CIC Scientific Report
Research Program

Coordinated by Alberto Orfao·6 research lines·13 groups

Translational and clinical research spanning hematological, breast, hepatobiliary, hereditary and therapy-resistant cancers.

The Translational and Clinical Research in Cancer Program is coordinated by Alberto Orfao and is organized into six research lines: the understanding, treatment and diagnosis of hematological tumors; breast tumors; hepatobiliary cancer; hereditary cancer; bioinformatics and artificial intelligence; and the mechanisms of therapy resistance.

Its groups combine basic, translational and clinical research, working in close connection with the Hematology and Oncology services of the University Hospital of Salamanca and with national and international consortia.

Alberto Orfao, Coordinator of the Translational and Clinical Research in Cancer Program

Program Coordinator

Alberto Orfao

6
Research lines
13
Groups
10
Group leaders

Research line 2.1

Understanding, treatment, and diagnosis of hematological tumors

6 research groups

Immunology and Cancer research group of Alberto Orfao at CIC

Immunology and Cancer

Group leader · Alberto Orfao

38
People
39
Publications
4
Grants

The research program focuses on the interplay between the immune response and cancer, with a particular emphasis on malignancies originating from immune system cells, such as leukemias and lymphomas. Key areas of interest include improving the diagnosis and classification of these hematological malignancies, as well as evaluating treatment efficacy during follow-up through the detection of minimal residual disease, specifically therapy-resistant malignant cells.

Given that many hematological malignancies closely resemble their normal cellular counterparts, integrated studies of normal hematopoietic cells and their malignant equivalents are crucial to elucidate oncogenic events that disrupt normal cellular processes and drive malignant transformation. This research also explores the potential role of immune responses and the immune system in both controlling and promoting neoplastic transformation and the expansion of malignant clones.

Immunophenotyping remains a cornerstone for the diagnosis, classification, and therapeutic monitoring of hematological malignancies. Recent technological advancements have enabled more rational and effective design of immunophenotypic panels for the study of leukemias and lymphomas. However, these innovations have also increased the complexity of flow cytometry data, with few tools available to facilitate their interpretation. To address this challenge, our group is dedicated to the design, development, and validation of high-throughput systems and tools for automated and standardized analysis of flow cytometry data. These tools are applied across diagnostic, classification, prognostic, and treatment-monitoring contexts and are actively translated into clinical practice.

A more recent direction of our research involves the development and implementation of sensitive and specific multiparametric flow cytometry approaches to measure and monitor immune responses following immunotherapy, particularly antitumor immunotherapy.

Chronic Lymphoid Neoplasms research group at CIC

Chronic Lymphoid Neoplasms: Factors Involved in Onto-Pathogenesis and Transformation of Preleukemic Conditions into Clonal/Malignant Diseases

Group leader · Alberto Orfao

12
People
11
Publications
3
Grants

Julia Almeida's research is focused on "Immunology and Cancer" applied to tumors derived from mature T/NK and B-cells (chronic lymphoproliferative disorders, from the onto-pathogenesis to clinical settings). Major research activities: i) identification of mechanisms involved in the transformation/evolution of reactive to clonal and malignant conditions (i.e. early stages of cancer), ii) phenotypic, genetic/molecular and functional characterization of these cells and iii) its translation to diagnosis, classification and treatment monitoring; iv) biological characterization of their normal cell counterparts; and v) role of the immune system in the control and progression of the disease.

In the past two years (2024–2025), the group has contributed to identify biomarkers for improved discrimination between normal/reactive and clonal NK-cells in clinical settings (Morán-Plata et al., Front Immunol, 2024), and to the characterization of novel phenotypic profiles in T-cell malignancies that may support more rational disease classification (Morán-Plata et al., Lab Invest, 2025). Furthermore, the application of flow cytometry panels—previously designed and developed by the group—to study the immune system in mature T-cell malignancies represents one of the first comprehensive analyses of the tumor microenvironment in these disorders (Morán-Plata et al., Front Immunol, 2025). Notably, the group has established international collaborations with leading teams in pre-tumor conditions, such as MBL/T-CUS (Ryan et al., BCJ 2025), alongside other contributions on MBL and chronic lymphocytic leukemia (Rodrigues et al., Frontiers in Oncology, 2024; Solano et al., Cancers, 2025; Diez et al., Molecular Oncology, 2025), providing immune-related biomarkers with potential impact on improving the clinical management of MBL and leukemia subjects. Finally, the group's participation in both national (Oliva-Ariza et al., Int J Mol Sci, 2025) and international consortia (Pérez-Jurado et al., Commun Biol, 2024; Cabrera-Alarcón et al., Commun Biol, 2025) has provided insights into factors associated with increased vulnerability to (severe) SARS-CoV-2 infection.

