well reproduce the high heterogeneity of human cancers, procedures for assessment of therapeutic efficacy are well standardized and easily allow the evaluation of combined therapies, and the possibilities of ex vivo genetic or therapeutic manipulations before xenotransplantation are important. In this, the Laboratory of Preclinical Investigation (LIP) has five main objectives:
- to develop, validate, and maintain preclinical models. More than 200 human primary xenografts have already been developed, including breast cancers, colon cancers, non small-cell and small-cell lung cancers, glioblastomas, uveal melanomas, lymphomas, ovarian cancers, prostate cancers, retinoblastomas, and others. Initial characterization of the models included histopathological and molecular evaluation and, as far as possible, genomic and gene expression profile studies (Figure 1). All these characterizations are performed concomitantly for the tumor graft and for the corresponding patient’s tumor. Charactérization also includes other biological assessments and study of stromal components.
- to evaluate the antitumor effect of new compounds and new combinations of treatment, and to define optimal schedule of administration. Initial characterization also includes the assessment of standard treatments efficacy. On this basis, new treatments are then evaluated, alone or in combination, concomitantly or as an adjuvant setting in chemotherapy-induced complete remission models (Figure 2A)
- to identify biological markers of response and resistance to tested therapies, and evaluate their predictive value on other well characterized preclinical models. Molecular events occurring under therapy are evaluated through in vivo kinetics experiments and further transcriptomic and proteomic studies. The occurrence of molecular events are then correlated to the in vivo therapeutic responses.
- to evaluate the efficacy of new therapies on metastatic localizations. Lung metastases are variably observed during spontaneous tumor growth of the xenografts and few models are defined by a high rate of metastases into mice. These models are therefore available for evaluation of new therapies on metastatic localizations.
- to develop specific models, such as orthotopic tumors (breast cancer, uveal melanoma, retinoblastoma), metastase- or clinically resistant- or circulating tumor cell-derived xenografts.