Programs & Groups

Please click on the corresponding programs below

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Joaquín Arribas

Director, Preclinical Research Program
Biosketch

“With emphasis on a multidisciplinary and collaborative approach to research, our expert preclinical groups continue to develop, pioneer and finely tune cancer models as critical tools to identify factors that influence tumor growth, predict cancer progression and response to certain treatments. We consequently strive to empower predictive science for the development of the next generation of precise anti-cancer therapies.”

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Preclinical research at VHIO focuses on establishing how highly aggressive tumors affecting the breast, pancreas, colon, lung, or brain can be treated more precisely and potently. Some of these cancers are highly prevalent and are either ultimately resistant to therapy, having worked for a limited period of time, or lack effective therapeutic avenues, resulting in poor prognosis. Our main goal is to investigate novel anti-cancer treatment approaches for these patients and unmask mechanisms of resistance to the array of currently available cancer medicines.

To deliver on this ambition, VHIO's Mouse Models of Cancer Therapies led by Laura Soucek has developed a novel therapeutic strategy centered on Myc inhibition based on peptides that enter the cell and block this particular oncogene that is activated in the majority of cancers. This novel approach has been recognized through several grants, including those awarded by the European Commission and several national agencies. Of note, the development of the new therapeutic strategy developed by Laura through Peptomyc S.L.- a VHIO-born biopharmaceutical spin-off company that she co-founded in 2014, has been awarded a NEOTEC and an APC grant from the Ministry of Economy, Innovation and Competitiveness. Further, Laura has been selected by EIT Health as Role Model for the project Empowering Women Entrepreneurship in Health, Innovation and Competitiveness.

Our Experimental Therapies Group headed by Violeta Serra continues to advance insights into the mechanism of action and resistance to targeted therapy in breast cancer, with special emphasis on the blockade of the PI3K and CDK4/6 to overcome endocrine resistance, as well as treatments targeting FGFR1 and cells with homologous recombination deficiency. Her group has developed a novel organoid culture model that facilitates research into anticancer drug activity as well as a comprehensive collection of breast cancer patient-derived xenografts (PDX) harboring FGFR1/4 amplification or BRCA1/2 mutations. These and similar models have been instrumental to the publication of relevant articles in top-tier journals including Nature and Nature Communications.

VHIO's Tumor Biomarkers Group led by Josep Villanueva has continued to redirect its main research focus to explore novel mechanisms of tumor progression by non-classical secretion. This switch has attracted funding from the Susan G. Komen Foundation, Instituto de Salud Carlos III (Institute of Health Carlos III - ISCIII), as well as the pharmaceutical company Servier. This has led to the recruitment of additional lab members to further expand his group. More specifically, Josep's team has transitioned from studying the cancer secretome following a methodology-driven approach to a more biologically-focused one, where non-classical secretion pathways play an important role. They will consequently continue to extend their studies to characterizing the non-classical secretome linked to tumor invasion and metastasis.

Finally, my own Growth Factors Group has continued to characterize a subtype of breast cancer known as HER2. We have developed a novel therapy to treat these tumors based on the recruitment of cytotoxic lymphocytes by a bispecific antibody. This antibody binds to a tumor specific antigen, p95HER2 and to the CD3 subunit of the T cell receptor. Importantly, to test its efficacy we have implemented humanized mouse models in which we recapitulate the interplay between the tumor and immune system. In addition, using the panel of pancreatic cancer patient-derived xenogratfs generated over the last few years, we have characterized the mechanism of primary resistance to anti-Mek inhibitors. We are currently finalizing our identification of factors that mediate this resistance.

In recognition of our efforts, we continue to receive essential support through international and national competitive grants from the European Commission, Breast Cancer Research Foundation (BCRF), Instituto de Salud Carlos III, FERO Foundation, and the Spanish Association Against Cancer (AECC). I am also proud to report that at the beginning of 2017, I was appointed as Scientific Director of CIBERONC - the largest network of cancer research groups in Spain.

In 2017, our groups' findings have been published in several journals of excellence including Nature, Nature Communications, Nature Reviews in Cancer, Cancer Research, Clinical Cancer Research, Oncogene, Oncotarget, Oncoscience, among others.