NanoMedicine, Immuno-Oncology and Proteomics research group at CIC

NanoMedicine, Immuno-Oncology and Proteomics Approaches for Biomarker and Drug Discovery in Cancer and Immunopathologies

Group leader · Alberto Orfao

7
People
6
Publications
2
Grants

Immunotherapies that train or stimulate the inherent immunological systems to recognize, attack & erradicate tumor cells with minimal damages to healthy cells have demonstrated promising clinical responses. Nowadays, there are several clinical trials which promotes the combination of ICIs (Immune Checkpoint Inhibitors) with other onco-therapeutic strategies which cause tumoral cell death in an immunogenic way. The Immunogenic Cell Death (ICD) enhances immune stimulatory or subvert immune suppressive effects to synergize with current ICI therapies. Hence, it is necessary to decipher molecular basis of anti-tumor immune response to design the therapy.

The steps of anti-tumor immune response: i.-Antigen released from tumoral cells are captured by antigen-presentation cells (APCs). ii.-Danger Associated Molecular Patterns (DAMPs) released by dying tumoral cells signal APCs maturation. iii.-Activated APCs present Tumor Associated Antigens (TAAs) on MHC-I & MHC-II to T cells, resulting in the activation of effector T cells against TAAs. iv.-Activated effector T cells traffic to and infiltrate tumor bed where specifically recognized tumoral cells through integration between TCR and MHC-I bound cognate antigen and kill tumor cells. v.-Tumor death cells release TAAs to increase the immune response.

Thus, there is a potential mechanism of combined benefits of Nanomedicines and Immunotherapy based on ICIs. Because Nanomedicines can address some of the challenges in Immuno-Oncology: i.-Enabling the combination of molecular targeted therapies with immunotherapies; ii.-Early monitoring of immunotherapies; iii.-Personalizing an immune response to a patient's tumor.

Our main goal is to design and validate an immunoproteogenomics strategy to improve the therapeutic scheme. This immunoproteogenomic methodology is based on the systematic integration of next generation genomic, transcriptomic, proteomics and immune monitoring that allows orthogonal validation of biomarkers (in haematological and solid tumors) to translation into the clinic. We are focused on: 1.-Proteogenomics correlation between somatic mutations and cell signaling pathways. 2.-Inter-relationship of TCR sequences and HLA immunopeptidomes. 3.-Proteomic quantification of proteins and their encoded proteoforms according to genomic alterations and immunpeptidomes. 4.-Identify differential TAAs profiles according to altered protein profiles and immunopeptidomes. 5.-Immune monitoring for the rapid and simultaneous determination soluble components of immune response and ICD.

Oncohematology research group of Maria Victoria Mateos Manteca at CIC

Oncohematology

Group leader · Maria Victoria Mateos Manteca

38
People
74
Publications
10
Grants

Prof Mateos mainly works in clinical and translational research, which stems from the interaction between laboratory 12 at the Cancer Research Center and the Hematology Department of the University Hospital of Salamanca. This interaction has been very fruitful in scientific publications and diagnostic achievements with therapeutic advances for patients. Research carried out by the group spans hematological malignancies, with a special focus on multiple myeloma (MM), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), as well as lymphoproliferative disorders (LPD) and lymphomas (NHL). The tumor clone is characterized by multiparametric studies (phenotypic, cytogenetic, molecular and functional) with the final goal of identifying novel prognostic markers, the development of diagnostic tools for clinical practice, and tumor target evaluation to design novel therapeutic strategies. Investigation about potential mechanisms of resistance is another goal in our group.

