Programs & Groups

Please click on the corresponding programs below


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Joaquín Arribas

Director, Preclinical Research Program
Biosketch

“We strive to advance prediction science against cancer by developing xenograft models to study tumorigenesis, elucidate the cross-talk between tumor cells and the microenvironment, and evaluate the efficacy of novel therapies. By upping the tempo in unmasking mutations and mechanisms of resistance to current anti-cancer medicines we are ultimately contributing to improved outcomes for patients.”

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VHIO’s Preclinical Program is dedicated to establishing how highly aggressive tumors affecting the breast, pancreas, colon, lung, or brain can be treated more precisely. 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 therapy, resulting in poor prognosis. The overarching goal of our Program is to investigate novel anti-cancer treatment approaches for these patients and to unveil mechanisms of resistance to 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 consisting of the inhibition of Myc, an oncogene activated in many of the aforementioned tumors, based on peptides that enter the cell and block Myc. This novel approach has been recognized through several grants, including those awarded by the European Commission's Horizon 2020 program, the European Commission's European Research Council's Proof-of-Concept, the Institute of Health Carlos III (ISCIII), the Spanish Ministry of Economy, Industry and Competitiveness, FERO Foundation, and BBVA Foundation. In addition, Laura has attracted funding from the EIT Health Summit as well as the Catalan Agency for Trade and Investment (ACCIÓ), to develop this therapy with Peptomyc S.L. - a start-up company based at VHIO.

Our Experimental Therapies Group headed by Violeta Serra focuses on understanding 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 homologous recombination deficiency. They have further established novel patient tumor-derived breast cancer models in vivo. These preclinical models have shown to faithfully recapitulate the clinical setting and have been extremely useful in the study of resistance to anti-cancer therapies. Of particular note, Violeta's group has established that RAD51 nuclear foci formation, a marker of DNA repair by homologous recombination, is associated with resistance to PARP inhibitors. Her group's research of excellence has been recognized through support received from funding entities including the European Commission's Horizon 2020 ERA (European Research Area) NET and Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) programs, the Susan G. Komen Foundation, the Institute of Health Carlos III (ISCIII), and the Agency for Management of University and Research Grants (AGAUR).

VHIO's Tumor Biomarkers Group directed by Josep Villanueva re-routed its principal focus of research three years ago which has this year crystallized in the form of additional funding received from the Susan G. Komen Foundation, the Institute of Health Carlos III (ISCIII), and most recently, important support from the pharmaceutical company Servier. This has led to the recruitment of additional lab members to enable the expansion of 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, and we have expanded our observations to the importance of the cytokine IL-6 in the progression of this tumor type. We have developed, characterized, and identified several new patient-derived xenografts and we are currently adapting them to analyze novel immune therapeutics against breast cancer. In recognition of our efforts, we continue to receive essential support through international and national competitive grants from the European Commission, the Breast Cancer Research Foundation (BCRF), Institute of Health Carlos III (ISCIII), the FERO Foundation, and the Spanish Association Against Cancer (AECC).

In 2016, our groups’ findings have been published in several journals of excellence including Cancer Research, Clinical Cancer Research, Nature Medicine, 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
› Alba Llop-Guevara
› Marta Palafox

Graduate Students
› Marta Castroviejo-Bermejo
› Albert Gris-Oliver
› Mònica Sánchez-Guixé

Technicians
› Judit Grueso
› Marta Guzmán
› 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 advanced 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 contributed to identifying PI3K-pathway activation downstream of PI3K, via upregulation of mTORC1, as a mechanism of resistance to PI3K inhibitors. To advance our understanding of the novel therapeutic strategies in breast cancer, we are exploring the mode of action and mechanisms of resistance of 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 results in 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 (HR) DNA repair deficient tumors. Our studies underpin the capacity of germline BRCA mutant tumors to recover HR functionality and develop resistance to PARPi. PM01183 is however active in most PARPi resistant tumors, as well as PARPi combinations that bypass cell cycle checkpoints such as WEE1 inhibitors.