Preclinical Research Groups

Please click on the corresponding groups below

Experimental Therapeutics
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Violeta Serra
Principal Investigator
Growth Factors
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Joaquín Arribas
Principal Investigator
Mouse Models Of Cancer Therapies
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Laura Soucek
Principal Investigator
Tumor Biomarkers
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Josep Villanueva
Principal Investigator

Experimental Therapeutics Group

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Principal Investigator
Violeta Serra

Medical Oncologists
Cristina Cruz
Jordi Rodón

Post-Doctoral Fellows
Albert Gris-Oliver
Alba Llop-Guevara
Marta Palafox

Masters Student
Laia Monserrat

Graduate Students
Marta Castroviejo-Bermejo
Judith Llena
Mònica Sánchez-Guixé

ESMO Translational Research Fellow
Benedetta Pellegrino

Technicians
Judit Grueso
Marta Guzmán
Mireia Parés
Olga Rodríguez

SUMMARY

VHIO's Experimental Therapeutics Group conducts bench-to-bedside preclinical research in breast cancer to advance insights into targeted-therapeutics response biomarkers. We have significantly contributed to the field of PI3K inhibitor resistance by firstly evidencing that an adaptive response activating the MEK/ERK pathway through receptor tyrosine kinase upregulation bypasses the PI3K-survival pathway and mediates resistance to PI3K inhibitor. Secondly, we have identified that RSK, a MEK/ERK downstream kinase limits the activity of dual PI3K/mTOR inhibitors partly through the attenuation of apoptotic response and upregulation of protein translation.

Our group has also identified PI3K-pathway activation downstream of PI3K, via upregulation of mTORC1, as a mechanism of resistance to PI3K inhibitors. To advance our understanding of novel therapeutic strategies in breast cancer, we are exploring the mode of action and mechanisms of resistance to CDK4/6 inhibitors (drug combinations with PI3K inhibitors and hormone therapy) in endocrine-resistant breast tumors. Using clinically relevant patient-derived tumor xenografts we have established that loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 or CCND1-amplification, is associated with lack of response to CDK4/6 blockade in estrogen receptor positive breast cancer PDX. The addition of a PI3Kalpha inhibitor improved and prolonged disease control in all experimental models analyzed.

Encouraged by the early success of DNA damage repair inhibitors in germline BRCA1/2 tumors, we have initiated a project aimed at identifying response biomarkers of PARP inhibitors (PARPi) and DNA binding agents including PM01183, a novel derivative of trabectedine, in homologous recombination repair (HRR) deficient tumors. Our studies underpin the capacity of germline BRCA mutant tumors to recover HR functionality and develop resistance to PARPi. The RAD51 assay can identify which germline BRCA tumors have restored HRR functionality, as well as tumors that are sensitive to PARPi through HRR alterations beyond the germline BRCA condition.

In short, our group has significantly improved the understanding of the mode of action of novel targeted therapies, identified new response biomarkers, and demonstrated the efficacy of hypothesis-based drug combinations.

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Figure: Antitumor and antiproliferative activity of the CDK4/6 inhibitor ribociclib in patient derived models. A) In vivo analysis of tumor growth or regression upon treatment with ribociclib during 35 days (75mg/kg, 6 days/week). B) Analysis of ex vivo cultures treated with ribociclib for 7 days and categorized according to the in vivo response shown in panel A.

STRATEGIC GOALS

  • Developing predictive biomarkers of PI3K-pathway, CDK4/6, FGFR and PARP inhibitors in ER+ and TN breast cancers.
  • Exploring novel treatment combinations for ER+ and TN breast cancers.
  • Unveiling novel mechanisms of resistance against targeted therapies in germline BRCA1/2 breast cancer.
  • Establishing a patient tumor-derived breast cancer preclinical model to explore hypothesis-based combinatorial therapies.

HIGHLIGHTS

  • We have established an organoid culture model that enables us to assess the activity of CDK4/6 inhibitors and recapitulates the in vivo response (Figure).
  • DK4/6 inhibitor sensitive PDX exhibit pRb expression and loss of p16. We have validated overexpression of cyclin D1/2 as a resistance biomarker.
  • We have established that the lack of RAD51 nuclear foci formation, a functional biomarker of homologous recombination deficiency, correlates with PARP inhibitor response in a panel of over 50 PDX and a dozen of clinical samples.
  • We have established a panel of 13 BC PDXs harboring FGFR1/4 amplification and another composed of 22 PDXs derived from BRCA1/2 mutation carriers.

PI PAPER PICK (full list for 2017 below)

Méndez-Pertuz M, Martínez P, Blanco-Aparicio C, Gómez-Casero E, Belen García A, Martínez-Torrecuadrada J, Palafox M, Cortés J, Serra V, Pastor J, Blasco MA. Modulation of telomere protection by the PI3K/AKT pathway. Nat Commun. 2017 Nov 2;8(1):1278.

Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, (…), Serra V, (…), Carracedo A. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature. 2017 Jul 6;547(7661):109-113.

Hierro C, Alsina M, Sánchez M, Serra V, Rodon J, Tabernero J. Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall? Ann Oncol. 2017 Jun 1;28(6):1207-1216.

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 Interrogating open issues in cancer precision medicine with Patient-Derived Xenografts. Nat Rev Cancer. 2017 Apr; 17(4):254-268.

HORIZONS 2018

  1. Identification of response and resistance biomarkers to PI3K/AKT, FGFR and CDK4/6 inhibitors in breast cancer.
  2. Unveil genetic and epigenetic mechanisms of acquired resistance to PARP inhibitors in hereditary BRCA1/2 breast cancer and beyond; e.g. by means of other HRR alterations in other diseases such as prostate cancer.
  3. 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 PARP inhibitors.

