VHIO’s Biomarkers and Clonal Dynamics Group is dedicated to unraveling the molecular complexities and variables influencing clinical outcomes in patients.We aim to advance cancer research through the innovative application of tumor evolutionary analyses using longitudinal tumor and circulating tumor DNA (ctDNA)-based liquid biopsy in different clinical and therapeutic settings including cancer immunotherapies and targeted therapies. We also study the impact of hypoxia on tumorigenesis and clinical features, EPAS1-HIF2α mutation selection, and the efficacy of HIF2α inhibitors.

Initiated in 2018 in collaboration with Elena Garralda, Head of VHIO’s Early Clinical Drug Development Group, our IMMUNOMICs project has entered its next phase. This year, we have started to analyze data from our multimodal liquid biopsy approach on longitudinal tumor and plasma circulating cell-free DNA (cfDNA) samples of >300 patients with metastatic, refractory tumors (PanCancer cohort) treated with immunotherapy in phase I clinical trials. This project will generate new insights into the utility of different liquid biopsy assays in characterizing the baseline and early dynamic ctDNA profiles in patients treated with immunotherapy. We will also correlate data with response to therapy and clinical outcome.

In collaboration with other VHIO groups, we previously described RNF43 mutations as predictive biomarkers of response to anti-BRAF/EGFR combinatory therapy in patients with microsatellite stable BRAF-V600E metastatic colorectal cancer (Élez et al. 2022). Our findings have now been validated by real-world data in patients in the USA (Quintanilha et al. 2023). We have participated in an international study to further assess the predictive role of RNF43 mutations. (Moretto et al. 2023). In collaboration with Elena Élez, Head of VHIO’s Colorectal Cancer Group, we continue to work on RNF43 and other factors that we have identified in BRAF-mutated CRC.

In 2023, we have applied our in-house liquid biopsy discovery platform in different clinical settings. In collaboration with Nicholas McGranahan’s lab at the University College London Cancer Institute (UCL, UK), we have developed a new liquid biopsy approach: ACT-Discover – Aneuploidy in Circulating Tumor DNA. This technique is 30% more sensitive than current methods in detecting ctDNA in plasma. We have shown that this platform can characterize the evolutionary history of pancreatic cancer (Hubner et al. 2023). We have also used ACT-Discover to study >150 samples from rare, therapeutically orphan, metastatic neuroendocrine tumors (mNETs).

We have also continued to work on the impact of hypoxia on clinical and genomic features. We have shown that, as with other therapies, hypoxia can shape cancer genomes by promoting specific selective pressures. Additionally, we have reviewed the efficacy of inhibitors of the hypoxia-inducible factor-2 alpha (HIF2α) in tumors harboring mutations in the hypoxia pathway (Toledo et al. 2023).

By pushing the boundaries of scientific discovery and translational research, our group endeavors to make meaningful progress toward a future where every patient receives optimal tailored care.

• Discover and characterize novel predictive biomarkers of response to targeted anticancer therapies.
• Apply multimodal circulating tumor DNA (ctDNA) assays to predict response to immunotherapy and targeted therapies across tumor types.
• Validate RNF43 mutations as biomarkers of clinical benefit in patients with BRAF-mutated CRC treated with anti-BRAF/EGFR combinatory therapies.
• Characterize tumor heterogeneity: examine the temporal heterogeneity of tumors using tumor and liquid biopsy sequencing approaches during treatment response and disease progression, particularly in the context of immunotherapy and targeted therapies.
• Investigate the mechanims of cancer drug resistance to immunotherapy and targeted therapies to identify potential biomarkers of resistance in liquid biopsy that inform more effective treatment strategies.
• Characterize the impact of hypoxia in shaping of cancer genomes and modulating response to cancer therapies.

• Initiated data analysis of the IMMUNOMICs-ctDNA immunotherapy project.
• Validation by international scientific groups of our discovery of RNF43 mutations as predictive biomarkers of response in patients with BRAF-mutated colorectal cancer (CRC) treated with anti-BRAF/EGFR therapy.
• Development of ACT-Discover to increase sensitivity of ctDNA detection in plasma samples.
• We have reviewed the efficacy of inhibitors of the hypoxia-inducible factor-2 alpha (HIF2α) in tumors harboring mutations in the hypoxia pathway.

• Huebner A, Black JRM, Sarno F, Pazo R, Juez I, Medina L, Garcia-Carbonero R, Guillén C, Feliú J, Alonso C, Arenillas C, Moreno-Cárdenas AB, Verdaguer H, Macarulla T, Hidalgo M, McGranahan N, Toledo RA. ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA. Genome Med. 2023 Apr 20;15(1):27. 

Headed by José A. Seoane, VHIO’s Cancer Computational Biology Group leverages epi(genetic) cancer datasets to identify the molecular mechanisms implicated in cancer initiation, progression, drug resistance and metastasis toward improving outcomes for patients.

We aim to advance insights into the role of chromatin regulatory elements in treatment response and metastasis, develop novel epigenetic synthetic lethality-based therapeutic options, improve patient stratification guided by multi-omics analysis, and discover novel epigenetic biomarkers of treatment response.

We have previously shown how the genetic modifiers of chromatin structure are associated with chemotherapy resistance in breast cancer (Seoane et al. 2019). Our group focuses on how these epigenetic alterations affect drug resistance and how epigenetic therapies can be used to target tumor suppressor genes.

We are also exploring how the machine learning-based integration of multi-omics datasets can facilitate the discovery of new cancer subgroups and biomarkers, as well as help to better predict treatment outcomes and drug response.

Our group has participated/participates in multiple international consortia including The Cancer Genome Atlas, the Human Tumor Atlas Network, Cancer Target Discovery and Development (CTD 2) Network, and, most recently, AURORA (metastatic breast cancer multi-omics cohort).

• Understand the role of chromatin regulatory elements in treatment response and metastasis.
• Discover new epigenetic biomarkers of drug response.
• Potentiate therapeutic options by combining epigenetic therapies with other agents.
• Discover potential environmental causes of early onset cancer.
• Develop clinically actionable machine learning algorithms for prediction and patient stratification.

• José A. Seoane was awarded with a Consolidación Investigadora grant from the State Investigation Agency (Agencia Estatal de Investigación - AEI). 
• Our group is a member of the Vall d'Hebron TACTICS project. This project was awarded with a FORTALECE grant from the Carlos III Health Institute (ISCIII). In total, 2.4 million euros will be allocated over four years.
• José Liñares read his PhD dissertation and graduated with distinction. He is currently a postdoc in Julio Saez-Rodriguez’s lab at the Institute for Computational Biomedicine in Heidelberg, Germany.
• In collaboration with Laura Attardi’s group at the Stanford University School of Medicine, USA, we identified that p53 is a key regulator in AT1 differentiator in lung adenocarcinoma.

• Determine epigenetic synthetic lethality changes in gastrointestinal cancers.
• Investigate the epigenetic changes in post hormone treatment for ER+ and its association with metastatic breast cancer.
• Identify a cell-cycle based signature of treatment prediction in colon cancer.
• Identify exposome-related causes of cancer initiation.

• Salahudeen AA, Seoane JA, Yuki K, Mah AT, Smith AR, Kolahi K, De la O SM, Hart DJ, Ding J, Ma Z, Barkal SA, Shukla ND, Zhang CH, Cantrell MA, Batish A, Usui T, Root DE, Hahn WC, Curtis C, Kuo CJ. Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis. Cell Rep. 2023 Nov 28;42(11):113355.
• Kaiser AM, Gatto A, Hanson KJ, Zhao RL, Raj N, Ozawa MG, Seoane JA, Bieging-Rolett KT, Wang M, Li I, Trope WL, Liou DZ, Shrager JB, Plevritis SK, Newman AM, Van Rechem C, Attardi LD. p53 governs an AT1 differentiation programme in lung cancer suppression. Nature. 2023 Jul;619(7971):851-859. 

