Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy.

Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy

Dynamic changes during the treatment of pancreatic cancer

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient\u27s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment

Patient-Derived Xenograft Models for Endometrial Cancer Research

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. Patient-derived xenograft models (PDX) represent nowadays a promising tool for translational research, since they closely resemble patient tumour features and retain molecular and histological features. In EC, PDX models have already been used, mainly as an individualized approach to evaluate the efficacy of novel therapies and to identify treatment-response biomarkers; however, their uses in more global or holistic approaches are still missing. As a collaborative effort within the ENITEC network, here we describe one of the most extensive EC PDX cohorts developed from primary tumour andmetastasis covering all EC subtypes. Ourmodels are histologically andmolecularly characterized and represent an excellent reservoir of EC tumour samples for translational research. This review compiles the information on current methods of EC PDX generation and their utility and provides new perspectives for the exploitation of these valuable tools in order to increase the success ratio for translating results to clinical practice.This work was supported by CIBERONC (CB16/12/00328), the “Fondo Europeo de Desarrollo Regional” FEDER (RTC-2015-3821-1), Grups consolidats de la Generalitat de Catalunya (2017 SGR-1661) and the Instituto de Salud Carlos III (PI14/02043; PI17/02071). An AGAUR grant funded CL-G (2018FI_B_00573), and a PERIS grant funded EC (SLT002/16/00315) from Generalitat de Catalunya. The present work has been also funded by the “Fonds National de la Recherche du Luxembourg” (FNR) via the PEARL-CPIL program to BD and an AFR grant to AL (PDR 2013-2, Project Reference 6835664)

Patient-Derived Xenograft Models for Endometrial Cancer Research

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. Patient-derived xenograft models (PDX) represent nowadays a promising tool for translational research, since they closely resemble patient tumour features and retain molecular and histological features. In EC, PDX models have already been used, mainly as an individualized approach to evaluate the efficacy of novel therapies and to identify treatment-response biomarkers; however, their uses in more global or holistic approaches are still missing. As a collaborative effort within the ENITEC network, here we describe one of the most extensive EC PDX cohorts developed from primary tumour and metastasis covering all EC subtypes. Our models are histologically and molecularly characterized and represent an excellent reservoir of EC tumour samples for translational research. This review compiles the information on current methods of EC PDX generation and their utility and provides new perspectives for the exploitation of these valuable tools in order to increase the success ratio for translating results to clinical practice