Investigación Traslacional en Linfoma
Aggressive B-cell lymphomas are clinically and pathologically diverse and reflect multiple pathways of transformation involving, among others, oncogenic signaling, lymphoma-stroma crosstalk and intrinsic protein homeostasis. Alterations in these highly regulated processes play a key role in the progression of the malignant clone and correlate with a high failure rate in treatment protocols. In the last decade, new therapies applied to the treatment of B-cell lymphoma have significantly improved the overall survival of these patients, but at present no drug can cure these diseases. At the origin of the gap between promising preclinical results and failure in clinical phase II/III, conventional preclinical models lack predictive value in the main trials carried out in these cancer subtypes. For the design of new therapies more selective and more suited to the biology of these lymphomas, our team focuses on the characterization of new drug targets and on the bench-to-bedside translation of innovative therapeutic strategies, using innovative experimental models of diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed follicular lymphoma (tFL).
Development of a patient-derived xenografts platform for the evaluation of new targeted therapies in aggressive B-cell lymphomas
Much of the new therapies applied to the treatment of aggressive B-cell lymphomas have not improved the overall survival of patients and there is no drug or drug combinations to cure these diseases. To counteract the resistance and toxicity observed in the clinic, novel and personalized approaches, new preclinical models that allow predicting more effectively the specificity and safety of each treatment, are urgently needed. Current therapeutic targets of highest interest in these entities include distinct signaling pathways that are activated constitutively by over-expression of MYC, BCL6, or CRBN, activation of phosphatidylinositol 3-kinase (PI3K) and B-cell receptor (BCR)-related kinases, or by the deregulation of apoptotic program. Currently, there are several therapeutic agents directed specifically towards these signaling axes, although their efficacy, safety and mode of action are still to be determined in some subtypes of B-cell lymphoma. To warrant the efficacy, safety and translationnality of these studies, we propose to associate standard in vitro assays with innovative in vivo models (PDX) that will allow us 1) to work directly with primary tumor cells, validating the most effective therapies and their biological effects with greater relevance, and taking into account the role of the tumor microenvironment and 2) to guarantee the possible translation of these therapies into clinical trials with the molecular and genetic determination of the factors that condition the response to the best therapies tested in each patient. The collaboration with pharmaceutical companies will allow the transfer of the results obtained to Hematology Departments for the design of new phase I/II clinical trials.
Modulation of lymphoid microenvironment by intrinsic protein homeostasis in aggressive B-cell lymphoma
The lack of efficacy of standard and experimental therapies in the clinical is likely due to the uncontrolled activity of some components of the tumor microenvironment (TME), including tumor-associated macrophages, mesenchymal cells, dendritic cells, NK cells or regulatory T cells. Although major advances have been done in the last decade about the role of accompanying immune effectors in the control of B-NHL tumor growth and resistance to standard and experimental therapies, how MCL and DLBCL malignant B cells modulate their environment to better adapt to adverse conditions, is poorly understood. Accumulating evidences in solid cancers suggest that increased expression and/or activity of the ubiquitin-proteasome system, including Ub and Ub-like protein modifiers, may modulate some TME components indirectly, thus promoting an immunosuppressive, protumoral environment. However, little is known about the relevance of the intrisinc tumoral Ub interactome (ubiquitome) in the bidirectional tumor-stroma crosstalk in MCL and DLBCL. From a therapeutic point of view, this field of research may be of special interest, as a number of new agents directed against proteasome, ubiquitin or ubiquitin-like ligases or deubiquitinase enzymes, are showing promising preclinical and clinical activity in MCL and DLBCL patients. The discovery of new Ub-regulated factors favoring or counteracting the recruitment and/or activation of immune effector cells, may pave the way for the comprehension of tumor-stroma interplay in MCL and DLBCL and for the design of new, rationally-based therapeutic approaches combining post-translational modifying drugs and immunotherapeutic agents.
The main objective of this project is the identification of new mechanisms related to intrinsic protein homeostasis that may regulate the complex interplay between MCL and DLBCL cells and their specific TME, using experimental models with the capacity to preserve the spatial architecture of the original tumor. The specific objectives are 1) to generate a collection of in vitro (3D organoid) and in vivo (PDX) models from MCL/DLBCL fresh samples able to maintain the spatial organization and the cell-cell interaction established in the original tumor. These experimental models will be fully characterized immunophenotypically for their content in immune effector cells; 2) to characterize the ubiquitome of malignant B cells by proteomic profiling and to correlate these intracellular complexes with the immunological pattern of each tumor model; 3) to validate the impact of tumor protein homeostasis on the development of B-cell lymphoma and on the intratumoral infiltration of immune cell, by automatic data analysis and CRISPR-Cas9-mediated gene silencing in DLBCL and MCL 3D organoid models.