1. Targeting synthetic lethality in Chromatin Regulatory Genes for gastrointestinal cancer treatment. Ref PID2020-115097RA-I00. Agencia Estatal de Investigación. 9/2021-8/2025. PI: Jose A. Seoane
2. Ramon y Cajal Grant. Agencia Estatal de Investigación. 2021-2025
3. Epigenetic differences associated with hormone treatment resistant breast cancer heterogeneity Fundación FERO. 2022-2024
4. Identificación in Silico de Respuesta a fármacos especifica de metastasis Entidad Financiadora: MCIN/AEI/10.13039/501100011033 Ref: CNS2022-135424 Periodo de Ejecución: 01/09/2023 – 31/08/2025.  PI: Jose Antonio Seoane
5. TACTIC: Explorando soluciones a los retos de salud mediante ciencia disruptiva, terapias avanzadas y medicina de sistemas. Programa FORTALECE ISCIII REF: FORT23/00034. 2024-2027

1. Salahudeen AA, Seoane JA, Yuki K, Mah AT, Smith AR, Kolahi K, De la O SM, Hart DJ, Ding J, Ma Z, Barkal SA, Shukla ND, Zhang CH, Cantrell MA, Batish A, Usui T, Root DE, Hahn WC, Curtis C, Kuo CJ. Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis. Cell Rep. 2023 Nov 28;42(11):113355.
2. Kaiser AM, Gatto A, Hanson KJ, Zhao RL, Raj N, Ozawa MG, Seoane JA, Bieging-Rolett KT, Wang M, Li I, Trope WL, Liou DZ, Shrager JB, Plevritis SK, Newman AM, Van Rechem C, Attardi LD. p53 governs an AT1 differentiation programme in lung cancer suppression. Nature. 2023 Jul;619(7971):851-859. 

We study the interplay between stress responses, cellular plasticity and cancer. Cellular plasticity is as a critical feature of cancer cells, enabling them to transit between different cellular states and promote tumor growth, disease progression after therapy, and metastasis.

We have previously reported that inducing cell dedifferentiation with the so-called Yamanaka factors can lead to the development of a variety of tumors. We have also demonstrated that tissue damage—the main driver of cancer—triggers the onset of cellular senescence which then induces dedifferentiation and the acquisition of stem cell properties in vivo. These findings have important therapeutic implications given that chemotherapy and radiotherapy—the cornerstones of treatment for most cancers—could have the side effect of inducing stemness in non-stem cancer cells and, in turn, possibly contribute to tumor recurrence and cancer cell spread.

Our main objective is to advance insights into the mechanisms and drivers implicated in this process, with the ultimate goal of developing novel therapies based on the inhibition of cancer cell plasticity.

Over the last few years, our efforts have mainly focused on identifying and characterizing novel cancer microproteins, encoded by previously assumed non coding regions, which could be novel actors in carcinogenesis. We have discovered several new cancer microproteins and have obtained compelling evidence in vitro and in vivo that they act as novel tumor suppressors, inducing cell cycle arrest, differentiation or inhibition of mesenchymal traits in cancer cells.
 

In recent years, using a peptidomics approach, we have identified a set of microproteins secreted by pancreatic tumors, either soluble or secreted in exosomes. Importantly, many of these microproteins are also detected in patients´plasma. During 2023 we have deeply characterized two of them, C9 and C13, and demonstrated that they are secreted by PDAC tumors and have a pro-metastatic role in preclinical mouse models. Our results suggest that microproteins are crucial cellular messengers for pancreatic cancer metastasis and they could also serve as novel cancer biomarkers for the early detection of disease and patient stratification for tailored therapies, as well as therapeutic targets.

In 2023 we have continued working on our collaborative project to study therapy-induced tumoral senescence and its potential as a therapeutic target, funded by the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer). Notably, we have observed that different chemotherapies currently used in the clinic to treat pancreatic cancer induce different types of cellular senescence, which intriguingly have opposite effects on the recognition of tumor cells by the tumor infiltrating lymphocytes (TILs). 

Some drugs induce a type of senescence that increases tumor cell recognition by TILs, while others impair tumor cell recognition. These are very interesting results with obvious clinical implications, and we aim to decipher the molecular mechanisms behind this effect in the coming years. In addition, in collaboration with Manuel Serrano’s group (IRB Barcelona) and Alena Gros’ VHIO group, we have published a paper in Cancer Discovery demonstrating the immunogenic role of therapy-induced senescence and (Marin et al. 2023).

• Advance insights into the interplay between therapy-induced senescence, cellular plasticity and cancer.
• Decipher the molecular mechanisms governing the acquisition of stem cell properties during tumorigenesis and after therapy.
• Discover and characterize novel microproteins involved in cancer cell plasticity.
• Develop novel anti-cancer therapies based on the inhibition of cancer cell plasticity.

• We have reported the immunogenic role of therapy-induced senescence in Cancer Discovery.
• We have demonstrated the pro-metastatic role of two microproteins that we identified as secreted by pancreatic tumors.

• Characterize the molecular mechanisms behind the pro-metastatic role of our newly identified microproteins.
• Investigate how different therapies can induced different types of cellular senescence, impacting on the immune system in a different manner.
• Investigate the tumor-stroma crosstalk after chemo/radiotherapy in PDAC and its impact on tumor cell plasticity.

• Marin I, Boix O, Garcia-Garijo A, Sirois I, Caballe A, Zarzuela E, Ruano I, Attolini CS, Prats N, López-Domínguez JA, Kovatcheva M, Garralda E, Muñoz J, Caron E, Abad M, Gros A, Pietrocola F, Serrano M. Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity. Cancer Discov. 2023 Feb 6;13(2):410-431. 
• Pujals M, Mayans C, Bellio C, Méndez O, Greco E, Fasani R, Alemany-Chavarria M, Zamora E, Padilla L, Mitjans F, Nuciforo P, Canals F, Nonell L, Abad M, Saura C, Tabernero J, Villanueva J. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene. 2023 Aug;42(35):2610-2628. 
• Álvarez-Sierra D, Sánchez-Gaona N, Cruz Cobo M, Escriche A, Abad M, Gómez-Brey A, Bello I, Caubet E, González Ó, Zafón C, Iglesias C, Moreno P, Petit A, Fernández-Sanmartín MA, Martínez-Gallo M, Pujol-Borrell R. Thyroid cells from normal and autoimmune thyroid glands suppress T lymphocytes proliferation upon contact revealing a new regulatory inhibitory type of interaction independent of PD1/PDL1. J Autoimmun. 2023 Apr;136:103013. 

1. Tumoral senescence induced by anti-cancer therapies constitutes a novel prognostic biomarker and a therapeutic target. Reference: PRYCO211023SERR. Spanish Association Against Cancer - AECC.
   Duration: 9/2021-8/2026.
   Co-PI: María Abad.
2. Defining the Role of Exosome-Secreted Micropeptides in Pancreatic Cancer. number: HR18-00256.
   Health Research Grant -”La Caixa”
   Duration: 9/2019-3/2023.
   PI: Maria Abad.

1. Marin I, Boix O, Garcia-Garijo A, Sirois I, Caballe A, Zarzuela E, Ruano I, Attolini CS, Prats N, López-Domínguez JA, Kovatcheva M, Garralda E, Muñoz J, Caron E, Abad M, Gros A, Pietrocola F, Serrano M. Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity. Cancer Discov. 2023 Feb 6;13(2):410-431. 
2. Pujals M, Mayans C, Bellio C, Méndez O, Greco E, Fasani R, Alemany-Chavarria M, Zamora E, Padilla L, Mitjans F, Nuciforo P, Canals F, Nonell L, Abad M, Saura C, Tabernero J, Villanueva J. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene. 2023 Aug;42(35):2610-2628. 
3. Álvarez-Sierra D, Sánchez-Gaona N, Cruz Cobo M, Escriche A, Abad M, Gómez-Brey A, Bello I, Caubet E, González Ó, Zafón C, Iglesias C, Moreno P, Petit A, Fernández-Sanmartín MA, Martínez-Gallo M, Pujol-Borrell R. Thyroid cells from normal and autoimmune thyroid glands suppress T lymphocytes proliferation upon contact revealing a new regulatory inhibitory type of interaction independent of PD1/PDL1. J Autoimmun. 2023 Apr;136:103013. 

We conduct bench-to-bedside preclinical research in breast cancer to advance insights into biomarkers of response to targeted therapies. To do so, we generate preclinical models including patient-derived xenografts (PDXs) and patient-derived cultures (PDCs) from primary or metastatic breast cancer.

We have significantly contributed to the field of endocrine resistance and continue to advance insights into mechanisms of sensitivity and resistance to CDK4/6 inhibitors, FGFR inhibitors, AKT inhibitors, and AR modulators (SARMs) in breast tumors. Using clinically relevant PDXs, we have further supported that the loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 or CCND1- amplification, is associated with the lack of response to CDK4/6 blockade in estrogen receptor-positive (ER+) breast cancer. Additionally, we have generated a collection of PDXs with FGFR amplification to study biomarkers of sensitivity to FGFR inhibitors; both pan-FGFR1-4 and multi-targeted tyrosine kinase inhibitors (MTKIs). 