PUBLICATIONS

  1. Méndez-Pertuz M, Martínez P, Blanco-Aparicio C, Gómez-Casero E, Belen García A, Martínez-Torrecuadrada J, Palafox M, Cortés J, Serra V, Pastor J, Blasco MA. Modulation of telomere protection by the PI3K/AKT pathway. Nat Commun. 2017 Nov 2;8(1):1278.
  2. Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, (…), Serra V, (…), Carracedo A. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature. 2017 Jul 6;547(7661):109-113.
  3. Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall? Hierro C, Alsina M, Sánchez M, Serra V, Rodon J, Tabernero J. Annals of Oncology. 2017 Jun 1;28(6):1207-1216.
  4. Resistance to Taxanes in Triple-Negative Breast Cancer Associates with the Dynamics of a CD49f+ Tumor-Initiating Population. Gómez-Miragaya J, Palafox M, Paré L, Yoldi G, Ferrer I, Vila S, Galván P, Pellegrini P, Pérez-Montoyo H, Igea A, Muñoz P, Esteller M, Nebreda AR, Urruticoechea A, Morilla I, Pernas S, Climent F, Soler-Monso MT, Petit A, Serra V, Prat A, González-Suárez E.  Stem Cell Reports. 2017 May 9;8(5):1392-1407.
  5. Interrogating open issues in cancer precision medicine with Patient-Derived Xenografts. Byrne et al (41 authors including Serra V). Nat Rev Cancer. 2017 Apr; 17(4):254-268.
  6. Lim E, Johnson SF, Geyer M, Serra V, Shapiro GI. Sensitizing HR-proficient cancers to PARP inhibitors. Mol Cell Oncol. 2017 Mar 3;4(6):e1299272.

PROJECTS

  • Project Title: Targeted agents against PARP, WEE1, ATR and ATM in TNBC: mechanisms of action, biomarkers of sensitivity and immunomodulation(PI17/01080).
    Principal Investigator: Violeta Serra
    Funding Agency: ISCIII
    Duration: 2018-2020
  • Project Title: New predictive factors of response to targeted therapies and prognostic factors in breast cancer with germline mutations in BRCA1 and BRCA2: DNA damage repair capacity and tumor immunological profile(LABAE16020PORT).
    Principal Investigator: Violeta Serra
    Funding Agency: AECC (Spanish Association Against Cancer)
    Duration: 2018-2020
  • Project Title: Targeting PI3K and CDK4/6 in breast cancer: Integrative Biomarkers of Response (CCR15330331).
    Principal Investigator: Violeta Serra
    Funding Agency: Susan G. Komen Foundation
    Duration: 2015-2018
  • Project Title: Targeting PI3K and CDK4/6 in breast cancer (CP14/00028).
    Principal Investigator: Violeta Serra
    Funding Agency: ISCIII (Spanish Ministry of Health)
    Duration: 2015-2019
  • Project Title: Clinical utility of tumor heterogeneity in triple negative breast cancer and high-grade serous ovarian carcinoma for prediction of therapy response (TH4RESPONS).
    Research Partner PI: Violeta Serra. Consortium coordinator: Manfred Dietel
    Funding Agency: ERA-NET
    Duration: 2016-2019
  • Project Title: Deciphering PI3K biology in health and disease (PhD)
    Research Partner PI: Violeta Serra and Jordi Rodón. Consortium coordinator: Mariona Graupera
    Funding Agency: European Commission
    Duration: 2016-2019

AWARDS

Growth Factors Group

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Principal Investigator
Joaquín Arribas

Scientific Manager
Cristina Bernadó

Medical Oncologist
César Serrano

Post-Doctoral Fellows
Enrique Javier Arenas
Cristina Bernadó
Beatriz Morancho
Mercedes Nadal
Bhavna Rani
Veronica Rodilla

Masters Student
Rita Casas

Graduate Students
Faiz Bilal
Luis Alfonso Garcia
Irene Rius
Junjie Zhang

Technicians
Marta Escorihuela
Antoni Luque
David Olivares
Jordi Rosell
Ismael Varela

SUMMARY

During 2017 our group has consolidated and expanded our platform of breast and pancreatic cancer patient-derived experimental models, which is key to unravelling mechanisms of resistance to anti-tumor therapies and developing novel immune-based strategies.

Our breast cancer models have been instrumental in several collaborations. With groups from the Centro Investigación del Cáncer (Salamanca, Spain), Hospital del Mar (Barcelona, Spain) and the Virginia Commonwealth University (Richmond, USA), we have described three novel mechanisms of resistance to drugs directed against the receptor tyrosine kinase HER2, a potent oncogene overexpressed in ~20 % of breast and gastric cancers (Rios Luci et al. 2017; A Sabbaghi et al. 2017; Floros et al. 2018). These mechanisms will help to refine current therapies against these cancer subtypes as well as generate novel and more effective anti-HER2 therapies.