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: RAD51 and DNA repair by homologous recombination functionality. The homologous recombination (HR) protein RAD51 is recruited to finalize the repair of double strand breaks in HR-competent cells. This biomarker enables the identification of breast tumors that lack HR-functionality and therefore sensitive to PARP inhibitors, both in the BRCA1/2-germline and in the somatic context.

STRATEGIC GOALS

  • Developing predictive and pharmacodynamic biomarkers of PI3K-pathway as well as CDK4/6 inhibitors.
  • 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

  • Small molecule inhibitors of the CDK4/6 cell cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer. We have reported that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part via non-canonical cyclin D1-CDK2 mediated S-phase entry.
  • Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control.
  • CDK4/6-inhibitor resistance in estrogen receptor positive breast cancer is mediated by early adaptation and bypass of cyclin D1–CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss.
  • In breast tumors from BRCA1-mutation carriers, resistance to PARP inhibitors is frequently associated with reactivation of functional DNA repair by homologous recombination.
  • We have established that 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.

PI PAPER PICK

Herrera-Abreu M, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortés J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor positive breast cancer. Cancer Res. 2016 Apr 15;76(8):2301-13.

Bruna A, Rueda OM, Greenwood W, Batra AS, Callari M, Batra RN, Pogrebniak K, Sandoval J, Cassidy JW, Tufegdzic-Vidakovic A, Sammut SJ, Jones L, Provenzano E, Baird R, Eirew P, Hadfield J, Eldridge M, McLaren-Douglas A, Barthorpe A, Lightfoot H, O'Connor MJ, Gray J, Cortes J, Baselga J, Marangoni E, Welm AL, Aparicio S, Serra V, Garnett MJ, Caldas C. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds. Cell. 2016 Sep 22;167(1):260-274.e22.

Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, Meier P, Gris-Oliver A, Cheang MCU, Perdrix-Rosell A, Shafat M, Noël E, Patel N, McEachern K, Scaltriti M, Castel P, Noor F, Buus R, Mathew S, Watkins J, Serra V, Marra P, Grigoriadis A & Tutt AN. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med. 2016 Nov;22(11):1303-1313.

Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I, Cruz C, Chondronasiou D, Castroviejo-Bermejo M, Boon U, Schut E, van der Burg E, Wientjens E, Pieterse M, Klijn C, Klarenbeek S, Loayza-Puch F, Elkon R, van Deemter L, Rottenberg S, van de Ven M, Dekkers DH, Demmers JA, van Gent DC, Agami R, Balmaña J, Serra V, Taniguchi T, Bouwman P, Jonkers J. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J Clin Invest. 2016 Aug 1;126(8):2903-18.

HORIZONS 2017

  • Identification of response biomarkers to PI3K/AKT and CDK4/6 inhibitors in breast cancer.
  • Unveil genetic and epigenetic mechanisms of acquired resistance to PARP inhibitors in hereditary BRCA1/2 breast cancer.
  • 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 anti-estrogen therapy as well as PARP inhibitors.