Our lines of research are divided into four main areas: 1) OncoHaematologic Molecular Cytogenetics; 2) Molecular Biology and Immunopathology; 3) Cell Therapy and Transplantation; and 4) Testing of novel therapies in hematological malignancies. The goal achievements of the Oncohematology group are: a) identification and description of prognostic biomarkers, including cytogenetic and molecular abnormalities in MM, NHL, MDS or LPD; b) contributing to the whole sequencing of chronic lymphocytic leukemias; c) standardization and assessment of minimal residual disease by flow cytometry and next generation sequencing (International Reference); d) identification of novel agents and combinations resulting in our leadership in several clinical trials (phase I to IV), and e) participation in CART and NK-cells trials for lymphoma and myeloma.

Future challenges of the group include to deepen into the genomic mechanisms of hematological neoplasms development and transformation into aggressive diseases, specially through the evaluation of clonal heterogeneity and identification of the ancestor clonogenic cell; evaluation of tumor microenvironment; analysis of drug-resistance mechanisms, testing of new immunotherapeutic approaches and identification of synthetic lethal vulnerabilities in MM.

Genetics in Oncohematology research group at CIC

Genetics in Oncohematology

Group leader · Maria Victoria Mateos Manteca

36
People
22
Publications
7
Grants

Prof. Dr. Hernández Rivas' group is dedicated to the molecular characterization of tumoral cells from hematological malignancies, including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes. Our research is centered on cutting-edge biomedicine technologies, including optical genome mapping (OGM), next-generation sequencing (NGS), and CRISPR genome editing, with a focus on integrating data across various research lines to deliver personalized treatments. Using CRISPR/Cas9 technology, we investigate drug resistance mechanisms in leukemia, generating novel cell lines and animal models that replicate genomic heterogeneity observed in hematological malignancies (HM). Additionally, we harness Big Data to enhance care for patients with HM, analyzing anonymous patient data to define clinical endpoints and outcomes, aiding decision-making for policy makers and physicians.

Noteworthy achievements include elucidating the prognostic significance of cytogenetic abnormalities across various hematological disorders. Furthermore, in collaboration with the Hemostasis and Thrombosis Unit from the University Hospital of Salamanca, we have identified new mutations in congenital thrombopathies. Engaging in international projects spanning expression and genomic microarrays, NGS, big data, and personalized medicine, we have made substantial contributions to scientific literature, publishing more than 300 papers in international scientific journals, developing 60 research projects, and overseeing 26 doctoral theses. Our group coordinates and leads the HARMONY Alliance, comprising the European projects HARMONY (2017-2023) and HARMONY PLUS (2021-2023), our collaboration involves analyzing NGS and clinical data to unearth patterns and insights that refine current medical protocols, emphasizing our commitment to advancing precision medicine in the field of blood cancer research. Additionally, we are involved in oncNGS (H2020 programme, 2020-2024), CAN.HEAL (EU for Health Programme, 2022-2024), RESOLVE, and IMPACT-AML, part of Horizon-Miss-2022 running from 2023 to 2027. The group is integrated into the national consortium Centro de Investigación Biomédica en Red (CIBER), specifically in the thematic area of cancer Area (CIBERONC, group CB16/12/00233), and the European Leukaemia Network (ELN).

Experimental Therapeutics and Translational Oncology research group of Isidro Sánchez García at CIC

Experimental Therapeutics and Translational Oncology Program: Stem Cells, Cancer Stem Cells and Cancer

Group leader · Isidro Sánchez García

9
People
3
Publications
7
Grants

Leukemia accounts for a third of all cancers in children and its incidence has increased in the last 20 years. Recent results have shown that around 5% of healthy children carry a preleukemic clone. These preleukemic cells can persist for years, without harm for the individual and it is the exposure to an oncogenic environment, which provides the necessary selection pressure for the leukemia outgrowth. However, these oncogenic environments are not known. Recently, our group, in collaboration with Prof. Arndt Borkhardt's group, has discovered for the first time the causal relationship between childhood B-cell leukemia (B-ALL) and exposure to natural infections, implying that B-ALL may be a preventable cancer.

The need for the clarification how genetic predisposition and exposure to infection act synergistically in B-ALL development is one of the current major goals and challenges in Oncology. Preclinical models of childhood B-ALL have been an essential unmet need to prevent the occurrence of this disease. A novel and unique feature of this proposal is the availability of mouse models for both the ETV6-RUNX1 and the Pax5-inherited susceptibility which only develop human-like B-ALL as a result of natural infection exposure. These mouse models have anticipated the second hit in childhood B-ALL and they will be used by our research team as the basis for understanding the molecular mechanisms that govern the development of B-ALL as a result of natural infection exposure. Now, state-of-the-art genetic and genomic approaches will be used to define the (epi)genetic and inmune events arising from leukemic reprogramming of pre-leukemic cells by the genetic predisposition–infection exposure interaction. The conceptual and mechanistic insights obtained in this experimental system represent an entirely novel strategy and the results of these endeavours will inform approaches for preventing childhood B-ALL.