In collaboration with groups from CABIMER (Centro Andaluz de Biología Molecular y Medicina Regenerativa - Andalusian Molecular Biology and Regenerative Medicine Centre, Seville, Spain) we have shown that p95HER2, an overactive fragment of HER2, sensitizes cells to apoptosis. This discovery opens up new avenues in developing novel therapies against p95HER2-positive tumors, which are particularly aggressive (Martín-Pérez, R. et al. 2017).

Finally, in collaboration with colleagues from the Institut de Recerca Biomédica de Barcelona (IRBB), our patient-derived models have be used to characterize the mechanism behind metastatic dormancy in breast cancer (Gawrzak, S et al. 2018).

A distinctive feature of our patient-derived experimental platform is that it facilitates the study of the interplay between the immune system and cancer cells. We have implemented co-cultures of lymphocytes and cancer cells donated by the same patients to model anti-tumor immunotherapies, as well as the humanization of mice that carry patient-derived tumor grafts with human hematopoietic cells. These models have been used to activate effector lymphocytes with anti-tumor activity by DNA-demethylating drugs (Loo Yau et al. –under review, pre-published in bioRxiv, 2017). As a reflection of our expertise in these models, we were invited to write the section on humanized mouse models in a recent and authoritative review on patient-derived xenografts (Byrne et al. 2017).

Regarding our more recent collection of pancreatic patient-derived xenografts, these models have been key to analyzing the efficacy of novel therapies using regimes that most closely resemble the treatments patients have received in the clinic. By adopting this mouse hospital concept, we have evidenced that a subset of pancreatic cancers are sensitive to inhibitors of a serine threonine kinase known as Mek; however, after an initial response tumors became resistant due to the proliferation of pre-existing resistant tumor cells (Pedersen et al. 2017).

Our highly collaborative approach has allowed us to participate in several large-scale projects funded by the European Union including EDIReX, an infrastructure for research into patient-derived cancer xenografts, and COLOSSUS, a collaborative project to study colon cancer, in which we will develop humanized mouse models. In addition, we are extremely grateful to both the Spanish Association Against Cancer (AECC), and the Breast Cancer Research Foundation (BCRF), for their continued funding and support.

Lastly, it has been an extremely productive year for the Centro de Investigación Biomédica en Red (CIBER-ONC: Center for the Biomedical Research Network in Oncology). This new network is comprised of several of the most active cancer research groups across Spain, including three groups from VHIO.

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Figure: A) p95HER2-TCB bispecific antibody that binds to bivalently to p95HER2 and monovalently to the CD3ε of the T-Cell receptor. B) Mechanism of action of p95HER2-TCB. The bispecific establishes a contact between cancer cells and lymphocytes inducing the killing of the former by the latter.

STRATEGIC GOALS

  • Development of novel therapeutic strategies for the treatment of HER2-positive tumors and identify mechanisms of resistance to current therapies.
  • Preclinical characterization of T cell bispecific antibodies (TCBs) against HER2 positive tumors.
  • Characterization of the role of premature senescence in breast cancer progression and treatment.
  • To evaluate the activity of novel anti-cancer therapies in our panels of breast and pancreatic cancer patient-derived xenografts.

HIGHLIGHTS

  • Identification of several novel mechanisms of resistance against anti-HER2 therapies in breast cancer.
  • Development of our platform of patient-derived models for immuno-oncology.
  • Discovery of a mechanism of resistance against targeted therapies in pancreatic cancer.

PI PAPER PICK (full list for 2017 below)

Ríos-Luci C, García-Alonso S, Díaz-Rodríguez E, Nadal-Serrano M, Arribas J, Ocaña A, Pandiella A. Resistance to the Antibody-Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity. Cancer Res. 2017 Sep 1;77(17):4639-4651.

Sabbaghi M, Gil-Gómez G, Guardia C, Servitja S, Arpí O, García-Alonso S, Menendez S, Arumi-Uria M, Serrano L, Salido M, Muntasell A, Martínez-García M, Zazo S, Chamizo C, González-Alonso P, Madoz-Gúrpide J, Eroles P, Arribas J, Tusquets I, Lluch A, Pandiella A, Rojo F, Rovira A, Albanell J. Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer. Clin Cancer Res. 2017 Nov 15;23(22):7006-7019.

Pedersen K, Bilal F, Bernadó Morales C, Salcedo MT, Macarulla T, Massó-Vallés D, Mohan V, Vivancos A, Carreras MJ, Serres X, Abu-Suboh M, Balsells J, Allende E, Sagi I, Soucek L, Tabernero J, Arribas J. Pancreatic cancer heterogeneity and response to Mek inhibition. Oncogene. 2017 Oct 5;36(40):5639-5647.

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.