PUBLICATIONS

  • CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, Primack B, Cao S, Bernhardy AJ, Coulson R, Lazaro JB, Kachupurakkal B, Sun H, Unitt C, Moreau LA, Sarosiek KA, Scaltriti M, Juric D, Baselga J, Richardson AL, Rodig SJ, D’Andrea AD, Balmaña J, Johnson N, Geyer M, Serra V, Lim E*, Shapiro GI*. Cell Reports. Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077. IF: 7.870
  • PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, Meier P, Gris-Oliver A, Cheang MCU, Perdrix-Rosell A, Shafat M, Noël E, Patel N, McEachern K, Scaltriti M, Castel P, Noor F, Buus R, Mathew S, Watkins J, Serra V, Marra P, Grigoriadis A & Tutt AN. Nature Medicine, Nov;22(11):1303-1313. IF: 30.357.
  • A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds. Bruna A, Rueda OM, Greenwood W, Batra AS, Callari M, Batra RN, Pogrebniak K, Sandoval J, Cassidy JW, Tufegdzic-Vidakovic A, Sammut SJ, Jones L, Provenzano E, Baird R, Eirew P, Hadfield J, Eldridge M, McLaren-Douglas A, Barthorpe A, Lightfoot H, O'Connor MJ, Gray J, Cortes J, Baselga J, Marangoni E, Welm AL, Aparicio S, Serra V, Garnett MJ, Caldas C. Cell. 2016 Sep 22;167(1):260-274.e22. IF: 28.710.
  • Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity. Mair B, Konopka T, Kerzendorfer C, Sleiman K, Salic S, Serra V, Muellner MK, Theodorou V, Nijman SM. PLoS Genet. 2016 Sep 2;12(9):e1006279. IF: 7.528.
  • Stratification and therapeutic potential of PML in metastatic breast cancer. Martín-Martín N, Piva M, Urosevic J, Aldaz P, Sutherland JD, Fernández-Ruiz S, Arreal L, Torrano V, Cortazar AR, Planet E, Guiu M, Radosevic-Robin N, Garcia S, Macías I, Salvador F, Domenici G, Rueda OM, Zabala-Letona A, Arruabarrena-Aristorena A, Zúñiga-García P, Caro-Maldonado A, Valcárcel-Jiménez L, Sánchez-Mosquera P, Varela-Rey M, Martínez-Chantar ML, Anguita J, Ibrahim YH, Scaltriti M, Lawrie CH, Aransay AM, Iovanna JL, Baselga J, Caldas C, Barrio R, Serra V, Vivanco Md, Matheu A, Gomis RR, Carracedo A. Nat Commun. 2016 Aug 24;7:12595. IF: 11.329.
  • Cancer network activity associated with therapeutic response and synergism. Serra-Musach J, Mateo F, Capdevila-Busquets E, de Garibay GR, Zhang X, Guha R, Thomas CJ, Grueso J, Villanueva A, Jaeger S, Heyn H, Vizoso M, Pérez H, Cordero A, Gonzalez-Suarez E, Esteller M, Moreno-Bueno G, Tjärnberg A, Lázaro C, Serra V, Arribas J, Benson M, Gustafsson M, Ferrer M, Aloy P, Pujana MÀ. Genome Med. 2016 Aug 24;8(1):88. IF: 5.850.
  • BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I, Cruz C, Chondronasiou D, Castroviejo-Bermejo M, Boon U, Schut E, van der Burg E, Wientjens E, Pieterse M, Klijn C, Klarenbeek S, Loayza-Puch F, Elkon R, van Deemter L, Rottenberg S, van de Ven M, Dekkers DH, Demmers JA, van Gent DC, Agami R, Balmaña J, Serra V, Taniguchi T, Bouwman P, Jonkers J Clin Invest. 2016 Jul 25. pii: 70196. IF: 12.575.
  • Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor positive breast cancer. Herrera-Abreu M*, Palafox M*, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortés J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC*, Serra V*. Cancer Research. 2016 Apr 1;76(8):2301-13. IF: 9.329.
  • The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapy Resistance. Wang Y, Bernhardy AB, Cruz C, Krais JJ, Nacson J, Nicolas E, Peri S, van der Gulden H, van der Heiiden I, O’Brien SW, Zhang Y, Harrell MI, Johnson SF, Candido Dos Reis FJ, Pharoah PDP, Karlan B, Gourley C, Lambrechts D, Chenevix-Trench G, Olsson H, Benitez JJ, Greene MH, Gore M, Nussbaum R, Sadetzki S, Gayther SA, Kjaer SK, kConFab Investigators, D’Andrea AD, Shapiro GI, Wiest DL, Connolly DC, Daly MB, Swisher EM, Bouwman P, Jonkers J, Balmaña J, Serra V and Johnson N. Cancer Research. 2016, May 1;76(9):2778-90. IF: 9.329.