Research line 2.2

Breast tumors

3 research groups

Functional Cancer Genomic Group of Toni Hurtado Rodríguez at CIC

Functional Cancer Genomic Group

Group leader · Toni Hurtado Rodríguez

7
People
3
Publications
2
Grants

My research focuses on transcriptional regulation and the modulation of signaling pathways in cancer, with particular emphasis on transcription factors and their therapeutic potential. Over the past two years, my work has been structured around two main axes: (i) a consolidated research line on the regulation of the transcription factor FOXA1 in breast cancer and its role in endocrine therapy resistance; and (ii) a complementary, exploratory line investigating interactions between bacterial factors and tumor cells, with potential translational implications.

The group have established a research line focused on the post-translational regulation of FOXA1, distinct from approaches based on its direct inhibition. Through high-throughput chemical screening and proteomics, we identified kinases and acetyltransferases that modulate FOXA1 DNA binding across different breast cancer subtypes. Building on this, I have characterized how FOXA1 acetylation and deacetylation regulate chromatin binding and hormonal response. Using genomic approaches and patient-derived xenograft (PDX) models, we demonstrated that HER2/HER3 signaling modulates HDAC2 activity, promoting FOXA1 deacetylation and contributing to endocrine resistance (NAR, 2025). Importantly, selective HDAC2 inhibition restores FOXA1 and estrogen receptor chromatin binding and re-sensitizes tumors to endocrine therapy, highlighting the translational relevance of these findings.

In parallel the group developed a novel research line exploring interactions between bacterial components and epithelial tumor cells. We investigated whether virulence factors from Vibrio cholerae could modulate tumor cell signaling. We identified that the bacterial protease HapA selectively targets PAR-1/2 receptors, inducing transient activation of the MEK–ERK pathway and triggering apoptosis via caspase-7 activation, resulting in reduced cell viability (Tena Chaves*, Pontes* et al., Cell Death Discovery). This study provides the first evidence that bacterial virulence factors can fine-tune oncogenic signaling pathways, opening new avenues for innovative therapeutic strategies based on exogenous modulators of cell signaling.

Kinases in Oncology research group of Atanasio Pandiella Alonso at CIC

Kinases in Oncology

Group leader · Atanasio Pandiella Alonso

8
People
13
Publications
2
Grants

During the last few years our research has been centered in the understanding of the role of several receptor tyrosine kinases (RTKs) and their signal transduction routes in cell proliferation and oncogenesis. Interest in the activation of RTKs by membrane anchored ligands has been a major focus of our laboratory with special emphasis on the study of the mechanisms responsible for the solubilization of membrane-anchored growth factors, and the biological properties of these factors in the membrane-anchored conformation. In addition, the role of novel RTK signaling intermediates, such as P-Rex1 or MMP13 have been analyzed. In this area of research, an effort is being paid to an integral understanding of the role of RTKs, especially those of the ErbB/HER family in cancer, by analyzing how their activating ligands act, and how downstream signaling molecules participate in proliferative responses to RTK activation. Studies with drugs (small molecule kinase inhibitors as well as monoclonal antibodies) that target these receptors or their signal transduction pathways are carried out in parallel with biological studies. We have become especially interested in the major clinical problem of the establishment of resistances to targeted therapies, especially in the context of HER2 positive breast cancer. In line with this, we have made an effort to generate new in vitro and in vivo models of resistance to anti-HER2 therapies and have identified novel mechanisms of acquired resistance to these drugs. Taking all these into consideration we are investigating and developing new therapeutic approaches to be used in this context. In line with this, the identification of new targets and the development of new therapeutic agents against them is, in this moment, an important goal in our team.