PUBLICATIONS

  1. Gawrzak S, Rinaldi L, Gregorio S, Arenas EJ, Salvador F, Urosevic J, Figueras-Puig C, Rojo F, Del Barco Barrantes I, Cejalvo JM, Palafox M, Guiu M, Berenguer-Llergo A, Symeonidi A, Bellmunt A, Kalafatovic D, Arnal-Estapé A, Fernández E, Müllauer B, Groeneveld R, Slobodnyuk K, Stephan-Otto Attolini C, Saura C, Arribas J, Cortes J, Rovira A, Muñoz M, Lluch A, Serra V, Albanell J, Prat A, Nebreda AR, Benitah SA, Gomis RR. MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer. Nat Cell Biol. 2018 Jan 22. doi: 10.1038/s41556-017-0021-z. [Epub ahead of print]
  2. Martín-Pérez, R., Yerbes, R., Mora-Molina, R., Cano- González, A., Arribas, J., Mazzone, M., López- Rivas, A.  and Palacios, C. Oncogenic p95HER2/611CTF primes human breast epithelial cells for metabolic stress-induced down-regulation of FLIP and activation of TRAIL-R/Caspase-8-dependent apoptosis.  2017. Oct 3;8(55):93688-93703. doi: 10.18632/oncotarget.21458. eCollection 2017 Nov 7.
  3. Ríos-Luci, C., García-Alonso S., Díaz-Rodríguez E., Nadal-Serrano, M., Arribas, J., Ocaña, A. and Pandiella, A. Deficient lysosomal proteolytic activity underlies resistance to the antibody-drug conjugate trastuzumab-emtansine. Cancer Res Sep 1;77(17):4639-4651. doi: 10.1158/0008-5472.CAN-16-3127. Epub 2017 Jul 7.
  4. Sabbaghi M, Gil-Gómez G, Guardia C, Servitja S, Arpí O, García-Alonso S, Menendez S, Arumi-Uria M, Serrano L, Salido M, Muntasell A, Martínez-García M, Zazo S, Chamizo C, González-Alonso P, Madoz-Gúrpide J, Eroles P, Arribas J, Tusquets I, Lluch A, Pandiella A, Rojo F, Rovira A, Albanell J. Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer. Clin Cancer Res. 2017 Nov 15. 23(22):7006-7019. doi: 10.1158/1078-0432.CCR-17-0696. Epub 2017 Aug 18.
  5. Pedersen, K.*, Bilal, F.*, Bernadó Morales, C., Salcedo, MT., Macarulla, T., Massó-Vallés, D., Mohan, V., Vivancos, V., Carreras, MJ., Serres, X., Abu-Suboh, M., Balsells, J., Allende, E., Sagi, I., Soucek, L., Tabernero, J., Arribas, J. Pancreatic cancer heterogeneity and response to Mek inhibition. Oncogene, 2017. Oct 5;36(40):5639-5647. doi: 10.1038/onc.2017.174. Epub 2017 Jun 5.
  6. Byrne, A. T., Alférez, A. G.,Amant, F., Annibali, D., Arribas, J., Biankin, A. V., Bruna, A., Budinská, E., Caldas, C., Chang, D. K., Clarke, R. B., Clevers, H., Coukos, G., Dangles-Marie, V., Eckhardt, S. G. , Gonzalez-Suarez, E. G. , Els Hermans, E, Hidalgo, M., Jarzabek, M., de Jong, S., Jonkers, J., Kemper, K., Lanfrancone, L., Mælandsmo, G. M., Marangoni, E., Marine, J.-C., Enzo Medico, E., Norum, J. H., Palmer, H. G., Peeper, D. S.,Pelicci, P.G., Piris, A., Roman-Roman, S., Rueda, O. M., Seoane, J., Serra, V., Soucek, L., Vanhecke, D., Villanueva, A., Vinolo, E., Bertotti, A., Trusolino, L. (2017) Interrogating open issues in cancer precision medicine with Patient-Derived Xenografts. Nature Rev Cancer Sep 15;17(10):632. doi: 10.1038/nrc.2017.85. [Epub ahead of print]