PROJECTS

  • 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
  • Targeting PI3K and CDK4/6 in breast cancer (CP14/00028)
    Principal Investigator: Violeta Serra
    Funding Agency: ISCIII (Spanish Ministry of Health)
    Duration: 2015-2019
  • Inhibition of PI3K in breast cancer: in-depth analysis of the predictive factors and rational design of therapeutic combinations (PI13/01704)
    Principal Investigator: Violeta Serra
    Funding Agency: ISCIII (Spanish Ministry of Health)
    Duration: 2014-2016
  • 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
  • Acknowledged Emerging Research Group (SGR): Experimental Therapeutics in Breast Cancer (2014-SGR-1331)
    Group Coordinator: Violeta Serra
    Funding Agency: AGAUR (Catalan Agency for Research)
    Duration: 2014-2016
  • 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

  • Miguel Servet Mobility Award as a Visiting Scientist at C. Caldas´ Laboratory of Breast Cancer Functional Genomics, Cancer Research UK, Cambridge Cancer Institute (UK).

Growth Factors Group

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Principal Investigator
› Joaquín Arribas

Scientific Manager
› Cristina Bernadó

Medical Oncologist
› César Serrano

Post-Doctoral Fellows
› Cristina Bernadó
› Beatriz Morancho
› Mercedes Nadal
› Bhavna Rani
› Verónica Rodilla

Masters Student
› Rita Casas

Graduate Students
› Faiz Bilal
› Irene Rius
› Rocio Vicario
› Junjie Zhang

Technicians
› Marta Escorihuela
› Antoni Luque
› David Olivares
› Ismael Varela

SUMMARY

Our group is dedicated to studying tumor progression and mechanisms of resistance to therapy in HER2-positive breast cancer as well as the development of novel immunotherapy strategies against this tumor subtype.
We have previously shown that constitutively activated HER2 leads to premature senescence. These senescent cells remain metabolically active and display a remarkable secretory phenotype. We deeply analyzed this secretome and evidenced that it contributes to the prometastatic effect of HER2-induced senescent cells.

We extended our studies to naturally-occurring senescent cells in HER2-positive tumors. In this scenario, senescent cells contribute to tumor growth by secreting cytokines that are required for non-senescent cells to proliferate. We identified IL-6 as one of the main contributors and established that the autocrine production of this element by naturally occurring senescent cells promotes growth of HER2-positive tumors.

Throughout 2016 our group has also evaluated the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). Results indicate that only tumors in which activation of STAT3 depends on IL-6, respond to the blocking antibodies, suggesting the necessary development of functional assays to determine the dependence of STAT3 activation on IL-6, and identify responsive tumors.

Most recently, we have focused on developing tools to better model anti-tumor immunotherapy strategies. The development of humanized PDX models (Hu PDXs), in which the human immune system is established in PDX-bearing immunodeficient mice, has proven a successful approach. We are currently using these models to preclinically validate the efficacy of T cell bispecific antibodies (TCBs).

In addition, our group has been setting up a new line of research focused on pancreatic cancer. In close collaboration with VHIO’s Gastrointestinal & Endocrine Tumors Group, led by Josep Tabernero, we are expanding our research to explore resistance mechanisms implicated in the response to targeted therapies against this tumor type.

We are extremely grateful to both the Spanish Association Against Cancer (AECC), and the Breast Cancer Research Foundation (BCRF), for their continued funding of our research. Lastly, after several years' coordination of the Breast Cancer Program of the Red Territorial de Investigación Cooperativa en Cáncer (RTICC), supported by the Instituto de Salud Carlos III (ISCIII), I am honored to have recently been appointed as Scientific Director of the virtual 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. We work in close connectivity to collectively deliver on complex projects requiring the collaboration and expertise of multiple groups.

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Figure: Strategies to generate humanized PDXs. Nature Reviews Cancer (2017) doi:10.1038/nrc.2016.140.

STRATEGIC GOALS

  • The development of novel therapeutic strategies to treat 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 patient-derived xenografts.

HIGHLIGHTS

  • Our group has shown that tumors in which the activation of the downstream factor STAT3 depends on IL-6, respond to therapies based on IL-6 blocking antibodies.
  • In collaboration with Roche Innovation Center Zurich (RICZ), we have co-developed T cell bispecific antibodies against p95HER2 (p95HER2-TCB). Promising preliminary results have shown p95HER2-TCB as favorable properties for therapeutic application, leading to the filing of a patent in September 2016.
  • The project entitled New Immunotherapies to Treat Colorectal and Breast Cancer, presented by Beatriz Morancho from our group, was awarded with the 10th FERO Foundation Annual Grant.