Molecular and Genetic Determinants of Cancer Susceptibility research group of Jesús Pérez Losada at CIC

Molecular and Genetic Determinants of Cancer Susceptibility, Evolution, and Treatment Response

Group leader · Jesús Pérez Losada

8
People
8
Publications
5
Grants

Our laboratory uses systems biology and translational approaches to study cancer susceptibility, evolution, and treatment response, with a major focus on breast cancer and cutaneous squamous cell carcinoma. In breast cancer, we investigate how genetic background, tumour-cell programmes, and physiological states shape risk and disease behaviour. A major line of work addresses postpartum mammary gland involution as a window of breast cancer susceptibility and prevention, with the aim of identifying mechanistic drivers and actionable chemopreventive strategies. We also study luminal A breast cancer to identify biologically distinct subgroups with unexpectedly poor outcomes and to develop biomarkers that improve recurrence prediction and treatment stratification. In parallel, we work on risk stratification and prognostic biomarkers in cutaneous squamous cell carcinoma, integrating clinical, histopathological, and computational approaches to improve patient management. Across these areas, our group combines mouse models, human cohorts, molecular profiling, and data-driven analyses to connect mechanisms with clinically relevant biomarkers. Overall, our goal is to translate mechanistic and systems-level insights into better prevention strategies, more accurate prognostic tools, and more personalized therapeutic decisions.

Research line 2.3

Hepatobiliary Cancer

1 research group

Hepato Biliary Tumors Lab of Javier Vaquero Rodríguez at CIC

Hepato Biliary Tumors Lab

Group leader · Javier Vaquero Rodríguez

7
People
9
Publications
2
Grants

Our group develops translational research focusing on the study of the pathogenesis and treatment of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In particular, we are interested in better comprehending the crosstalk interactions between cancer and stromal cells from the tumor microenvironment. We apply our results to discover new therapeutic targets and to develop novel therapies that improve tumor progression. To achieve this, the group uses a wide range of experimental methods, which include analyses of patient samples, unbiased analysis of omics data, 2D and 3D in vitro models of liver cancer and state-of-the-art in vivo models of liver carcinogenesis, where we test new potential therapies.

Our research currently focusses on 3 axes: (1) Understanding the roles of TGFbeta in tumor and stromal cells to identify new efficient ways to target this signaling pathway. (2) Dissecting the role of ZEB1 in the crosstalk of cholangiocarcinoma tumor and stromal cells. (3) Evaluating the impact of sorafenib acquired resistance in the suppressor effects of TGFbeta signaling pathway in hepatocellular carcinoma cells.

Research line 2.4

Hereditary cancer

1 research group

Hereditary cancer research group of Rogelio González Sarmiento at CIC

Hereditary cancer

Group leader · Rogelio González Sarmiento

7
People
7
Publications
0
Grants

The group is responsible for the Hereditary Cancer Genetic Counseling Unit, a regional program financed by the General Directorate of Public Health of the Ministry of Health of the Government of Castilla y León. The Unit collaborates closely with the Genetic Counseling Unit of the Oncology Service of the University Hospital of Salamanca and carries out studies for patients in the provinces of Ávila, León, Salamanca and Zamora. In addition, the group is developing "in vitro" methods to reclassify mutations of unknown significance (VUS) in the BRCA1 and BRCA2 genes, improving the genetic counseling of patients with familial cancer.

We are also studying patients with early onset colorectal cancer (EOCRC), being part of national (Spanish Early-Onset Colorectal Cancer Consortium (SECOC)) and international groups (Global Early-Onset Colorectal Cancer Database (GEOCODE)). Besides these collaborations, our group is focused in the analysis of genes located in 16p13.12, that we have showed is deleted in patients with EOCRC.

Another project is the study of the molecular bases of head and neck cancer. The group is currently developing a study on the mechanisms of resistance to microtubule inhibitors in this type of tumors through the development of cell lines resistant to these drugs. In the line of drug trials and in collaboration with the Department of Pharmaceutical Sciences of the Faculty of Pharmacy, we are studying the effect of combretastatin derivatives on different cell lines. We are studying also the effect of the combination of panobinostat and chloroquine in ovarian cancer, and enzalutamide in breast cancer.

The group is also working on ovarian cancer, characterizing molecular abnormalities either in germline as in tumor. Finally, the group is a national reference for the genetic study of Ichthyosis and is leading a gene therapy project for this disease.

