Programs & Groups

Please click on the corresponding programs below

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Joan Seoane

Director, Translational Research Program
Biosketch

“The secret behind the swift translation and application of cancer science and medicine is the two-way collaboration and dialect between researchers and clinical investigators in a multidisciplinary setting. It is thanks to our team science that translational and clinical research at VHIO are tightly connected, enabling us to deliver on the promise of precision medicine for an increasing number of our patients. Rapidly transforming cancer discovery into real benefits can and will only continue to happen through the pooling of expertise from bench to bedside and back.”

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VHIO's Translational Research Program promotes and accelerates the integration of preclinical and clinical research. By tackling cancer from all angles and establishing synergies between molecular and clinical cancer research, we rapidly translate scientific advances into benefits for our patients.

In our collective battle to solve cancer sooner, one of the major challenges we face is tumor diversity. Cancer is an extremely complex, heterogeneous, fluctuating and 'smart' disease given that tumors are molecularly diverse and evolve over time. Tumors are formed by cells with multifarious states of proliferation, differentiation, motility, and, importantly, varying sensitivity to anti-cancer medicines. Each individual patient consequently has a unique tumor with a particular combination of genomic aberrations that can alter during tumor progression. Patients should therefore be treated with the optimal compound/combination of therapies that more effectively target the specificities of their respective disease.

Selecting the most appropriate treatment depends on the specific molecular taxonomy of a particular tumor at a given time, and the challenge is therefore to identify which treatment should be precisely matched to which patient and in so doing, further advance personalized medicine in oncology. To potentiate cancer therapies through the combination of compounds targeting all cell types within a tumor, we must achieve a deeper understanding of the nature of intratumoral heterogeneity.

Among the different cell types forming intratumoral heterogeneity, some cells with stem cell characteristics have been identified. Known as Cancer-Initiating Cells (CICs), or Cancer Stem Cells (CSCs), they are characterized by their self-renewing capacity, multi-lineage differentiation properties, high oncogenic potential, and ability to replicate the heterogeneity of original human tumors in mouse models. CICs are also responsible for the initiation, recurrence and chemo- and radio-resistance of tumors indicating that more effective therapies could be identified via strategies targeting the stem-cell-like component of tumors. To-date, few pharmacological compounds have proven successful.

To explore the two levels of cancer heterogeneity, we investigate cancer as closely as possible to the actual tumor and generate patient-derived in vitro and in vivo cancer models. Tumor specimens are obtained shortly upon surgical resection and we study their respective tumor cells and cancer stem cells. We then develop mouse models that recapitulate the characteristics of patients' tumors as faithfully as possible.

Both VHIO's Stem Cells & Cancer Group led by Héctor G. Palmer, and my own Gene Expression & Cancer Group, have developed these models for brain and colon cancer respectively; work which has led to important publications in top-tier journals. Providing optimal therapy tailored to individual patients relies on teamwork, studying cancer as closely as possible to the actual patient, and collectively tackling cancer heterogeneity head-on. VHIO's Translational Research Program is committed to delivering on the promise of precision medicine in oncology by catalyzing the transfer of new insights generated by cancer research into true benefits for patients.

In 2017, Héctor's Group has explored novel strategies to combat slow-cycling cancer-initiating cells and discovered new therapeutic targets that can be used to develop anti-cancer compounds. Moreover, they have identified biomarkers to more precisely stratify patients for enrollment in clinical trials performed at out Hospital, and have shed light on the molecular mechanisms implicated in the Wnt pathway.

My own group has developed novel and barely invasive liquid biopsies to disentangle the complexity and heterogeneity of brain tumors. The analysis of ctDNA in cerebrospinal fluid has opened new avenues for research aimed at achieving a better understanding of central nervous system cancers. We have also generated insights into the TGF-beta pathway as an effective therapeutic target. Finally, we have developed an anti-cancer drug, MSC1, in close collaboration with VHIO spin-off company Mosaic Biomedicals. MSC1, a humanized LIF neutralizing antibody, will be tested in clinical trials in early 2018.

As VHIO embarks on its second decade of Translation toward precision oncology, we can rightly expect to mark many more breakthroughs in ultimately improving outcomes for those who matter most – our patients.