PI PAPER PICK

Morancho B, Zacarías-Fluck M, Esgueva A, Bernadó-Morales C, Di Cosimo S, Prat A, Cortés J, Arribas J, Rubio IT. Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts. Oncotarget. 2016 Oct 18;7(42):67956-67965.

Serra-Musach J, Mateo F, Capdevila-Busquets E, de Garibay GR, Zhang X, Guha R, Thomas CJ, Grueso J, Villanueva A, Jaeger S, Heyn H, Vizoso M, Pérez H, Cordero A, Gonzalez-Suarez E, Esteller M, Moreno-Bueno G, Tjärnberg A, Lázaro C, Serra V, Arribas J, Benson M, Gustafsson M, Ferrer M, Aloy P, Pujana MÀ. Cancer network activity associated with therapeutic response and synergism. Genome Med. 2016 Aug 24;8(1):88.

Hergueta-Redondo M, Sarrio D, Molina-Crespo Á, Vicario R, Bernadó-Morales C, Martínez L, Rojo-Sebastián A, Serra-Musach J, Mota A, Martínez-Ramírez Á, Castilla MÁ, González-Martin A, Pernas S, Cano A, Cortes J, Nuciforo PG, Peg V, Palacios J, Pujana MÁ, Arribas J, Moreno-Bueno G. Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. Oncotarget. 2016 Aug 30;7(35):56295-56308.

Nuciforo, P., Thyparambil, S., Aura, C., Garrido-Castro, A., Marta Vilaro, M., Peg, V., Jimenez, J., Hoos, W., Burrows, J., Todd Hembrough, T., Ferreres, J. C., Perez-Garcia, J., Arribas, J., Cortes, J., and Scaltriti, M. High HER2 protein levels correlate with increased overall survival in breast cancer patients treated with anti-HER2 therapy. Mol. Oncol. 2016 Jan;10(1):138-47.

PUBLICATIONS

  • Morancho B, Zacarías-Fluck M, Esgueva A, Bernadó-Morales C, Di Cosimo S, Prat A, Cortés J, Arribas J, Rubio IT. Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts. Oncotarget. 2016 Sep 1. Vol. 7, No. 42. doi: 10.18632/oncotarget.11815. *Co-corresponding authors.
  • Hutchinson E, Pujana MA, Arribas J. Cancer therapeutic resistance: progress and perspectives. Drugs Today (Barc). 2016 Jun;52(6):347-54.
  • Serra-Musach J, Mateo F, Capdevila-Busquets E, de Garibay GR, Zhang X, Guha R, Thomas CJ, Grueso J, Villanueva A, Jaeger S, Heyn H, Vizoso M, Pérez H, Cordero A, Gonzalez-Suarez E, Esteller M, Moreno-Bueno G, Tjärnberg A, Lázaro C, Serra V, Arribas J, Benson M, Gustafsson M, Ferrer M, Aloy P, Pujana MA. Cancer network activity associated with therapeutic response and synergism. Genome Med. 2016 Aug 24;8(1):88. doi: 10.1186/s13073-016-0340-x.
  • Hergueta-Redondo M, Sarrio D, Molina-Crespo Á, Vicario R, Bernadó-Morales C, Martínez L, Rojo-Sebastián A, Serra-Musach J, Mota A, Martínez-Ramírez Á, Castilla MÁ, González-Martin A, Pernas S, Cano A, Cortes J, Nuciforo PG, Peg V, Palacios J, Pujana MÁ, Arribas J, Moreno-Bueno G. Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cáncer. Oncotarget. 2016 Jul 22. Vol. 7, No. 35. doi: 10.18632/oncotarget.10787.
  • Esparís-Ogando A, Montero JC, Arribas J, Ocaña A, Pandiella A. Targeting the EGF/HER Ligand-Receptor System in Cancer. Curr. Pharm. Des. 2016 22(39):5887-5898
  • Nuciforo P, Thyparambil S, Aura C, Garrido-Castro A, Marta Vilaro M, Peg V, Jimenez J, Hoos W, Burrows J, Todd Hembrough T, Ferreres JC, Perez-Garcia J, Arribas J, Cortes J, Scaltriti M. High HER2 protein levels measured by multiplex mass spectrometry correlate with increased overall survival in patients treated with anti-HER2 therapy. Mol. Oncol. 2016 Jan;10(1):138-47. doi: 10.1016/j.molonc.2015.09.002.