We are also currently exploring the potential of a novel antibody-drug conjugate (ADC) as a therapeutic strategy for advanced breast cancers that have developed resistance to standard of care treatments.

Encouraged by the early success of DNA damage repair inhibitors in germline BRCA1/2 mutated tumors, we initiated a project to identify biomarkers of response to PARP inhibitors (PARPi) as well as other DNA damage repair inhibitors including those targeting WEE1 or ATR. 

Our studies underpin the capacity of germline BRCA1/2 mutant tumors to recover DNA repair functionality and develop resistance to PARPi. We have developed an assay, the RAD51 test, which accurately identifies germline BRCA1/2 tumors that have restored DNA repair functionality and become resistant to these therapies. Importantly, this test also identifies tumors that are sensitive to PARPi through alterations in DNA repair by homologous recombination beyond the germline BRCA1/2 condition. We filed a patent (EU application in 2017 and PCT in 2018), and we are currently validating the use of this test in tumor samples from breast, ovarian, pancreatic, and prostate cancer patients.

Finally, we are also investigating the effects of PARPi on the tumor immune environment. DNA repair-deficient tumors accumulate cytosolic DNA, which can elicit an innate immune signal (the STING pathway) and upregulate interferon-related genes, leading to lymphocytic infiltration and PD-L1 expression. We are testing the hypothesis that treatment of DNA repair-deficient tumors with PARPi elicits a DNA damage response, resulting in the upregulation of PD-L1 that might limit the antitumor immune-mediated cytotoxicity by lymphocytes, but sensitizes to anti-PD-L1 treatments.

Our group works closely together with Cristina Saura’s Breast Cancer Group, and Judith Balmaña’s Hereditary Cancer Genetics Group. Reflective of VHIO’s purely multidisciplinary and translational approach, our research is also carried out in collaboration with other groups including VHIO’s Molecular Oncology Group, Cancer Genomics Group, and Oncology Data Science – ODysSey Group, directed by Paolo Nuciforo, Ana Vivancos and Rodrigo Dienstmann, respectively.

In short, our group has significantly advanced insights into the mode of action of novel targeted therapies, identified new response biomarkers, and developed a biomarker-based assay with potential clinical application. We have also demonstrated the efficacy of hypothesis-based drug combinations.

• Develop predictive biomarkers of targeted treatments in estrogen receptor-positive (ER+) breast cancer and triple-negative breast cancer (TNBC), including inhibitors directed against DNA damage response (PARP, ATR) as well as signaling/cell cycle kinases (CDK4/6, PI3K/AKT, or FGFR).
• Explore novel treatment combinations for ER+ breast cancer and TNBC. 
• Contribute to personalized medicine by developing diagnostic tests to better guide treatment strategies based on targeted therapies including PARPi.
• Establish patient tumor-derived breast cancer preclinical models to explore hypothesis-based combinatorial therapies.

• Our group has advanced insights into the underlying mechanisms of resistance to PARPi in breast cancer, as well as the clinical utility of diagnostic tools based on the identification of DNA repair deficiency.
• We have obtained funding from the Instituto de Salud Carlos III - ISCIII (Carlos III Health Institute) to study functional homologous repair deficiency (HRD) in early and metastatic breast cancer, as part of our validation program.
• We have established a panel of over one hundred ER+ breast cancer and TNBC patient-derived xenografts (PDXs), mainly from the metastatic setting. We focus on models that recapitulate progression on CDK4/6 inhibitors, and BRCA1/2-associated tumors.

• Validation of the homologous repair deficiency (HRD) biomarker based on the detection of RAD51 in retrospective and prospective clinical trials.
• Optimization of the RAD51 assay to be used in liquid biopsies (CTCs in blood) and automatization of the staining and image analysis of the test to facilitate its future implementation in the clinic.
• Identification of mechanisms of resistance to CDK4/6 inhibitors and the study of novel therapeutic strategies including AR modulators or antibody-drug conjugates (ADCs) for the treatment of advanced breast cancer. Based on these results, new patient stratification and therapeutic algorithms will be proposed for improving outcomes in patients who do not derive clinical benefit from current therapies.
• Unveil genetic and epigenetic mechanisms of acquired resistance to PARP inhibitors (PARPi) in hereditary BRCA1/2 breast cancer and beyond; by other HRR alterations. Propose novel therapeutic strategies for patients who do not respond to these drugs.
• Dissect the role of the STING pathway in BRCA mutated tumors and explore the combination of PARPi and therapies exploiting the autologous immune response.
• Continue expanding the panel of patient tumor-derived breast cancer models to investigate hypothesis-based, clinically-applicable therapy combinations in breast cancer aimed at overcoming resistance to both anti-estrogen therapy and PARPi.

• Ring A, Kilburn LS, Pearson A, Moretti L, Afshari-Mehr A, Wardley AM, Gurel B, Macpherson IR, Riisnaes R, Baird RD, Martin S, Roylance R, Johnson H, Ferreira A, Winter MC, Dunne K, Copson E, Hickish T, Burcombe R, Randle K, Serra V, Llop-Guevara A, Bliss JM, Turner NC. Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010). Clin Cancer Res. 2023 Dec 1;29(23):4751-4759. 
• Yndestad S, Engebrethsen C, Herencia-Ropero A, Nikolaienko O, Vintermyr OK, Lillestøl RK, Minsaas L, Leirvaag B, Iversen GT, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Aase HS, Aas T, Gudlaugsson EG, Llop-Guevara A, Serra V, Janssen EAM, Lønning PE, Knappskog S, Eikesdal HP. Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. JCO Precis Oncol. 2023 Sep;7:e2300338. 
• Blanc-Durand F, Yaniz-Galende E, Llop-Guevara A, Genestie C, Serra V, Herencia-Ropero A, Klein C, Berton D, Lortholary A, Dohollou N, Desauw C, Fabbro M, Malaurie E, Bonichon-Lamaichhane N, Dubot C, Kurtz JE, de Rauglaudre G, Raban N, Chevalier-Place A, Ferron G, Kaminsky MC, Kramer C, Rouleau E, Leary A. A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer. Gynecol Oncol. 2023 Apr;171:106-113. 
• Serra-Camprubí Q, Verdaguer H, Oliveros W, Lupión-Garcia N, Llop-Guevara A, Molina C, Vila-Casadesús M, Turpin A, Neuzillet C, Frigola J, Querol J, Yáñez-Bartolomé M, Castet F, Fabregat-Franco C, Escudero-Iriarte C, Escorihuela M, Arenas EJ, Bernadó-Morales C, Haro N, Giles FJ, Pozo ÓJ, Miquel JM, Nuciforo PG, Vivancos A, Melé M, Serra V, Arribas J, Tabernero J, Peiró S, Macarulla T, Tian TV. Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation. Clin Cancer Res. 2023 Jan 17;29(2):432-445. 

 
Newly awarded project in 2023:

• Utilidad clínica de testar RAD51 como test de DIAgNósTico de HRD funcional para cáncer de mama (RADIANT), (PI23/00506).
  Principal Investigator: Violeta Serra.
  Funding Agency: ISCIII-Project Grant.
  Duration: 2024-2026.

 Ongoing projects 2023:

• Understanding CDK4/6i and SERD resistance in metastatic ER+ breast cancer using patient samples and PDXs.
  Funding Agency: AstraZeneca.Principal Investigators: Cristina Saura and Violeta Serra.
  Duration: 2022-2023.
• Identification of response biomarkers of a novel HER3-topoisomerase I inhibitor antibody drug conjugate (U3-1402) using breast cancer patient-derived xenoimplant models.
  Funding Agency: Metastatic Breast Cancer Association.
  Duration: 2022-2023.
• Inter-observer validation of the RAD51 test in samples from VIOLETTE and in an “intent-to-test” population from VHUH patients with breast, ovarian, prostate and pancreatic tumors. Integration with non-commercial genetic/genomic tests.
  Funding Agency: AstraZeneca.
  Principal Investigator: Violeta Serra.
  Duration: 2022-2023.
• Developing new therapeutic strategies to overcome CDK4/6 resistance in estrogen receptor positive breast cancer (PI20/00892).
  Funding Agency: ISCIII.
  Principal Investigators: Violeta Serra and Meritxell Bellet.
  Duration: 2021-2023.
• Acknowledged Consolidated Research Group (SGR): “Experimental Therapeutics in Breast Cancer” (2021 SGR 01510).
  Coordinating Group: Violeta Serra.
  Funding Agency: AGAUR-SGR.
  Duration: 2022-2024.
• Overcoming CDK4/6 inhibitor resistance with TEAD inhibitors in Estrogen Receptor-Positive Breast Cancer Patient-Derived Xenografts (PDX).
  Principal Investigator: Violeta Serra.
  Funding: IKENA Oncology.