PROJECTS

  • Novel therapies against HER2-positive breast tumors: targeting oncogene-induced senescence and the immune system.
    Breast Cancer Research Foundation (BCRF-17-008)
  • EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
    Horizon 2020 call H2020-INFRAIA-2016-2017. 731105
  • COLOSSUS.
    Horizon 2020 call SC1-PM-02-2017. 754923
  • Immunotherapy against p95HER2 positive breast cancer.
    Agència de Gestió d’Ajuts Universitaris i de Recerca AGAUR/Fons Europeus de Desenvolupament Regional (FEDER) 2014-2020. 2016 PROD 00108
  • Preclinical antitumor evaluation of MEN1611 on Breast Cancer PDX models.
    Menarini Riserche S.p.A.
  • Collaboration VHIO and Molecular Partners AG - Preclinical development of MP0274.
    Molecular Partners AG
  • CIBER-ONC Breast Cancer Program.
    Instituto de Salud Carlos III (Subdirección General de Evaluación y Fomento de la Investigación). CB16/12/00449
  • Immunotherapy Against HER2-positive Breast and Gastric Cancers.
    Instituto de Salud Carlos III. PI16/00253
  • Immunoterapia contra tumores de mama apositivos para p95HER2.
    ghD - FERO
  • Novel immunotherapies to treat colorectal and breast cancer.
    BECA FERO
  • Clinical Impact of Intratumor heterogeneity in metastatic breast cancer – CCE.
    European Research Area Net (ERA-NET). Joint Translational Call for Proposals 2014 (JTC). Instituto de Salud Carlos III co-funded by the European Commission/DG Research and Innovation. AC15/00062
  • Establishment of PDX models using patient-derived material from BP29541 phase la/b clinical trial and treatment with RO6958688 (CEA TCB) and CEA TCB2.
    ROCHE GLYCART AG
  • Nuevas Estrategias para Tratar el Cáncer de Mama Positivo para HER2.
    Asociación Española Contra el Cáncer
  • PI3K/AKT/Mtor and RAS/MEK/ERK pathway inhibition in gastrointestinal stromal tumors (GISTs): Identifying novel treatment strategies to overcome resistance to KIT/PDGFRA inhibition in GIST.
  • Immune profiles during breast cancer treatment. Indication of biomarkers of sensitivity/resistance.
    Consorcio de Investigación Biomédica y Oncológica (CIBOT) - Novartis Farmacéutica S.A.
  • Overcoming heterogeneity in gastrointestinal stromal tumors: early detection of resistant subpopulations for tyrosin kinase inhibitor rotation.
    Characterizarion of resistances to ADCs targeting HER2.
    Synthon Biopharmaceuticals B.V.

Mouse Models of Cancer Therapies Group

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Principal Investigator
Laura Soucek

Staff Scientist
Jonathan Whitfield

Post-Doctoral Fellows
Daniel Massó Vallés
Mariano Zacarías-Fluck

Graduate Students
Toni Jauset González
Sandra Martínez Martín

Technicians
Virginia Castillo Cano
Laia Foradada Felíp
Génesis Martín Fernandez
Meritxell Sánchez Hervás
Erika Serrano del Pozo

SUMMARY

Our group focuses on the pleiotropic and ubiquitous Myc oncoprotein, whose deregulation is implicated in almost all human cancers. The technical challenges of targeting nuclear transcription factors such as Myc – and the concern regarding potential side effects – had until recently precluded any preclinical validation of Myc inhibition as a possible therapeutic strategy. Over the past few years, we have since demonstrated in several mouse models that Myc inhibition has a dramatic therapeutic impact across several tumor types, with very mild and reversible side effects in normal tissue.

Encouraged by our results in mice, we are now interested in developing viable, non-toxic pharmacological options for Myc targeting in the clinic. To do so, we have created a spin-off company, Peptomyc S.L., for the development of Myc-inhibiting peptides for cancer therapy. We are currently validating our novel therapeutic strategy in notoriously difficult-to-treat cancers that are resistant to standard treatments and in dire need of new therapeutic avenues (i.e. KRAS-driven Non-Small Cell Lung Cancer, glioblastoma, and metastatic triple negative breast cancer).

The Soucek lab has continued to contribute to groundbreaking science at both regional and international levels by publishing in top-tier journals of prestige. This year Laura was invited to contribute as a key opinion leader on advances in drugging “undruggable” targets in cancer treatment for several publications (Dang et al., Nat Rev Cancer 2017; Whitfield et al., Front Cell Dev Biol, 2017), as well as the power and predictive value of patient-derived xenograft models (PDX) in cancer precision medicine (Byrne et al., Nat Rev Cancer, 2017).

Finally, our group has shared its scientific expertise with others resulting in two other important publications in 2017 (Pedersen et al., Oncogene 2017; Maltais et al., PLoS One, 2017).

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Figure: Adapted from Whitfield JR et al., Front Cell Dev Biol., 2017: Multiple strategies to target Myc: reducing Myc stability and function. Direct (right side) and indirect (left side) inhibitors are shown related to how they affect Myc's stability or binding to its partners or DNA. Other approaches impede Myc-dependent transcription of target genes. Some examples of each inhibitor strategy are listed. Omomyc functions through at least two of these mechanisms, blocking both Myc/Max heterodimerization and their binding to DNA.

STRATEGIC GOALS

  • Validation of new Omomyc-based cell penetrating peptides for cancer therapy.
  • Preclinical validation of novel anti-Myc therapies in breast, brain, lung, neuroblastoma, melanoma, and multiple myeloma.
  • Define the role of Myc in cancer-associated immune tolerance.