PROJECTS

  • CIBER-ONC Breast Cancer Program.
  • Immunotherapy Against HER2-positive Breast and Gastric Cancers.
  • Novel therapies against HER2-positive breast tumors: targeting oncogene-induced senescence and the immune system.
  • Immunoterapia contra tumores de mama apositivos para p95HER2.
  • Novel immunotherapies to treat colorectal and breast cancer.
  • Clinical Impact of Intratumor heterogeneity in metastatic breast cancer – CCE.
  • Nuevas Estrategias para Tratar el Cáncer de Mama Positivo para HER2.
  • PI3K/AKT/Mtor and RAS/MEK/ERK pathway inhibition in gastrointestinal stromal tumors (GISTs): Identifiying novel treatment strategies to overcome resistance to KIT/PDGFRA inhibition in GIST.
  • Immune profiles during breast cancer treatment. Indication of biomarkers of sensitivity/resistance.
  • Overcoming heterogeneity in gastrointestinal stromal tumors: early detection of resistant subpopulations for tyrosin kinase inhibitor rotation.
  • Characterizarion of resistances to ADCs targeting HER2.

Mouse Models of Cancer Therapies Group

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Principal Investigator
› Laura Soucek

Staff Scientist
› Jonathan Whitfield

Post-Doctoral Fellow
› Marie-Eve Beaulieu
› Silvia Casacuberta
› Mariano F. Zacarias

Graduate Students
› Toni Jauset González
› Sandra Martínez
› Daniel Massó Vallés

Technicians
› Virginia Castillo
› Laia Foradada
› Érika Serrano del Pozo

Visiting Postdoctoral Scholar
› Roberta Laranga

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 approach. However, over the past few years, we have 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, nontoxic 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, and we are validating our new therapeutic strategy in notoriously difficult to treat cancers that are currently resistant to standard therapies and are in dire need of new therapeutic options (i.e. KRas-driven Non-Small Cell Lung Cancer, glioblastoma, and metastatic triple negative breast cancer).

In recognition of research of excellence, Laura's laboratory has been awarded numerous grants since its inception. This year she has received a prestigious European Research Council (ERC) Proof-of-Concept grant within the framework of the EU's Horizon 2020 Program, a grant from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) for a FIS - Fondo de Investigación en Salud (Health Research Fund) project, and a grant from the Spanish Ministry of Economy, Industry and Competitiveness within the Retos de Colaboración program.

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Figure: Laura Soucek’s laboratory is pre-clinically validating Myc inhibition as a therapeutic strategy in different types of cancer. To do so, among other strategies, they are using Omomyc, the best Myc inhibitor known to date, and Omomyc-derived peptides.

STRATEGIC GOALS

  • Validation of new cell penetrating peptides for cancer therapy.
  • Pre-clinical validation of novel anti-Myc therapies in breast, brain, lung, prostate, colorectal cancer, melanoma, and multiple myeloma.
  • Define the role of Myc in cancer-associated immune tolerance.
  • To evaluate the activity of novel anti-cancer therapies in our panels of breast and pancreatic patient derived xenografts.