Research line 2.5

Bioinformatics and artificial intelligence

1 research group

Bioinformatics and Functional Genomics of Cancer research group of Javier De Las Rivas at CIC

Bioinformatics and Functional Genomics of Cancer

Group leader · Javier De Las Rivas

8
People
13
Publications
5
Grants

Research framed within the field of Bioinformatics, Computational Biology and Functional Genomics applied to the biomedical areas of Cancer, Oncology and Neurodegenerative diseases.

Functional Genomics and Bioinformatics: Development of methods and strategies for the analysis of omic data derived from different large-scale technologies (such as RNAseq, DNAseq, single-cellRNAseq, etc.) to determine the expression of genes, miRNAs and ncRNAs; or to identify gene splicing, copy-number alterations, changes in the methylation pattern, etc. Data mining, integration and analysis of proteo-transcriptomic profiles to determine absolute signal values and identify gene signatures associated with specific biological or pathological stages. All of this work is focused on cancer samples from patients to identify disease subtypes, disease progression and treatment response or resistence.

Data Science, Machine and Deep Learning, Computational Omics: Application of data mining and artificial intelligence methods (such as Machine & Deep Learning, Reverse Engineering, etc) to omic, biomedical and clinical data to: (i) discover biomolecular signatures associated with specific pathological states; (ii) build prognosis predictors derived from survival analysis; (iii) build treatment response predictors; (iv) identify resistance features. Currently, our studies are mainly focused on cancer, but also on some neurodegenerative disorders. As mentioned above, most of the work is performed on patient-derived samples and in close collaboration with medical-clinical groups.

Proteomics, Interactomics and Network Biology: Development of a biomolecular database of experimentally determined protein-protein interactions (PPIs), including strategies for quality control and validation. Use of this PPIs-DB to build human interactome networks and infer cancer-related networks. Integration of gene co-expression data and protein interaction data to build multiplex biomolecular networks. Identification of regulatory circuits associated with these networks to identify causal genes (gene drivers) in specific cancer subtypes or pathological states. Construction of bipartite drug-protein interaction networks using pharmacogenomic data. Analysis of these networks for drug target prediction.

Research line 2.6

Mechanisms of therapy resistance

1 research group

Mechanisms of therapy resistance in squamous cell carcinomas research group of Mónica Álvarez Fernández at CIC

Mechanisms of therapy resistance in squamous cell carcinomas

Group leader · Mónica Álvarez Fernández

5
People
9
Publications
3
Grants

Despite advances in cancer research, chemotherapy (CT) and radiotherapy (RT) remain the conventional treatments for many tumors. It is estimated that up to 50% of cancer patients are treated with RT and cisplatin-based CT is administered to 10-20% of all cancer patients. This is the case of head and neck squamous cell carcinomas (HNSCC) which arises from the epithelial cells of the oral cavity, pharynx or larynx, and whose survival rate, around 50%, has not improved in the last 30 years. Cisplatin-based chemoradiotherapy (CRT) is the standard treatment of choice for this type of tumor, with a response rate barely exceeding 50%. HNSCCs are very heterogeneous and complex at the genomic level and share many commonalities with squamous cell carcinomas (SCCs) arising from other anatomical sites, such as lung squamous cell carcinoma (LUSC), which accounts for 20-25% of all lung cancers and has an estimated 5-year survival rate of only 17%. As for HNSCCs, there are almost no approved targeted therapies for LUSCs and treatment options for advanced cases are limited to platinum- and/or taxane-based CT alone or in combination with immunotherapy (PD-(L)1 inhibitors). The main limitation of CT and RT in the clinic is, beyond their toxicity, the high incidence of resistance and, consequently, the frequent tumor relapse. Therefore, we aim to identify new therapeutic strategies to overcome resistance to the standard of care in SCCs by using patient-derived organoids (PDOs) as the main preclinical experimental model.

Our main approaches are: (1) Search for mechanisms of treatment resistance in cancer (chemotherapy/radiotherapy and targeted therapies) using CRISPR/Cas9 screening and multi-omic characterization of patient-derived organoids as a source for identifying new biomarkers and/or therapeutic targets. (2) Preclinical evaluation of the therapeutic value of CDK4/6 inhibitors as enhancers of chemotherapy and radiotherapy treatments. (3) Analysis of the predictive value of PDOs and their clinical utility in functional precision medicine: effect of tumor heterogeneity and contribution of the tumor microenvironment.

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