HIGHLIGHTS

  • Invited as a key opinion leader within the field, Laura Soucek was one of the main authors of two high impact reviews published this year in Nature Reviews Cancer.
  • Daniel Massó-Vallés is the first graduate student in our group to have been awarded a PhD for a project entitled: Inhibiting Myc and Myc dependent inflammatory response as cancer therapies. Congratulations Daniel!
  • Thanks to another successful year of awards and grants, VHIO's Mouse Models of Cancer Therapies Group has incorporated three new technicians: Virginia Castillo Cano, Génesis Martín Fernández and Meritxel Sánchez Hervás.
  • Along with other VHIO peers, Laura Soucek was co-applicant of a successful H2020 INFRAIA 2017 Grant: EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
  • Peptomyc S.L. was awarded a NEOTEC and an APC grant from the Ministry of Economy, Innovation and Competitiveness, with Laura Soucek as Principal Investigator.
  • Laura was selected by EIT Health as a Role Model for the project Empowering Women Entrepreneurship in Health Innovation (WE Health) aimed at promoting the participation of women in health innovation and entrepreneurship. For more information: http://www.we.eithealth.eu/en/role-models.

PI PAPER PICK (full list for 2017 below)

Dang C, Reddy EP, Shokat K, and Soucek L. Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer. 2017 Aug;17(8):502-508.

Pedersen K, Bilal F, Bernadó Morales C, Salcedo MT, Macarulla T, Massó-Vallés D, Mohan V, Vivanco A, Carreras MJ, Serres X, Abu-Suboh M, Balsells J, Allende E, Sagi I, Soucek L, Tabernero J, Arribas J. Pancreatic cancer heterogeneity and response to Mek inhibition. Oncogene. 2017 Oct 5;36(40):5639-5647.

Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front Cell Dev Biol. 2017 Feb 23;5:10. eCollection 2017.

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 using Patient-Derived Xenograft Models. Nat Rev Cancer. 2017 Apr;17(4):254-268.

HORIZONS 2018

  • Validate Myc inhibition as a viable therapeutic strategy in the clinic, beyond gene therapy, in glioblastoma, non-small-cell lung cancer, metastatic breast cancer, melanoma, multiple myeloma, and neuroblastoma.
  • Developing Omomyc-based Myc inhibitor peptides for clinical cancer treatment.
  • Define the role of Myc in cancer-associated immune tolerance.

PUBLICATIONS

  1. Dang C, Reddy EP, Shokat K, andSoucek L. Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer.  2017 Jun 23. doi: 10.1038/nrc.2017.36.
  2. Pedersen K, Bilal F, Bernadó Morales C, Salcedo MT, Macarulla T, Massó-Vallés D, Mohan V, Vivanco A, Carreras MJ, Serres X, Abu-Suboh M, Balsells J, Allende E, Sagi I, Soucek L, Tabernero J and Arribas J. Pancreatic cancer heterogeneity and response to Mek inhibition. Oncogene.2017 Jun 5. doi: 10.1038/onc.2017.174.
  3. Maltais L, Montagne M, Bédard M, Tremblay C, Soucek L and Lavigne P. Biophysical Characterization of the b-HLH-LZ of ΔMax, an Alternatively Spliced Isoform of Max Found in Tumor Cells: Towards the Validation of a Tumor Suppressor Role for the Max Homodimer. PLoS One. 2017 Mar 28;12(3): e0174413. https://doi.org/10.1371/journal.pone.0174413.
  4. Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front. Cell Dev. Biol., 23 February 2017.
  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 using Patient-Derived Xenograft Models. Nat Rev Cancer. 2017 Jan 20. doi: 10.1038/nrc.2016.140.
  6. Beaulieu ME, Jauset T, Massó-Vallés D, Soucek L*and Whitfield JR. Mouse Models in Personalized Cancer Medicine. Chapter 6 of Cancer genetics and Genomics for Personalized Medicine. 2017. ISBN: 9789814669887. Book Chapter. *Corresponding author.

PROJECTS

Ongoing Projects:

  • Grantor: H2020 INFRAIA 2017 Title: EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts
    Role: Co-applicant
    2017-2021
  • Grantor: APC grant to Peptomyc from the Ministry of Economy, Innovation and Competitiveness
    Role: Principal Investigator, Laura Soucek
    2017-2019
  • Grantor: NEOTEC grant to Peptomyc from the Ministry of Economy, Innovation and Competitiveness
    Role: Principal Investigator, Laura Soucek
    2017-2019
  • Grantor: Retos de Colaboraciónfrom the Spanish Ministry of Economy, Industry and Competitiveness
    Title: Preclinical development of Omomyc-CPP as a therapy for cancer treatment
    Role: Principal Investigator, Laura Soucek
    2016-2019
  • Grantor:Instituto de Salud Carlos III: Proyectos FIS de Investigación en Salud
    Title: In vivo validation of innovative anti-Myc therapies in glioblastoma
    Role: Principal Investigator, Laura Soucek
    2016-2019
  • Grantor: ERC (European Commission) Consolidator Grant
    Title: Pushing Myc inhibition towards the clinic
    Role: Principal Investigator, Laura Soucek
    2014-2019
  • Grantor: Catalan Agency for Trade and Investment (ACCIÓ)
    Title/Description: Peptomyc received a grant for the project: Pre-clinical development of OmomycCPP:characterization of the immune response
    Role: Principal Investigator, Laura Soucek
    2016-2018