1.  RAD51 as a biomarker for homologous recombination deficiency in high-grade serous ovarian carcinoma: robustness and interobserver variability of the RAD51 test. Kramer CJ, Llop-Guevara A, Yaniz-Galende E, Pellegrino B, Ter Haar NT, Herencia-Ropero A, Campanini N, Musolino A, Bosse T, Leary A, Serra V, Vreeswijk MP. J Pathol Clin Res. 2023 Nov;9(6):442-448. doi: 10.1002/cjp2.336. Epub 2023 Jul 28. PMID: 37504067; PMCID: PMC10556259. 
2. Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer. Pascual-Reguant L, Serra-Camprubí Q, Datta D, Cianferoni D, Kourtis S, Gañez-Zapater A, Cannatá C, Espinar L, Querol J, García-López L, Musa-Afaneh S, Guirola M, Gkanogiannis A, Miró Canturri A, Guzman M, Rodríguez O, Herencia-Ropero A, Arribas J, Serra V, Serrano L, Tian TV, Peiró S, Sdelci S. EMBO Mol Med. 2023 Nov 8:e18459. doi: 10.15252/emmm.202318459. Online ahead of print. PMID: 37937685.
3.  Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Ring A, Kilburn LS, Pearson A, Moretti L, Afshari-Mehr A, Wardley AM, Gurel B, Macpherson IR, Riisnaes R, Baird RD, Martin S, Roylance R, Johnson H, Ferreira A, Winter MC, Dunne K, Copson E, Hickish T, Burcombe R, Randle K, Serra V, Llop-Guevara A, Bliss JM, Turner NC. Clin Cancer Res. 2023 Sep 29. doi: 10.1158/1078-0432.CCR-23-1696. Online ahead of print. PMID: 37773077.
4.  Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. Yndestad S, Engebrethsen C, Herencia-Ropero A, Nikolaienko O, Vintermyr OK, Lillestøl RK, Minsaas L, Leirvaag B, Iversen GT, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Aase HS, Aas T, Gudlaugsson EG, Llop-Guevara A, Serra V, Janssen EAM, Lønning PE, Knappskog S, Eikesdal HP. JCO Precis Oncol. 2023 Sep;7:e2300338. doi: 10.1200/PO.23.00338.PMID: 38039432.
5. The next-generation oral selective estrogen receptor degrader camizestrant (AZD9833) suppresses ER+ breast cancer growth and overcomes endocrine and CDK4/6 inhibitor resistance. Lawson M, Cureton N, Ros S, Cheraghchi-Bashi-Astaneh A, Urosevic J, D'Arcy S, Delpuech O, DuPont M, Fisher DI, Gangl ET, Lewis H, Trueman D, Wali N, Williamson SC, Moss J, Montaudon E, Derrien H, Marangoni E, Miragaia RJ, Gagrica S, Morentin Gutierrez P, Moss T, Maglennon GA, Sutton D, Polanski R, Rosen A, Cairns J, Zhang P, Sánchez-Guixé M, Serra V, Critchlow SE, Scott JS, Lindemann JPO, Barry ST, Klinowska T, Morrow CJ, Carnevalli LS. Cancer Res. 2023 Sep 19. doi: 10.1158/0008-5472.CAN-23-0694. Online ahead of print. PMID: 37725704.
6. Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma. Gleason CE, Dickson MA, Klein Dooley ME, Antonescu CR, Gularte-Mérida R, Benitez M, Delgado JI, Kataru RP, Tan MWY, Bradic M, Adamson TE, Seier K, Richards AL, Palafox M, Chan E, D'Angelo SP, Gounder MM, Keohan ML, Kelly CM, Chi P, Movva S, Landa J, Crago AM, Donoghue MTA, Qin LX, Serra V, Turkekul M, Barlas A, Firester DM, Manova-Todorova K, Mehrara BJ, Kovatcheva M, Tan NS, Singer S, Tap WD, Koff A. Clin Cancer Res. 2023 Sep 11. doi: 10.1158/1078-0432.CCR-23-2378. PMID: 37695642.
7. BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.  Petrelli A, Rizzolio S, Pietrantonio F, Bellomo SE, Benelli M, De Cecco L, Romagnoli D, Berrino E, Orrù C, Ribisi S, Moya-Rull D, Migliore C, Conticelli D, Maina IM, Puliga E, Serra V, Pellegrino B, Llop-Guevara A, Musolino A, Siena S, Sartore-Bianchi A, Prisciandaro M, Morano F, Antista M, Fumagalli U, De Manzoni G, Degiuli M, Baiocchi GL, Amisano MF, Ferrero A, Marchiò C, Corso S, Giordano S. Cancer Res. 2023 May 15;83(10):1699-1710. doi: 10.1158/0008-5472.CAN-22-2620. PMID: 37129948.
8. A RAD51 functional assay as a candidate test for homologous recombination deficiency in ovarian cancer. Blanc-Durand F, Yaniz-Galende E, Llop-Guevara A, Genestie C, Serra V, Herencia-Ropero A, Klein C, Berton D, Lortholary A, Dohollou N, Desauw C, Fabbro M, Malaurie E, Bonichon-Lamaichhane N, Dubot C, Kurtz JE, de Rauglaudre G, Raban N, Chevalier-Place A, Ferron G, Kaminsky MC, Kramer C, Rouleau E, Leary A. Gynecol Oncol. 2023 Apr;171:106-113. doi: 10.1016/j.ygyno.2023.01.026. PMID: 36868112.
9. Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models. Rodriguez MJ, Perrone MC, Riggio M, Palafox M, Salinas V, Elia A, Salgueiro ND, Werbach AE, Marks MP, Kauffman MA, Vellón L, Serra V, Novaro V. Sci Rep. 2023 Feb 15;13(1):2710. doi: 10.1038/s41598-023-29425-y. PMID: 36792625.
10. Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation. Serra-Camprubí Q, Verdaguer H, Oliveros W, Lupión-Garcia N, Llop-Guevara A, Molina C, Vila-Casadesús M, Turpin A, Neuzillet C, Frigola J, Querol J, Yáñez- Bartolomé M, Castet F, Fabregat-Franco C, Escudero-Iriarte C, Escorihuela M, Arenas EJ, Bernadó-Morales C, Haro N, Giles FJ, Pozo ÓJ, Miquel JM, Nuciforo PG, Vivancos A, Melé M, Serra V, Arribas J, Tabernero J, Peiró S, Macarulla T, Tian TV. Clin Cancer Res. 2023 Jan 17;29(2):432-445. doi: 10.1158/1078-0432.CCR-22-2551. PMID: 36374558.
11. MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer. Dinami R, Pompili L, Petti E, Porru M, D'Angelo C, Di Vito S, Rizzo A, Campani V, De Rosa G, Bruna A, Serra V, Mano M, Giacca M, Leonetti C, Ciliberto G, Tarsounas M, Stoppacciaro A, Schoeftner S, Biroccio A. EMBO Mol Med. 2023 Jan 11;15(1):e16033. doi: 10.15252/emmm.202216033. Epub 2022 Nov 25. PMID: 36426578.

In 2023, we have continued to expand our platform of patient-derived xenograft (PDX) models, investigate novel therapies against human epidermal growth factor receptor 2-positive (HER2+) breast cancer, and foster collaboration with other VHIO groups.

PDXs are advanced research models in which tumor tissues from patients are implanted into immunocompromised or humanized mice. These models faithfully recapitulate the characteristics of cancer, such as intratumor heterogeneity, and represent a powerful tool for testing novel drugs. By preserving the histological structure and genetic characteristics of original patient tumors, PDX are proving invaluable for mechanistic research, drug development and personalized therapy. 

Our PDX platform has been key to the success of three collaborative projects, the outcomes of which were published this year – as described below.

First, our collection of PDX enabled us to evaluate MEN1611, a PI3K δ-sparing inhibitor, in PIK3CA-mutated trastuzumab-resistant HER2+ breast cancer models. Preclinical results point to its potential as a viable treatment option for patients who have exhausted conventional therapies (Fiascarelli et al. 2023). 