Translational Research Groups

Please click on the corresponding groups below

Gene Expression & Cancer
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Joan Seoane
Principal Investigator
Stem Cells & Cancer
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Héctor G. Palmer
Principal Investigator

Gene Expression & Cancer Group

Imagen

Principal Investigator
Joan Seoane

Post-Doctoral Fellows
Ester Bonfill
Raffaella Iurlaro
Regina Mayor
Josep Lluis Parra-Palau
Monica Pascual
Ester Planas
Ada Sala

Graduate Student
Ester Arroba

Technicians
Alexandra Arias
Isabel Cuartas
Carolina Raventós
Cristina Sánchez

SUMMARY

Our group focuses on the study of brain tumors: primary tumors and brain metastasis. These are some of the most aggressive cancers and advancing progress within this field is consequently crucial.

In brain tumors, as in many other malignancies, evolving heterogeneity represents one of the most important challenges that are currently hampering our efforts aimed at more effectively treating cancer. We are studying genomic heterogeneity at the level of genomic alterations.

Tumors are composed of a mosaic of cell subclones that differ in their genomic alterations. We explore this genomic diversity present in glioblastoma and are analyzing intratumor genomic heterogeneity as it evolves over time in response to therapy. Following Darwinian selection rules, the cellular subclones enriched in response to treatment are those that will confer resistance and facilitate the identification of novel therapeutic targets to counter tumor resistance and relapse.

We have identified some of the candidate genes responsible for disease recurrence and are designing therapeutic approaches to prevent the reappearance of brain tumors. Moreover, in order to track, assess and better understand their evolving genomic heterogeneity, we are studying cell-free circulating tumor DNA in fluids from patients with brain tumors. Tumors shed DNA into the blood stream and the sequencing of this circulating DNA enables the accurate, less invasive molecular characterization of tumors, and these blood-based markers facilitate a more precise diagnosis, monitoring and identification of actionable gene mutations.

Finally, we study the role of the tumor microenvironment which, in the case of brain cancers, plays a critical role in cancer progression. Tackling the tumor microenvironment might be a way of attacking cancer independently of its heterogeneity. By eliminating the niche where cancer resides and thrives should help us to develop more effective anti-cancer compounds.

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Figure: Studying brain tumors from all angles.

STRATEGIC GOALS

  • Identify both new therapeutic targets against brain tumors as well as novel biomarkers to more precisely predict response to therapy.
  • Study intratumor heterogeneity.
  • Investigate the tumor microenvironment.
  • Develop methods for non-invasive molecular diagnosis through the study of circulating biomarkers.
  • Generate patient-derived mouse models of brain tumors.

HIGHLIGHTS

  • Translating our discoveries into a clinical trial. Our efforts during 2017 have led to an IND submission, and next year will result in a novel compound for the treatment of cancer patients, designed and developed in our lab with the spin off company derived from our group; Mosaic Biomedicals in partnership with Northern Biologics Inc. (Toronto, Canada).

PI PAPER PICK (full list for 2017 below)

Seoane J. Division hierarchy leads to cell heterogeneity. Nature. 2017 Sep 14;549(7671):164-166.

Huber-Ruano I, Raventos C, Cuartas I, Sánchez-Jaro C, Wosikowski K, Janicot M, Seoane J. An Antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages. Ann Oncol. 2017 Sep 1;28(9):2278-2285

Seoane J, Gomis RR. TGFβ Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb Perspect Biol. 2017 Dec 1;9(12).

Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Apr;17(4):254-268.

HORIZONS 2018

  • Better understand genomic heterogeneity.
  • Identify novel therapeutic targets against brain tumors.
  • Advance insights into the brain tumor microenvironment.
  • Develop and translate methods for non-invasive characterization of brain tumors (liquid biopsy) into clinical practice.