AWARDS

  • Daniel Massó-Valles received one of this year’s Pioneer Awards from the Research Centres of Catalonia (CERCA) Institute, for his PhD entitled Inhibiting Myc and the Myc dependent inflammatory response as cancer therapies. CERCA’s Pioneer Awards recognize up-and-coming research talents who have presented a doctoral thesis with results promising commercial exploitation and technology transfer for societal gain.
  • Peptomyc S.L. was awarded a NEOTEC and an APC grant from the Ministry of Economy, Innovation and Competitiveness, with Laura Soucek as Principal Investigator.
  • Soucek was selected by EIT Health as a Role Model for the project Empowering Women Entrepreneurship in Health Innovation(WE Health) aiming to enhance the participation of women in health innovation and entrepreneurship activities. For more information: http://www.we.eithealth.eu/en/role-models.

Tumor Biomarkers Group

Imagen

Principal Investigator
Josep Villanueva

Post-Doctoral Fellows
Juan Manuel Duran
Mercè Juliachs
Olga Méndez
Nathalie Meo-Evoli

Graduate Student
Mireia Pujals

Technicians
Ana Matres
Candida Salvans

SUMMARY

Tumor cell communication with its microenvironment performs an important role in tumor initiation and progression. Tumor cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is crucial for the development of primary and metastatic tumors.

Our main aim is to characterize the mechanisms adopted by cancer cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis. We intend to exploit these findings to advance biomarker and drug target discovery. Our group's working hypothesis is that cellular signaling pathways undergo alteration during the tumorigenesis process and that these changes are translated into differential protein secretion, which can also potentially be used to identify secreted markers. In addition, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to fundamental stages implicated in cancer initiation and progression, thus representing potential therapeutic targets.

The methodological focus of our group centers on profiling the secreted sub-proteome (‘secretome’) of cells by quantitative mass spectrometry. Most secreted proteins contain a signal peptide that directs their sorting to the extracellular space through the endoplasmic reticulum (ER)–Golgi secretory pathway. One of the most striking observations when secretome profiles are carefully produced and analyzed is that they contain hundreds of theoretical intracellular proteins. Recent reports showing intracellular proteins with alternative extracellular functions suggest that new protein functions associated with alternative subcellular localizations could be relevant in tumorigenesis. In line with this new view, our recent efforts in the context of therapeutics and tumor invasion have led us to hypothesize that the characterization of non-classical protein secretion could lead to novel therapies against cancer.

The cancer secretome contains classical and non-classical secreted proteins that tumor cells use as molecular SMS to communicate to each other and with their microenvironment. Our main goal is to characterize the mechanisms adopted by cancer cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis, and exploit these data to advance biomarker and drug target discovery.

Imagen

Figure: The nuclear protein HMGA1 is enriched in the invasive front of primary breast tumors. Immunofluorescence analysis of HMGA1 in an orthotopic xenograft model of breast cancer. HMGA1 expression (green) increased towards the invasive front. Cytokeratin (red) is used to stain human epithelial cells, and Hoechst to counterstain the nuclei. The inset shows the histology of the tumor tissue.

STRATEGIC GOALS

  • The characterization of mechanisms adopted by tumor cells to communicate with their microenvironment during tumorigenesis and targeted drug therapy. This data is then used for biomarker and drug target discovery.
  • Characterize the role of extracellular HMGA1 in breast cancer invasion and metastasis.
  • Exploit the role of non-classical secretion linked to tumor invasion for the identification of therapeutic targets in breast cancer.

HIGHLIGHTS

  • This year we have established a role for HMGA1 in the tumor invasion of breast cancer cells.
  • We have expanded our studies to delineate the impact of non-classical secretion pathways on the cancer secretome. We have initiated the functional validation of two candidate drug targets non-classically secreted in the tumor invasion of breast cancer.

HORIZONS 2018

  • Expand our studies to characterize the role of HMGA1 in tumor invasion and metastasis.
  • Continue to characterize the invasive secretome in breast cancer aimed at identifying new drug targets.

PROJECTS

  • Diagnostic and Therapeutic implications of extracellular HMGA1 in Breast Cancer
    Agency : Susan G Komen
    Duration: 15/09/2015 - 15/09/2017
    Principal Investigator: Josep Villanueva
  • Characterization of the role of HMGA1 as a mediator of tumor progression in breast cáncer
    Agency: Instituto Carlos III
    Duration: 1/01/2016 - 31/12/2018
    Principal Investigator: Josep Villanueva