A second study leveraged PDX models to decipher the complex interactions between BRD4S, LOXL2, and MED1 as drivers of cell cycle transcription in triple-negative breast cancer (TNBC). Results of this study could ultimately lead to the development of new targeted therapeutic strategies for TNBC (Pascual‐Reguant et al. 2023). 

Carried out in collaboration with our Upper Gastrointestinal Tumors Group translational research lab led by Teresa Macarulla and Tian Tian, research focused on metastatic cholangiocarcinoma (CCA) used PDX and tumoroid models for the preclinical evaluation of treatment response to PARP inhibitors. By mirroring the unique genetic make-up of each patient’s cancer, these models constitute a valuable resource in advancing personalized medicine in oncology (Serra-Camprubí et al. 2023).

HER2 is a crucial protein implicated in the development and progression of various tumor types, playing a key role cell growth, survival and differentiation. HER2 overexpression is linked to aggressive tumor growth, a poorer prognosis, and reduced response to some conventional therapies, making it a highly sensitive target for cancer treatment.

We continue to work on the development of immune-based therapies against HER2. We have created three-dimensional (3D) cell cultures for chimeric antigen receptor (CAR) T cells that are specific to HER2 and derived from peripheral blood mononuclear cells. This approach aims to enhance their proliferaton, functionality, and therapeutic efficacy for use in cellular therapies. By adopting a 3D culture system, we have mimicked the natural cellular microenvironment more closely, potentially overcoming the limitations of conventional two-dimensional cultures and enhancing the success of CAR T cell-based treatments (Río et al. 2023).

We have also studied the factors and mechanisms that regulate immune infiltration in TNBC (Quintana et al. 2023). These and other recent findings on novel therapies against HER2 were the subject of two review articles that we also co-authored (Duro-Sánchez et al., Adam-Artigues et al. 2023). 

Led by VHIO’s Breast Cancer Group directed by Cristina Saura, we have participated in a novel proof-of-concept study demonstrating the viability of detecting tumor DNA in breast milk. This discovery could open new avenues for the early diagnosis and treatment of postpartum breast cancer (Saura et al. 2023).

• Generate and characterize chimeric antigen receptor (CAR)-T cells against tumor-specific antigens.
• Determine the role of cellular senescence in breast cancer progression and response to treatment.
• Characterize new mechanisms of resistance to targeted therapies.

• The production of a fourth-generation CAR-T for a phase I clinical trial.
• We have contributed to deciphering the role of the programmed cell death  ligand 2 (PD-L2) in response to chemotherapy.
• We have continued to study the differential role of cellular senescence in stage-dependent tumor progression.

• Pascual-Reguant L, Serra-Camprubí Q, Datta D, Cianferoni D, Kourtis S, Gañez-Zapater A, Cannatá C, Espinar L, Querol J, García-López L, Musa-Afaneh S, Guirola M, Gkanogiannis A, Miró Canturri A, Guzman M, Rodríguez O, Herencia-Ropero A, Arribas J, Serra V, Serrano L, Tian TV, Peiró S, Sdelci S. Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer. EMBO Mol Med. 2023 Dec 7;15(12):e18459.
• Serra-Camprubí Q, Verdaguer H, Oliveros W, Lupión-Garcia N, Llop-Guevara A, Molina C, Vila-Casadesús M, Turpin A, Neuzillet C, Frigola J, Querol J, Yáñez-Bartolomé M, Castet F, Fabregat-Franco C, Escudero-Iriarte C, Escorihuela M, Arenas EJ, Bernadó-Morales C, Haro N, Giles FJ, Pozo ÓJ, Miquel JM, Nuciforo PG, Vivancos A, Melé M, Serra V, Arribas J, Tabernero J, Peiró S, Macarulla T, Tian TV. Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation. Clin Cancer Res. 2023 Jan 17;29(2):432-445. 
• Pérez Del Río E, Román Alonso M, Rius I, Santos F, Castellote-Borrell M, Veciana J, Ratera I, Arribas J, Guasch J. Three-dimensional cell culture of chimeric antigen receptor T cells originated from peripheral blood mononuclear cells towards cellular therapies. Cytotherapy. 2023 Dec;25(12):1293-1299. 
• Quintana Á, Arenas EJ, Bernadó C, Navarro JF, González J, Esteve-Codina A, Moliné T, Marti M, Curigliano G, Schmid P, Peg V, Arribas J, Cortés J. Evaluation of triple negative breast cancer with heterogeneous immune infiltration. Front Immunol. 2023 May 4;14:1149747.

1. Fiascarelli, A., Merlino, G., Capano, S., Talucci, S., Bisignano, D., Bressan, A., Bellarosa, D., Carrisi, C., Paoli, A., Bigioni, M., et al. (2023). Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer. Breast Cancer Res. Treat. 199, 13–23. 10.1007/s10549-023-06895-2.
2. Pascual‐Reguant, L., Serra‐Camprubí, Q., Datta, D., Cianferoni, D., Kourtis, S., Gañez‐Zapater, A., Cannatá, C., Espinar, L., Querol, J., García‐López, L., et al. (2023). Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer. EMBO Mol. Med. 15, e18459. 10.15252/emmm.202318459.
3. Serra-Camprubí, Q., Verdaguer, H., Oliveros, W., Lupión-Garcia, N., Llop-Guevara, A., Molina, C., Vila-Casadesús, M., Turpin, A., Neuzillet, C., Frigola, J., et al. (2023). Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation. Clin. Cancer Res. 29, 432–445. 10.1158/1078-0432.ccr-22-2551.
4. Río, E.P. del, Alonso, M.R., Rius, I., Santos, F., Castellote-Borrell, M., Veciana, J., Ratera, I., Arribas, J., and Guasch, J. (2023). Three-dimensional cell culture of chimeric antigen receptor T cells originated from peripheral blood mononuclear cells towards cellular therapies. Cytotherapy 25, 1293–1299. 10.1016/j.jcyt.2023.08.003.
5. Quintana, Á., Arenas, E.J., Bernadó, C., Navarro, J.F., González, J., Esteve-Codina, A., Moliné, T., Marti, M., Curigliano, G., Schmid, P., et al. (2023). Evaluation of triple negative breast cancer with heterogeneous immune infiltration. Front. Immunol. 14, 1149747. 10.3389/fimmu.2023.1149747.
6. Duro-Sánchez, S., Alonso, M.R., and Arribas, J. (2023). Immunotherapies against HER2-Positive Breast Cancer. Cancers 15, 1069. 10.3390/cancers15041069.
7. 7. Adam-Artigues, A., Arenas, E.J., Arribas, J., Prat, A., and Cejalvo, J.M. (2023). AXL – a new player in resistance to HER2 blockade. Cancer Treat. Rev. 121, 102639. 10.1016/j.ctrv.2023.102639.
8. Saura, C., Ortiz, C., Matito, J., Arenas, E.J., Suñol, A., Martín, Á., Córdoba, O., Martínez-Sabadell, A., García-Ruiz, I., Miranda, I., et al. (2023). Early-Stage Breast Cancer Detection in Breast Milk. Cancer Discov. 13, OF1–OF12. 10.1158/2159-8290.cd-22-1340.

Our research focuses on advanced prostate cancer and follows a bench-to-bedside-and-back model. We have set up a platform for acquiring longitudinal samples from advanced prostate cancer patients—both tumor tissue and liquid biopsies—that can be used to investigate the evolving features of disease. We also generate patient-derived laboratory models of advanced prostate cancer that we can leverage to investigate new therapeutic strategies at the bench.

The launch of investigator-initiated clinical trials is a key element of our research strategy, as a platform for correlative studies that can optimize the drug development pathway for prostate cancer patients. We currently serve as the central laboratory for two academic multi-center clinical trials, as well as the national repository in Spain for the IRONMAN registry; an important international project aimed at building up a large collection of clinical data and biospecimens from metastatic prostate cancer (mPC) patients.

We aim to integrate insights in molecular biology, genomics, transcriptomics, computational sciences and clinical data toward developing precision medicine strategies for prostate cancer patients. To do so, our team comprises biomedical scientists with expertise in cancer biology, genomics and transcriptomics, bioinformatics and liquid biopsy, as well as medical oncologists and clinical data managers.

One of our main lines of research is to decipher how prostate cancers adapt to exposure to systemic therapies (mainly androgen-targeting agents), with a particular focus on cell cycle regulation and DNA damage response and the emergence of quiescent and senescent phenotypes as drivers of drug resistance, for the development of new anti-cancer strategies.