PUBLICATIONS

  1. Yates LR, Seoane J, Le Tourneau C, Siu LL, Marais R, Michiels S, Soria JC, Campbell P, Normanno N, Scarpa A, Reis-Filho J, Rodon J, Swanton C, AndreF. The European Society of Medical Oncology (ESMO) Precision Medicine Glossary. Ann Oncol. 2017 Nov 13.
  2. Seoane J. Division hierarchy leads to cell heterogeneity. Nature. 2017 Sep 14;549(7671):164 166.
  3. Huber-Ruano I, Raventos C, Cuartas I, Sánchez-Jaro C, Wosikowski K, Janicot M,Seoane J.An Antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages. Ann Oncol. 2017 Sep 1;28(9):2278-2285
  4. Seoane J, Gomis RR. TGFβ Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb Perspect Biol. 2017 Dec 1;9(12).
  5. Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Apr;17(4):254-268.

PROJECTS

  • Grantor:Fundación Científica de la AECC
    Title: Study of the molecular mechanisms involved in primary (glioblastoma) and secondary (metastasis) brain tumors to identify novel therapeutic targets and anti-cancer agents, biomarkers to select treatments and novel non-invasive methods for molecular diagnosis.
    Project Reference: GCTRA16015SEDA
    Role in the Project: Principal Investigator | 2017-2022
  • Grantor: IBEC-La Caixa
    Title: Understanding and measuring mechanical tumor properties to improve cancer diagnosis. treatment, and survival: Application to liquid biopsies
    Project Reference:
    Role in the Project: Principal Investigator | 2017-2020
  • Grantor: Institute of Health Carlos III – FIS (Ministry of Science and Innovation-MICINN)
    Title:Identificación de mecanismos de resistencia a tratamiento a través del estudio de la heterogeneidad intra-tumoral en glioblastoma
    Project Reference: Ref. PI16/01278
    Role in the project: Principal Investigator | 2017-2019
  • Grantor: Institute of Health Carlos III – FIS (Ministry of Science and Innovation-MICINN)
    Title: CIBER – Área Temática:  Characterization and therapeutic use of stem cells and organoids in cancer
    Project Reference: Ref. CB16/12/00450
    Role in the project: Principal Investigator |2017-2018
  • Grantor: FERO
    Title: Caracterización molecular de los tumores cerebrales pediátricos mediante el estudio del DNA circulante en sangre y líquido cefalorraquídeo
    Role in the project: Principal investigator |2015-2018
  • Grantor: MINECO-RETOS
    Title: Desarrollo de un fármaco innovador y personalizado para el tratamiento del cáncer que reactiva el sistema inmune contra el tumor y elimina las células madre tumorales
    Project Reference: RTC-2015-3771-1
    Role in the project: Principal Investigator |2015-2018
  • Grantor: Ridgeline Therapeutics, GmbH
    Title: Test Ridgeline compounds in VHIO's PDX model and molecular characterization of HNSCC tissue samples.
    Principal Investigator: Joan Seoane |2017-2019

AWARDS

  • Elected Member of the European Academy of Cancer Sciences (EACS).

Stem Cells & Cancer Group

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Principal Investigator
Héctor G. Palmer

Post-Doctoral Fellows
Oriol Arqués
Jordi Martínez-Quintanilla
Isabel Puig

Graduate Student
Estefania Cuesta

Technicians
Irene Chicote
Lorena Ramírez

SUMMARY

We aim to better understand the molecular mechanisms that confer tumors the capacity to self-renew, resist therapy, relapse and metastasize – all definitive factors in the survival of patients. We are dedicated to studying the consequences of intratumoral cell heterogeneity for tumor evolution and patient survival. Among the various cell populations that construct heterogeneous tumors, Cancer Stem Cells (CSC) are at the apex of a differentiation process within the cancerous tissue -- somewhat reminiscent of the hierarchy present in the normal tissue from which they originate. CSC can also compose the small reservoir of drug-resistant cells that trigger relapse after chemotherapy-induced remission, or give rise to distant metastasis. It is therefore becoming increasingly evident that the failure to eradicate cancer stem cells can promote tumor regrowth.

Our studies mainly focus on colorectal cancer. At molecular level we are analyzing the role of oncogenic pathways controlling the fate of Colon Cancer Stem Cells (CoCSC). RAS/PI3K/AKT, Wnt/beta-catenin and Notch pathways are drivers of cancer stem cell fate and lead to disease progression in many tumor types. Over recent years we have described a novel mechanism of resistance to PI3K and AKT inhibitory drugs conferred by beta-catenin in colorectal cancer. This is of great relevance since many patients in clinical studies do not respond to these therapies, and no molecular explanation behind such resistance had previously been described.