HIGHLIGHTS

  • Laura's laboratory was awarded a European Research Council (ERC) Proof-of-Concept grant within the framework of the EU's Horizon 2020 Program. Title: Developing an anti-Myc cell-penetrating peptide for cancer treatment.
  • Her group also received a grant from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) for a FIS - Fondo de Investigación en Salud (Health Research Fund) to support the project entitled In vivo validation of innovative anti-Myc therapies in glioblastoma.
  • She also received a Retos de Colaboración grant from the Spanish Ministry of Economy, Industry and Competitiveness for the Preclinical development of Omomyc-CPP as a therapy for cancer treatment, as well as funding from the FERO Foundation for the project: Use of liposomal nanotechnology to optimize systemic administration of Omomyc in metastatic breast cancer.
  • In collaboration with Jun Yokota's group, the Institute of Predictive and Personalized Medicine (IMPPC), Badalona - Barcelona, Spain, we demonstrated a dramatic therapeutic impact of Myc inhibition in the treatment of Small Cell Lung Cancer (SCLC) (Fiorentino et al. Oncotarget 2016)
  • Thanks to another successful year of awards and grants, VHIO's Mouse Models of Cancer Therapies Group has now expanded to incorporate a total of 12 people.
  • Peptomyc S.L. was awarded an SME Instrument Phase I by the European Commission within the Horizon 2020 Program. Title: Feasibility study of a novel treatment for cancer based on a recombinant peptide therapy — PEPTO1. Of note, this grant was the only one awarded in biotechnology for this specific call.
  • Peptomyc S.L. also received a Business Plan Aggregator Prize at the EIT Health Summit, as well as a grant from Catalonia Trade & Investment (a unit of ACCIÓ, the Agency for Business Competitiveness), for the Pre-clinical development of Omomyc-CPP: characterization of the immune response.

PI PAPER PICK

Massó-Vallés D, Jauset T, Soucek L. Ibrutinib repurposing: from B cell malignancies to solid tumors. Oncoscience. 2016 Jun 10;3(5-6):147-8.

Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, Kohno T, Perucho M, Soucek L, Yokota J. Growth Suppression by MYC Inhibition in Small Cell Lung Cancer Cells with TP53 and RB1 Inactivation. Oncotarget. 2016 May 24;7(21):31014-28.

HORIZONS 2017

  • 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, prostate, and colorectal cancer.
  • Define the role of Myc in cancer-associated immune tolerance. .

PUBLICATIONS

  • Massó-Vallés D, Jauset T, Soucek L. Ibrutinib repurposing: from B cell malignancies to solid tumors. Oncoscience. 2016 Jun 10;3(5-6):147-8.
  • Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, Kohno T, Perucho M, Soucek L, Yokota J. Growth Suppression by MYC Inhibition in Small Cell Lung Cancer Cells with TP53 and RB1 Inactivation. Oncotarget. 2016 May 24;7(21):31014-28.

PROJECTS

New Projects:

  • Retos de Colaboración grant from the Spanish Ministry of Economy, Industry and Competitiveness. Title: Preclinical development of Omomyc-CPP as a therapy for cancer treatment. 2016-2019.
  • Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) FIS grant - Fondo de Investigación en Salud (Health Research Fund). Title: In vivo validation of innovative anti-Myc therapies in glioblastoma. 2016-2019.
  • European Research Council – ERC (European Commission) Proof-of-Concept Grant. Title: Developing an anti-Myc cell-penetrating peptide for cancer treatment. 2016-2017.
  • Grant from Catalonia Trade & Investment (a unit of ACCIÓ, the Agency for Business Competitiveness). Title: Pre-clinical development of OmomycCPP: characterization of the immune response. 2016.
  • SME Instrument Phase I grant by the European Commission within the Horizon 2020 Program to Peptomyc S.L. Title: Feasibility study of a novel treatment for cancer based on a recombinant peptide Therapy. 2016.
  • FERO Foundation grant. Title: Use of liposomal nanotechnology to optimize systemic administration of Omomyc in metastatic breast cancer. 2016.

Ongoing:

  • BBVA Foundation Grant in Biomedicine. Title: Validation of an innovative anti-Myc therapy in glioblastoma. 2015-2017.
  • Grant for Emerging Research Group of Catalunya from the Agency for Management of University and Research Grants (AGAUR). 2014-2016.
  • European Research Council - ERC Consolidator Grant. Title: Pushing Myc inhibition towards the clinic. 2014-2019.
  • Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) FIS grant - Fondo de Investigación en Salud (Health Research Fund). Title: Advancing Myc inhibition towards the clinic for the treatment of lung cancer. 2014-2017.
  • Worldwide Cancer Research Grant. Title: Advancing Myc inhibition towards the clinic: characterization of an Omomyc cell-penetrating peptide. 2013-2016.