By studying in-vitro and in-vivo models, including patient-derived xenografts (PDX) from the patients participating in our clinical studies, we aim to target emergent phenotypes through drug combinations. These studies are currently funded by grants from the Spanish Ministry of Health, Fundación FERO (FERO Foundation), Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer), and through collaborations with biopharmaceutical companies.

Our group focuses on the molecular characterization of advanced prostate cancer to advance insights into how tumors evolve in a heterogeneous manner as they acquire resistance to different treatments. We have therefore established a genomics and transcriptomics platform in the lab to perform DNA and RNA profiling from patient biopsies. We are developing novel liquid biopsy assays that will enable us to study disease through longitudinal samples. By exploiting publicly available genomics datasets from patients at different stages of disease, our computational scientists investigate how the genomic profile of disease changes over time. These studies are currently funded by grants from the U.S. Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP), the Spanish Ministry of Health, CRIS Cancer Foundation, AECC, Fundación FERO, and the ”la Caixa” Foundation.

Lastly, given that well-annotated correlative clinical data is crucial to establish the potential relevance of molecular data, our team maintains databases collecting outcome data for all patients who donate samples for our studies to perform subsequent correlative analysis.

To more rapidly advance the field, we believe in team science. We therefore participate in several different collaborations that pool resources and combine cross-border expertise across several different research teams and groups.

In summary, our research integrates different modalities of data generated in the lab that can lead to the design of therapeutic interventions aimed at improving outcomes for prostate cancer patients.

• Investigate correlations between patient molecular profiling and clinical outcome data that can guide more precise prostate cancer treatment strategies.
• Study how prostate cancers adapt to therapy, with a focus on targeting emerging vulnerabilities to delay disease recurrence.
• Investigate tumor heterogeneity in response to therapy in preclinical and patient-derived xenograft models (PDX), as well as by interrogating patient biopsies.
• Develop new liquid biopsy tools that can be used to monitor tumor evolution.
• Apply computational pipelines toward investigating genomic signatures in prostate cancer.
• Development of academic clinical trials to validate our laboratory results in the clinic, and leveraging patient biopsies for correlative studies.

• Launch of HOPE PROSTATE - SOLTI-2102, an academic clinical study implementing genomic testing in real-world clinical practice for patients metastatic prostate cancer.
• Launch of MARION, an academic clinical study of dual PET-MRI and liquid biopsies to study prostate cancer response to standard-of-care therapies.
• We presented our work on the characterization of extracellular vesicles from prostate cancer liquid biopsies at the American Association for Cancer Research (AACR) Annual Meeting, 2023, April 14-19, Orlando, Florida, and the 30th Annual Prostate Cancer Foundation Scientific Retreat, October 26-28, 2023, Carlsbad, California. 

• Build a platform for collaborative research, integrating clinical and genomics data.
• Develop genomics and transcriptomics assays, from both tumor tissue and liquid biopsies, to stratify prostate cancer to clinically relevant signatures.
• Generate laboratory models from patients’ biopsies for the investigation of new therapeutic strategies.
• Validate genomic and transcriptomics signatures associated with DDR defects in prostate cancer.

• Mateo J, de Bono JS, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Agarwal N, Olmos D, Thiery-Vuillemin A, Özgüroğlu M, Mehra N, Matsubara N, Young Joung J, Padua C, Korbenfeld E, Kang J, Marshall H, Lai Z, Barnicle A, Poehlein C, Lukashchuk N, Hussain M. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. J Clin Oncol. 2023 Nov 14:JCO2300339.
• Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney CJ, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis C, Mahal B, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro CJ, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, Sydes MR, Taplin ME, Tilki D, Türkeri L, Turco F, Uemura H, Uemura H, Ürün Y, Vale CL, van Oort I, Vapiwala N, Walz J, Yamoah K, Ye D, Yu EY, Zapatero A, Zilli T, Omlin A. Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer. 2023 May;185:178-215. 
• Chi KN, Barnicle A, Sibilla C, Lai Z, Corcoran C, Barrett JC, Adelman CA, Qiu P, Easter A, Dearden S, Oxnard GR, Agarwal N, Azad A, de Bono J, Mateo J, Olmos D, Thiery-Vuillemin A, Harrington EA. Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound. Clin Cancer Res. 2023 Jan 4;29(1):81-91.
• Mateo J, Beltran H. Moving Precision Oncology for Advanced Prostate Cancer from Theory to Practice. Eur Urol Focus. 2023 Jan;9(1):110-113. 

New in 2023:

• Title: Development of NT1, a potent and selective best-in-class drug targeting the Androgen Receptor disordered domain for the treatment of Castration Resistant Prostate Cancer.
  Grantor: Programa RETOS Colaboracion Publico-Privada, Spanish Ministry of Science.
  Duration: 2024-2026.
  PI: Joaquin Mateo.
• Title: Multimodal Biomarkers for Precise Management of Metastatic Prostate Cancer.
  Grantor: Programa RETOS Colaboracion Publico-Privada, Spanish Ministry of Science.
  Duration: 2023-2025.
  Co-PIs: Joaquin Mateo and Raquel Perez Lopez.
• Title: Impact of hormonal therapy-induced senescence in the immune-tumor interaction in prostate cancer.
  Grantor: Spanish Ministry of Health, FIS Program.
  Duration: 2024-2026.
  PI: Nicolas Herranz.
• Studying intra-tumor heterogeneity in the evolution of metastatic hormone-naïve prostate cancer to castration-resistance after intensified hormonal therapy.
  Grantor: Department of Defense CDMRP (United States) 2022 Call.
  Duration: 2023-2026.
  PI: Joaquin Mateo.

Ongoing projects in 2023:

• Title: Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays.
  Grantor: US Department of Defense Congressionally-Directed Medical Research Program.
  Duration: 2018-2023.
  PI: Joaquin Mateo.
• Title: Leveraging the AR-DDR interaction in de-novo metastatic prostate cancer towards precision combination therapies with PARP inhibitors.
  Grantor: AECC (Fundación Asociación Española contra el Cáncer).
  Duration: 2020-2023.
  PI: Joaquin Mateo.
• Title: Integrated analysis of blood circulating tumor signatures to monitor genomic evolution and therapy responses in advanced Prostate Cancer.
  Grantor: ”la Caixa” Foundation.
  Duration: 2021-2024.
  PI: Irene Casanova-Salas
• Title: Exploiting senescence in a two-step approach to treat advanced Prostate Cancer.
  Grantor: Instituto de Salud Carlos III (ISCIII).
  Duration: 2021-2023.
  PI: Nicolas Herranz.
• Title: Tumoral senescence induced by anti-cancer therapies constitutes a novel prognostic biomarker and a therapeutic target.
  Grantor: AECC (Fundación Asociación Española contra el Cáncer).
  Duration: 2022-2026.
  Co-PIs: Manuel Serrano, Maria Abad, Raquel Perez and Joaquin Mateo
• Title: Prostate Cancer Genomic Evolution and Signatures of DNA Damage Repair Deficiencies.
  Grantor: CRIS Cancer Foundation.
  Duration: 2021-2025.
  PI: Joaquin Mateo.

• Premio Jóvenes Investigadores Fundación AstraZeneca 2023.
• DoD CDMRP Physician Science Award.