Our findings will facilitate the selection of ‘sensitive’ patients based on their expression of particular biomarkers predicting drug-response. We are currently focusing on a new generation of EGFR, Wnt/beta-catenin and Notch inhibitors in close collaboration with several major pharmaceutical companies, and have already experimentally evidenced the efficacy and mechanisms of action of these drugs in pre-clinical models of colorectal cancer with patient-derived xenografts. This marks an important milestone within the field; for decades colorectal cancer had been described as a paradigmatic tumor addicted to the oncogenic Wnt/beta-catenin pathway.

We also seek to identify the molecular determinants of response to these anti-cancer therapies that could consequently become robust biomarkers for the selection of ‘sensitive’ patients as well as better guide the design of future clinical trials. Some of these predictive biomarkers are mutations affecting components of the Wnt/beta-catenin pathway, whose identification can be perfectly standardized in clinical practice for patient selection.

Our collaboration with the Vall d'Hebron University Hospital's Medical Oncology Department, led by Josep Tabernero, as well as partnerships with pharmaceutical companies, will accelerate the translation of our findings into clinical practice, and hopefully revert the long-stalled scenario of CRC drugs.

Our group has developed a collection of PDX models derived from primary tumors or liver metastasis of more than 150 CRC patients. Most recently, we have also generated around 50 clinical trial associated xenografts (CTAX) from patients enrolled in these studies. During this past year we have also been developing translational research projects focusing on lung cancer, hepatocarcinomas and neuroendocrine tumors. We are generating PDX models, evaluating mechanisms of drug action, treatment resistance and sensitivity to novel therapeutic strategies tested in clinical trials.

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Figure: Labeling dormant tumor cells. A. Lentivirus to label slow cycling cancer cells. B. Cells with chromatin labeled with H2BeGFP. C. Tumor organoid labeled with H2BeGFP to identify slow cycling cancer cells resistant to chemotherapy. D. A pulse chase labelling marks slow cycling cancer cells with low proliferation and differentiation and high self-renewal.

STRATEGIC GOALS

  • Describe key molecular mechanisms that confer CSC their capacity to self-renew and resist conventional or target-directed therapies.
  • Unmask molecular drivers of CSC quiescence, clinical relevance in cancer progression and evaluate their potential inhibition to eradicate CSC.
  • Study the efficacy and mechanism of action of new Wnt/ beta-catenin, Notch and EGFR inhibitory drugs for the treatment of CRC, lung or neuroendocrine tumors.
  • Identify the genetic determinants of sensitivity or resistance to the novel generation of EGFR, Notch and Wnt/beta-catenin inhibitors.
  • Implement predictive biomarkers of response to therapeutic EGFR, Notch and Wnt/beta-catenin inhibitors and other targeted therapies.
  • Expand our collection of PDX models and start working on those derived from other tumor types.

HIGHLIGHTS

  • We have unmasked the molecular mechanisms governing the delicate link between stemness and quiescence in chemo-resistant colon cancer cells. Many genes and proteins playing a central role in this process are epigenetic chromatin remodelers. Their activity could potentially be inhibited as a new therapeutic approach to eliminating slow-cycling cancer-initiating cells. These molecular mechanisms are common in several solid tumors (CRC, breast, lung, melanoma, glioblastoma).
  • Identification of a biomarker and a drug target to identify and eliminate slow-cycling cancer-initiating cells. Both could become essential tools in improving patient survival and reducing disease relapse.
  • We have accumulated evidence surrounding the efficacy and mechanisms of action of a novel generation of Wnt/ beta-catenin inhibitory drugs on CRC and identified biomarkers to predict response to these inhibitors.
  • We have revealed new molecular mechanisms behind the response of advanced lung cancer patients to novel target-directed therapies.

PI PAPER PICK (full list for 2017 below)

Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumägi A, Arjama M, Danielsen SA, Kryeziu K, Elez E, Tabernero J, Guinney J, Palmer HG, Nesbakken A, Kallioniemi O, Dienstmann R, Lothe RA. Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. Clin Cancer Res. Epub 2017 Dec 14.