AWARDS

  • European Research Council ERC Proof-of-Concept grant within the framework of the EU Horizon 2020 Program. Title: Developing an anti-Myc cell-penetrating peptide for cancer treatment.
  • Laura´s group also received a grant from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) for a FIS - Fondo de Investigación en Salud (Health Research Fund) to support the project entitled In vivo validation of innovative anti-Myc therapies in glioblastoma.
  • She also received a Retos de Colaboración grant from the Spanish Ministry of Economy, Industry and Competitiveness for the Preclinical development of Omomyc-CPP as a therapy for cancer treatment, as well as funding from the FERO Foundation for the project: Use of liposomal nanotechnology to optimize systemic administration of Omomyc in metastatic breast cancer.
  • Peptomyc S.L. was awarded an SME Instrument Phase I by the European Commission within the Horizon 2020 Program. Title: Feasibility study of a novel treatment for cancer based on a recombinant peptide therapy — PEPTO1. Of note, this grant was the only one awarded in biotechnology for this specific call.
  • Peptomyc S.L. also received a Business Plan Aggregator Prize at the EIT Health Summit, as well as a grant from Catalonia Trade & Investment (a unit of ACCIÓ, the Agency for Business Competitiveness), for the Pre-clinical development of Omomyc-CPP: characterization of the immune response.
  • Daniel Massó-Valles, PhD student in the lab, was awarded a Nature Reviews Cancer poster prize at the VHIO -“la Caixa” Banking Foundation´s International Symposium: Towards Predictive Cancer Models, 26 – 27 May 2016. Title of poster: Targeting Myc in Breast Cancer Metastasis.

Tumor Biomarkers Group

Imagen

Principal Investigator
› Josep Villanueva

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

Graduate Student
› Mireia Pujals

Technicians
› Ana Matres
› Candida Salvans

SUMMARY

Tumor cell communication with its microenvironment plays 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 both amongst themselves as well as with their microenvironment during tumorigenesis. We then exploit these findings to contribute to the advancement of biomarker and drug target discovery. Our group’s working hypothesis is that cellular signaling pathways undergo alteration during tumorigenesis and that these changes translate in differential protein secretion, which can also potentially be explored 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, however, is that they contain hundreds of theoretical intracellular proteins. Recent reports evidence intracellular proteins with alternative extracellular functions, suggesting that new protein functions associated with alternative subcellular localizations might be implicated in tumorigenesis. Considering this novel concept, in the context of therapeutics and tumor invasion, we 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 messaging to communicate with each other and their microenvironment during tumorigenesis. Our principal goal is to characterize the mechanisms adopted by cancer cells which enable this cross-talk, and exploit our findings in order to accelerate biomarker and drug target discovery.

Imagen

Figure: Proteins change their sub-cellular localization in breast cancer. IHC analysis of secretome proteins in both normal and cancer breast tissue obtained from Protein Atlas database. In each case, one normal breast tissue and three different breast tumors are shown. (Top panel) IHC analysis of known extracellular proteins (CTGF and Cyr61) showing a clear cytoplasmic/membranous staining in both normal and breast cancer. (Bottom panel) IHC analysis of the two secretome proteins: Ssb and Thrap3, both classified as nuclear by Gene Ontology. In this case, these theoretically nuclear proteins show a clear cytoplasmic staining in some tumors but not in normal tissue, which is compatible with a change in subcellular localization in breast cancer.

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

  • Initiated three years ago, our subsequent switch in research direction has attracted additional funding and led to the recruitment of additional lab members in 2016. We transitioned from studying the cancer secretome following a methodology-driven approach to a biology-orientated approach, whereby non-classical secretion pathways will constitute an important area of our research over the coming years.
  • We have also established an important collaboration with the pharmaceutical company Servier.

HORIZONS 2017

  • 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 cancer
    Agency: Instituto Salud Carlos III
    Duration: 1/01/2016 - 31/12/2018
    Principal Investigator: Josep Villanueva