1. Mateo J, de Bono JS, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Agarwal N, Olmos D, Thiery-Vuillemin A, Özgüroğlu M, Mehra N, Matsubara N, Young Joung J, Padua C, Korbenfeld E, Kang J, Marshall H, Lai Z, Barnicle A, Poehlein C, Lukashchuk N, Hussain M. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. J Clin Oncol. 2023 Nov 14:JCO2300339. doi: 10.1200/JCO.23.00339. Epub ahead of print. PMID: 37963304.
2.  Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney CJ, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis C, Mahal B, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro CJ, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, Sydes MR, Taplin ME, Tilki D, Türkeri L, Turco F, Uemura H, Uemura H, Ürün Y, Vale CL, van Oort I, Vapiwala N, Walz J, Yamoah K, Ye D, Yu EY, Zapatero A, Zilli T, Omlin A. Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer. 2023 May;185:178-215. doi: 10.1016/j.ejca.2023.02.018. Epub 2023 Mar 3. PMID: 37003085.
3.  Chi KN, Barnicle A, Sibilla C, Lai Z, Corcoran C, Barrett JC, Adelman CA, Qiu P, Easter A, Dearden S, Oxnard GR, Agarwal N, Azad A, de Bono J, Mateo J, Olmos D, Thiery-Vuillemin A, Harrington EA. Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound. Clin Cancer Res. 2023 Jan 4;29(1):81-91. doi: 10.1158/1078-0432.CCR-22-0931. PMID: 36043882; PMCID: PMC9811161.
4.  Mateo J, Beltran H. Moving Precision Oncology for Advanced Prostate Cancer from Theory to Practice. Eur Urol Focus. 2023 Jan;9(1):110-113. doi: 10.1016/j.euf.2022.08.004. Epub 2022 Aug 20. PMID: 35999168.
5.  Schostak M, Bradbury A, Briganti A, Gonzalez D, Gomella L, Mateo J, Penault-Llorca F, Stenzinger A, Wyatt AW, Bjartell A. Practical Guidance on Establishing a Molecular Testing Pathway for Alterations in Homologous Recombination Repair Genes in Clinical Practice for Patients with Metastatic Prostate Cancer. Eur Urol Oncol. 2023 Sep 13:S2588-9311(23)00166-9. doi: 10.1016/j.euo.2023.08.004. Epub ahead of print. PMID: 37714762.
6.  Turpin A, Delliaux C, Parent P, Chevalier H, Escudero-Iriarte C, Bonardi F, Vanpouille N, Flourens A, Querol J, Carnot A, Leroy X, Herranz N, Lanel T, Villers A, Olivier J, Touzet H, de Launoit Y, Tian TV, Duterque-Coquillaud M. Fascin-1 expression is associated with neuroendocrine prostate cancer and directly suppressed by androgen receptor. Br J Cancer. 2023 Dec;129(12):1903-1914. doi: 10.1038/s41416-023-02449-x. Epub 2023 Oct 24. PMID: 37875732; PMCID: PMC10703930.
7.  Grochot R, Carreira S, Miranda S, Figueiredo I, Bertan C, Rekowski J, Yuan W, Ferreira A, Riisnaes R, Neeb A, Gurel B, de Los Dolores Fenor de la Maza M, Guo C, Carmichael J, Westaby D, Mateo J, Sharp A, McVeigh TP, De Bono J. Germline ATM Mutations Detected by Somatic DNA Sequencing in Lethal Prostate Cancer. Eur Urol Open Sci. 2023 May 2;52:72-78. doi: 10.1016/j.euros.2023.04.003. PMID: 37284046; PMCID: PMC10240520.
8.  Beije N, Abida W, Antonarakis ES, Castro E, de Wit R, Fizazi K, Gillessen S, Hussain M, Mateo J, Morris MJ, Olmos D, Sartor O, Sharp A, Sweeney CJ, de Bono JS. PARP Inhibitors for Prostate Cancer: Tangled up in PROfound and PROpel (and TALAPRO-2) Blues. Eur Urol. 2023 Sep;84(3):253-256. doi: 10.1016/j.eururo.2023.03.038. Epub 2023 Apr 20. PMID: 37087376.
9.  Lozano R, Castro E, Lopez-Campos F, Thorne H, Ramirez-Backhaus M, Aragon IM, Cendón-Florez Y, Gutierrez-Pecharroman A, Salles DC, Romero-Laorden N, Lorente D, González-Peramato P, Calatrava A, Alonso C, Anido U, Arévalo-Lobera S, Balmaña J, Chirivella I, Juan-Fita MJ, Llort G, Y Cajal TR, Almagro E, Alameda D, López-Casas PP, Herrera B, Mateo J, Pritchard CC, Antonarakis ES, Lotan TL, Rubio-Briones J, Sandhu S, Olmos D. Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers. Eur J Cancer. 2023 May;185:105-118. doi: 10.1016/j.ejca.2023.02.022. Epub 2023 Mar 5. PMID: 36972661.
10.  Casolino R, Johns AL, Courtot M, Lawlor RT, De Lorenzo F, Horgan D, Mateo J, Normanno N, Rubin M, Stein L, Subbiah V, Westphalen BC, Lawler M, Park K, Perdomo S, Yoshino T, Wu J, Biankin AV; Lancet Oncology Commission on Cancer Omics and Precision Oncology. Accelerating cancer omics and precision oncology in health care and research: a Lancet Oncology Commission. Lancet Oncol. 2023 Feb;24(2):123-125. doi: 10.1016/S1470-2045(23)00007-4. PMID: 36725142.

• IRONMAN-ES: Estudio prospectivo observacional de parámetros clínicos y biomarcadores en cáncer de próstata avanzado en hospitales de España.
• ZZ-First: A Biomarker–Discovery Phase II Trial of Enzalutamide and Talazoparib (BMN 673) for the Treatment of Metastatic Hormone–Naïve Prostate Cancer.
• HOPE PROSTATE - SOLTI-2102: real world clinical practice study to assess the feasibility and impact of liquid biopsy-based genomic profiling on treatment decision making for patients with metastatic prostate cancer in spain. Sponsor: SOLTI cooperative group.
  PIs: Joaquin Mateo and Joan Carles.
• MARION: Multimodal biomarkers for precise management of metastatic prostate cancer. Sponsor: VHIO.
  PI: Joaquin Mateo.

We study the mechanisms underlying the persistence of cancer cells that enable tumors to evade effective therapies and progress to advanced stages of disease.

Using multi-omics approaches we aim to unravel unexpected alterations linked to tumor and single cell phenotypes. Combining gene editing (CRISPR/Cas) with classical signaling biochemistry in cancer cell lines as well as genetically modified mice, patient-derived organoids (PDO) and xenografts (PDX), our group focuses on the functional relevance of these newly identified alterations in patients' response to treatment.

We participate in a global and multidisciplinary task force incorporating medical oncologists, surgeons, radiologists, and nurses. We work closely together to rapidly translate laboratory results to the clinic.

Main research lines include:

Tumor cell dormancy
The study of the intriguing biology of cancer cell dormancy as a driver of chemoresistance, formation of minimal residual disease, and relapse in patients.

We previously discovered a core epigenetic network that governs cancer cell dormancy (Puig et al. 2018)*, and are now investigating the function of TET2, DPPA3 (Cuesta et al. 2023), and other epigenetic and transcription factors in tumor cell dormancy.

Our group is making important progress in developing drugs that modulate drivers of cancer cell dormancy including TET2, as well as defining novel biomarkers to detect chemo-resistant dormant tumor cells. We founded ONIRIA Therapeutics as a spin-off company for the development of innovative therapies that modulate cell dormancy as a new strategy to fight cancer (https://www.oniriatherapeutics.com/).

Response to target-directed treatments
We work in close collaboration with oncologists and pharmaceutical companies to identify molecular mechanisms underlying sensitivity or resistance to drugs blocking Wnt/beta-catenin, Notch, PI3K/AKT, EGFR/LGR5, BRAF/MEK/ERK, CDKs or hippo oncogenic signals (Tenbaum et al. 2012; Puig et al. 2013; Capdevila et al. 2020; Lehal et al. 2020, Harmstron et al. 2021; Herpers et al. 2022 )**.

Based on our discoveries, we are designing new prescreening tests for the genetic-guided selection of patients for possible enrolment in clinical trials. Importantly, our findings are helping to define new rational drug combinations to treat cancer patients with progressive disease that will be evaluated in new academic clinical trials.

Advanced preclinical cancer models
We are expanding and characterizing our PDX collection (colorectal cancer, neuroendocrine cancer, and peritoneal pseudomyxoma), and optimizing their use in evaluating drug efficacy and metastasis by orthotopic injection and live imaging (positron emission tomography and computed tomography, and echography).

Lastly, we are developing ambitious projects through our participation in the EuroPDX, PERSIST-SEQ, CRCelerate, and PMP Accelerate European Consortia for studying cancer resistance and novel preclinical modelling.

----

* Puig I, Tenbaum SP, Chicote I, Arqués O, Martínez-Quintanilla J, Cuesta-Borrás E, Ramírez L, Gonzalo P, Soto A, Aguilar S, Eguizabal C, Caratù G, Prat A, Argilés G, Landolfi S, Casanovas O, Serra V, Villanueva A, Arroyo AG, Terracciano L, Nuciforo P, Seoane J, Recio JA, Vivancos A, Dienstmann R, Tabernero J, Palmer HG. TET2 controls chemoresistant slowcycling cancer cell survival and tumor recurrence. J Clin Invest. 2018 Aug 31;128(9):3887-3905. 

** Tenbaum SP, Ordóñez-Morán P, Puig I, Chicote I, Arqués O, Landolfi S, Fernández Y, Herance JR, Gispert JD, Mendizabal L, Aguilar S, Ramón y Cajal S, Schwartz S Jr, Vivancos A, Espín E, Rojas S, Baselga J, Tabernero J, Muñoz A, Palmer HG. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012 Jun;18(6):892-901. 