Martinez-Marti A, Felip E, Matito J, Mereu E, Navarro A, Cedrés S, Pardo N, Martinez de Castro A, Remon J, Miquel JM, Guillaumet-Adkins A, Nadal E, Rodriguez-Esteban G, Arqués O, Fasani R, Nuciforo P, Heyn H, Villanueva A, Palmer HG, Vivancos A. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2017 Oct 1;28(10):2451-2457.

Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Sep 15;17(10):632.

Dienstmann R, Elez E, Argiles G, Matos I, Sanz-Garcia E, Ortiz C, Macarulla T, Capdevila J, Alsina M, Sauri T, Verdaguer H, Vilaro M, Ruiz-Pace F, Viaplana C, Garcia A, Landolfi S, Palmer HG, Nuciforo P, Rodon J, Vivancos A, Tabernero J. Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights. Mol Oncol. 2017 Sep;11(9):1263-1272.

PUBLICATIONS

  1. Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumägi A, Arjama M, Danielsen SA, Kryeziu K, Elez E, Tabernero J, Guinney J, Palmer HG, Nesbakken A, Kallioniemi O, Dienstmann R, Lothe RA. Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. Clin Cancer Res. Epub 2017 Dec 14.
  2. Martinez-Marti A, Felip E, Matito J, Mereu E, Navarro A, Cedrés S, Pardo N, Martinez de Castro A, Remon J, Miquel JM, Guillaumet-Adkins A, Nadal E, Rodriguez-Esteban G, Arqués O, Fasani R, Nuciforo P, Heyn H, Villanueva A, Palmer HG, Vivancos A. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2017 Oct 1;28(10):2451-2457.
  3. Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Sep 15;17(10):632.
  4. Dienstmann R, Elez E, Argiles G, Matos I, Sanz-Garcia E, Ortiz C, Macarulla T, Capdevila J, Alsina M, Sauri T, Verdaguer H, Vilaro M, Ruiz-Pace F, Viaplana C, Garcia A, Landolfi S, Palmer HG, Nuciforo P, Rodon J, Vivancos A, Tabernero J. Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights. Mol Oncol. 2017 Sep;11(9):1263-1272.

PROJECTS

  • Grantor: Instituto de Salud Carlos III
    Title: Hipermutant colorectal cancer.
    Principal Investigator: Héctor G. Palmer
    Duration: 2017 – 2021
  • Grantor: Cellestia biotech
    Title: Notch inhibition in Colorectal cancer.
    Principal Investigator: Héctor G. Palmer
    Duration: 2017 - 2018
  • Grantor: MERUS
    Title: Anti-LGR5/EGFR bi-specific antibodies for the treatment of mCRC.
    Principal Investigator: Héctor G. Palmer
    Duration: 2016 – 2018
  • Grantor: TRANSCAN. European Commission – Instituto de Salud Carlos III
    Title: TArgeting Colon Tumor Initiating Cell heterogeneity – TACTIC.
    Principal Investigator: Dr. Héctor G. Palmer
    Duration: 2015 - 2017
  • Grantor: Novartis International AG
    Title: New drugs to target the oncogenic Wnt/beta-catenin pathway (CIBOT).
    Principal Investigator: Héctor G. Palmer
    Duration: 2013 - 2016
  • Grantor: Instituto de Salud Carlos III
    Title: Inhibición terapéutica de la ruta oncogénica Wnt/beta-catenina en cáncer colorectal (PI14/00103).
    Principal Investigator: Héctor G. Palmer
    Duration: 2015 - 2017
  • Grantor: Fundación de la Asociación Española Contra el Cáncer (AECC)
    Title: inhibición terapéutica de la ruta oncogénica Wnt/beta-catenina en cáncer colorectal.
    Principal Investigators: Stephan Tenbaum & Héctor G. Palmer
    Duration: 2015 – 2018
  • Grantor: European Commission. MARIE SKŁODOWSKA-CURIE ACTIONS
    Title: Therapeutic inhibition of the oncogenic Wnt/beta-catenin pathway in mismatch repair deficient hypermutant tumors.
    Principal Investigators: Jordi Martínez & Héctor G. Palmer
    Duration: 2016-2018