Puig I, Chicote I, Tenbaum SP, Arqués O, Herance JR, Gispert JD, Jimenez J, Landolfi S, Caci K, Allende H, Mendizabal L, Moreno D, Charco R, Espín E, Prat A, Elez ME, Argilés G, Vivancos A, Tabernero J, Rojas S, Palmer HG. A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells. Clin Cancer Res. 2013 Dec 15;19(24):6787-801. 

Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P, Lopez Lopez C, Garcia-Carbonero R, Hernando J, Matos I, Paolo N, Hernández-Losa J, Esteller M, Martínez-Cardús A, Tabernero J, Vivancos A, Palmer HG. Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas. Clin Cancer Res. 2020 Feb 15;26(4):902-909.

• Study the role of epigenetic factors governing tumor cell dormancy in chemoresistance, minimal residual disease, relapse, dissemination and metastasis.
• Support ONIRIA Therapeutics spin-off company for the development of novel therapies that modulate cell dormancy as a new strategy to combat cancer. 
• Develop small molecule modulators of cancer cell dormancy to block cancer progression.
• Unveil the mechanisms of response to therapies targeting the EGFR, BRAF, MEK, ERK, LGR5, Wnt, PARP or Hippo pathways.
• Refine and expand our collection of patient-derived xenograft (PDX) and advanced cancer models, and develop live imaging techniques.

• We have revealed key epigenetic factors governing cancer cell dormancy, hypoxia, chemoresistance and tumor recurrence, as well as developed effective small molecule drugs targeting some of these processes.
• Molecularly matched cancer therapies: our group has described relevant determinants of response to BRAF, MEK, Hippo, and Notch pathway inhibitors, demonstrated the efficacy of new rational drug combinations, and evaluated minimal residual disease in RET fusion-positive tumors.
• Advanced cancer models: in collaboration with several European-funded networks, we have generated and refined new preclinical models of colorectal cancer.

• ONIRIA Therapeutics spin-off company 

We are committed to consolidating our spin-off company for developing drug modulators of cancer cell dormancy as a novel strategy to combat cancer.
We have already selected a lead compound with a low toxicity profile that activates TET2 and blocks tumor growth in advanced mouse models of cancer. Our first-in-class drug is ready to enter the preclinical regulatory phase. For this ambitious project, we have set up a team of experts in all stages of drug development.
Importantly, given VHIO’s successful track record in launching spin-off companies, ONIRIA is based at VHIO. Our researchers are evaluating  first-in-class drugs in partnership with VHIO’s clinical investigators who have extensive expertise in early phase clinical studies.

• Revealing new drivers of cancer cell dormancy 

We aim to demonstrate the relevance of different epigenetic or transcription factors as master regulators of dormant tumor cells’ (DTC) distinctive phenotype. Specifically, our discovery of DPPA3 as a crucial factor in hypoxia and chemoresistance has opened many lines of investigation to explore its mechanisms of action and potential as a new drug target.
Supervised by our group’s senior investigators, our PhD students are currently  studying other drivers governing cancer cell dormancy. This research is technically complex and relatively unexplored. Making a significant contribution to better understanding cancer cell dormancy and chemoresistance is particularly challenging. We aim to identify new drug targets and biomarkers to seek out and eradicate DTC and reduce chemoresistance and the risk of disease relapse.

• Defining new effective therapies based on rational drug combinations

We have identified novel mechanisms of resistance to EGFR, BRAF, MEK, Wnt, Notch, RET, LGR5 or PARP inhibitors and will design and evaluate novel drug combinations that could benefit patients whose disease has progressed to first-line treatments. Based on the analyses of paired patients’ tumor samples and PDX models treated with matched therapies, this approach is already showing great promise.
We expect to report new insights into the mechanisms of action of some targeted drugs that will help guide oncologists to design and assess more precise and effective treatments. Within the framework of a recently granted EU IMI Innovative Medicines Initiative project, we will perform single cell multiomics analyses to evaluate drug resistance in our PDX models and fresh tissue samples from patients.

• Innovating preclinical cancer models 

One of our challenges is to integrate several imaging techniques (positron emission tomography and computed tomography (PET-CT) and echography) for the longitudinal evaluation of tumor growth in mice orthotopically implanted with patient-derived cells or genetically modified mouse models in response to new drug combinations. These comprehensive models could more faithfully recapitulate advanced disease in cancer patients, and therefore constitute a powerful tool in translating our laboratory results to the clinic.

• Cuesta-Borràs E, Salvans C, Arqués O, Chicote I, Ramírez L, Cabellos L, Martínez-Quintanilla J, Mur-Espinosa A, García-Álvarez A, Hernando J, Tejedor JR, Mirallas O, Élez E, Fraga MF, Tabernero J, Nuciforo P, Capdevila J, Palmer HG, Puig I. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype. Cell Rep. 2023 Aug 29;42(8):112927. 
• Puig I, Chicote I, Pálmer HG. Identifying Cell Differentiation in Colorectal Cancer. Methods Mol Biol. 2023;2650:227-233. 
• Martini G, Belli V, Napolitano S, Ciaramella V, Ciardiello D, Belli A, Izzo F, Avallone A, Selvaggi F, Menegon Tasselli F, Santaniello W, Franco R, Puig I, Ramirez L, Chicote I, Mancuso F, Caratu G, Serres X, Fasani R, Jimenez J, Ros J, Baraibar I, Mulet N, Della Corte CM, Troiani T, Vivancos A, Dienstmann R, Elez E, Palmer HG, Tabernero J, Martinelli E, Ciardiello F, Argilés G. Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer. ESMO Open. 2023 Jun;8(3):101198.
• Chicote I, Martínez-Quintanilla J, Cámara JA, Palmer HG. Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer. J Vis Exp. 2023 Feb 10;(192).

•  PERSIST-SEQ. Building a reproducible single-cell experimental workflow to capture tumour drug persistence. FINANCIAL ENTITY: IMI Program. Pharma Industry and UE (Horizon 2020-JTI-IMI2-2020-20-two-stage). Duration: 2021-2024. PI: Héctor G. Palmer.
• Targeting dormant tumor cells as a new strategy to fight cancer. PI20/00897. FINANCIAL ENTITY: Instituto de Salud Carlos III (ISCIII). Duration. 2021-2023. PI: Héctor G. Palmer.
• Tumor microenvironment-derived factors in localized colon cancer: clinical impact and therapeutic implications. FINANCIAL ENTITY: Fundación de la Asociación Española Contra el Cáncer (AECC). Duration: 2020-2024. PI: Héctor G. Palmer (Coordinator: Andrés Cervantes).
• Accelerator Award. Pseudomyxoma peritonei: building a European multicentric cohort to accelerate new therapeutic perspectives. FINANCIAL ENTITY: Cancer Research UK (CRUK), Asociación Española contra el Cancer (AECC) & Associazione Italina per la Ricerca sul Cancro (AIRC). Duration: 2019-2024. PI: Héctor G. Palmer. (Consortium Coordinator: Marcello Deraco).

1. Cuesta-Borràs E, Salvans C, Arqués O, Chicote I, Ramírez L, Cabellos L, Martínez-Quintanilla J, Mur-Espinosa A, García-Álvarez A, Hernando J, Tejedor JR, Mirallas O, Élez E, Fraga MF, Tabernero J, Nuciforo P, Capdevila J, Palmer HG, Puig I. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype. Cell Rep. 2023 Aug 29;42(8):112927. 
2.  Puig I, Chicote I, Palmer HG. Identifying Cell Differentiation in Colorectal Cancer. Methods Mol Biol. 2023;2650:227-233. 
3. Martini G, Belli V, Napolitano S, Ciaramella V, Ciardiello D, Belli A, Izzo F, Avallone A, Selvaggi F, Menegon Tasselli F, Santaniello W, Franco R, Puig I, Ramirez L, Chicote I, Mancuso F, Caratu G, Serres X, Fasani R, Jimenez J, Ros J, Baraibar I, Mulet N, Della Corte CM, Troiani T, Vivancos A, Dienstmann R, Elez E, Palmer HG, Tabernero J, Martinelli E, Ciardiello F, Argilés G. Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer. ESMO Open. 2023 Jun;8(3):101198.
4.  Chicote I, Martínez-Quintanilla J, Cámara JA, Palmer HG. Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer. J Vis Exp. 2023 Feb 10;(192).

• We have participated in the design of the BRAVE academic clinical trial that will start recruiting patients with BRAF-mutated colorectal cancer I 2024.