PROGRAMS & GROUPS

PLEASE CLICK ON THE CORRESPONDING PROGRAMS BELOW

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Joaquín Arribas

Preclinical Research Director
“Our Program is dedicated to advancing prediction science against cancer. At molecular level we develop xenograft models with explant tumors from patients in mice to study tumor development in optimized research models. By accelerating the detection of mutations and mechanisms of resistance to current therapies we are ultimately contributing to better outcomes for cancer patients.”

Click here to read our Program Director´s synopsis 2015

VHIO’s Preclinical Program is dedicated to developing novel strategies to treat highly aggressive tumors affecting the breast, pancreas, colon, lung or brain. These tumors are either resistant to therapy that worked for a limited period of time or lack an effective therapy, resulting in a bad prognosis. We aim to contribute to the discovery of new therapeutic opportunities for these patients and improve their outcomes. Furthermore, our Program also focuses on the discovery of novel tumor biomarkers that will help in the early diagnosis and follow-up of tumors.

We have developed several models to accomplish these objectives, including genetically modified mice and patient-derived xenografts. The latter, generated by implanting tumor pieces resected from patients at the Vall d’Hebron University Hospital (HUVH) into immunodeficient mice, closely resemble the original tumors.

Mouse models are also adequate for the study of tumor progression and the interactions between the microenvironment and tumor cells. These combined strategies allow us to both discover and tackle mechanisms of resistance to current anticancer agents and as well as test novel therapies.

Our Mouse Models of Cancer Therapies Group, headed by Laura Soucek, has continued to carry out research on the Myc oncogene and inflammatory components in cancer. They recently showed that inhibition of the tyrosine kinase BTK is an effective strategy to reduce fibrosis in pancreatic cancer. Pursuing the inactivation of Myc, they are developing several strategies based on cell-penetrating peptides and nanoparticles with particular emphasis on metastatic breast cancer and glioblastoma.

Josep Villanueva leads our Tumor Biomarkers Group which centers research on the characterization of mechanisms used by tumor cells to communicate with their microenvironment during tumorigenesis, mainly through secretion. Their expertise has been presented in a recent review providing an excellent overview of the main technical and biological issues related to cell line secretome analysis, discussing both the challenges and opportunities in its use for tumor biomarker discovery.

VHIO’s Experimental Therapeutic’s Group led by Violeta Serra has focused on the blockade of the PI3K/mTOR pathway, CDK4/6 as well as therapies targeting homologous recombination deficiency.

Finally, my own Growth Factors Group has continued to characterize a subtype of breast cancer known as HER2, and we have identified senescent cells as principal contributors to the growth of these tumors. We have also expanded insights into the mechanisms of resistance to anti-HER2 treatments and their relationship with different patterns of gene amplification. We have also characterized the role of proteolytic remodeling of the cell surface during breast cancer progression.

Our groups’ results have been published in several journals of excellence including The Journal of the National Cancer Institute (JNCI), Cancer Research, and Clinical Cancer Research among others. Our teams are also supported through international and national competitive grants from the Breast Cancer Research Foundation (BCRF), Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII), the BBVA Foundation and the Asociación Española Contra el Cáncer (Spanish Association Against Cancer, AECC).

PRECLINICAL RESEARCH GROUPS

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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 / Violeta Serra

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Principal Investigator
Violeta Serra

Medical Oncologists
Cristina Cruz
Jordi Rodón

Post-Doctoral Fellows
Alba Llop
Marta Palafox

Graduate Students
Marta Castroviejo
Albert Gris

Technicians
María Teresa Calvo
Judit Grueso
Marta Guzmán
Olga Rodríguez

Summary / Experimental Therapeutics Group

VHIO’s Experimental Therapeutics Group was set up to conduct bench-to-bed-side preclinical research in breast cancer to advance insights into HER2- and PI3K-therapeutic resistance. We have 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 PI3Ki 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, i.e. 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 tested.

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 DNAbinding 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. Nonetheless, PM01183 is active in most PARPiresistant 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, discovered new response biomarkers, and demonstrated the efficacy of hypothesis-based drug combinations.

Strategic Goals / Experimental Therapeutics Group

  1. Developing predictive and pharmacodynamic biomarkers of PI3K-pathway as well as CDK4/6 inhibitors.
  2. Unveiling novel mechanisms of resistance against targeted therapies in germline BRCA1/2 breast cancer.
  3. Establishing a patient tumor-derived breast cancer preclinical model to explore hypothesis-based combinatorial therapies.

Highlights 2015 / Experimental Therapeutics Group

  1. We have uncovered a potential mechanism or resistance to combined MEK and PI3K/Mtorc blockade in dual pathway Ras/PI3K- activated CRC.
  2. We have screened the antitumor activity of PI3K and CDK4/6 in six estrogen receptor-positive PDX, and establish that the combination of these two inhibitors results in superior response rate compared to single agents.
  3. 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 twenty-eight PDX.

PI Paper Pick / Experimental Therapeutics Group

García-García C, Rivas MA, Ibrahim YH, Calvo MT, Gris-Oliver A, Rodriguez O, Grueso J, Anton P, Guzman M, Aura C, Nuciforo P, Jessen K, Argiles G, Dienstmann R, Bertotti A, Trusolino L, Matito J, Vivancos A, Chicote I, Palmer HG, Tabernero J, Scaltriti M, Baselga J, Serra V. MEK plus PI3K/mTORC1/2 therapeutic efficacy is impacted by TP53 mutation in preclinical models of colorectal cancer. Clin Cancer Res. 2015;21(24):5499-5510.

Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, Tao JJ, Spratt DE, Viola-Villegas NT, Castel P, Minuesa G, Morse N, Rodón J, Ibrahim Y, Cortes J, Perez-Garcia J, Galvan P, Grueso J, Guzman M, Katzenellenbogen JA, Kharas M, Lewis JS, Dickler M, Serra V, Rosen N, Chandarlapaty S, Scaltriti M, Baselga J. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med. 2015;7(283):283ra51.

Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, Müller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM. Targeting a cell state common to triple-negative breast cancers. Mol Syst Biol. 2015;11(1):789.

Horizons 2016 / Experimental Therapeutics Group

  1. Identification of sensitivity/resistance biomarkers to PI3K 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.
  3. Continue expanding the panel of patient tumor-derived breast cancer models to investigate hypothesis-based, clinically-applicable therapy combinations in breast cancer:
    Overcoming resistance to anti-estrogen therapy
    Overcoming resistance to PARP inhibitors

Publications / Experimental Therapeutics Group

  1. MEK plus PI3K/mTORC1/2 therapeutic efficacy is impacted by TP53 mutation in preclinical models of colorectal cancer. García-García C, Rivas MA, Ibrahim YH, Calvo MT, Gris-Oliver A, Rodriguez O, Grueso J, Anton P, Guzman M, Aura C, Nuciforo P, Jessen K, Argiles G, Dienstmann R, Bertotti A, Trusolino L, Matito J, Vivancos A, Chicote I, Palmer HG, Tabernero J, Scaltriti M, Baselga J, Serra V. Clin Cancer Res. 2015 Dec 15;21(24):5499-510.
  2. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, Tao JJ, Spratt DE, Viola-Villegas NT, Castel P, Minuesa G, Morse N, Rodón J, Ibrahim Y, Cortes J, Perez-Garcia J, Galvan P, Grueso J, Guzman M, Katzenellenbogen JA, Kharas M, Lewis JS, Dickler M, Serra V, Rosen N, Chandarlapaty S, Scaltriti M, Baselga J. Sci Transl Med. 2015 Apr 15;7(283):283ra51.
  3. Targeting a cell state common to triple-negative breast cancers. Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, Müller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM. Mol Syst Biol. 2015 Feb 19;11:789.

Projects / Experimental Therapeutics Group

  1. 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
  2. Targeting PI3K and CDK4/6 in breast cancer
    (CP14/00028)
    Principal Investigator: Violeta Serra
    Funding Agency: ISCIII (Spanish Ministry of Health)
    Duration: 2015-2019
  3. TInhibition 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
  4. Translational research on human tumor heterogeneity to overcome recurrence and therapy
    Research Partner PI: Violeta Serra
    Funding Agency: ERA-NET
    Duration: 2015-2017
  5. 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
  1. Genetic determinants of sensitivity to PARP and Wee1 inhibitors in breast cancer and Genetic determinants of Wee1 inhibitors in TNBC
    Principal Investigator: Violeta Serra
    Funding Pharma: AstraZeneca
    Duration: 2014-2015
  2. Defining clinically actionable genetic alterations in DNA repair with in vivo response to the PARP inhibitor olaparib
    Principal Investigators: Violeta Serra, Joan Seoane, and Héctor G. Palmer
    Funding Pharma: AstraZeneca - Spain
    Duration: 2014-2015
  3. Anti-tumor activity of PM01183 in olaparib resistant patient-derived tumor xenografts with BRCA mutation
    Principal Investigator: Judith Balmaña
    Funding Pharma: Pharmamar
    Duration: 2014-2015
  4. Novel strategies in the breast cancer treatment: PI3K inhibitors and Rational design of combined therapy with PI3K inhibitors in breast cancer
    Principal Investigators: Violeta Serra and José Baselga
    Funding Agencies: GHD / FERO Foundation
    Duration: 2012-2015

Awards / Experimental Therapeutics Group

Miguel Servet Researcher, Instituto de Salud Carlos III (ISCIII)

Growth Factors Group / Joaquín Arribas

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Principal Investigator
Joaquín Arribas

Medical Oncologist
César Serrano

Post-Doctoral Fellows
Cristina Bernadó
Águeda Martínez Barriocanal
Beatriz Morancho
Kim Pedersen
Verónica Rodilla
Mariano F. Zacarías

Graduate Students
Faiz Bilal
Irene Rius
Rocío Vicario

Technicians
Marta Escorihuela
Cristina Ferrer
Mariona Gelabert
Antoni Luque
David Olivares

PhD Student
Junjie Zhang

Summary / Growth Factors Group

Our group has continued to investigate tumor progression and mechanisms of resistance to therapy focusing on HER2-positive breast cancer. We have previously shown that constitutively activated HER2 leads to premature senescence. These senescent cells remain metabolically active and display a remarkable secretory phenotype with a pro-metastatic effect. We have now deeply analyzed this secretome and evidenced that is enriched in the extracellular domain of membrane-bound proteins, concluding that cell-surface proteolytic remodeling tightly regulates secretion. Critically, this contributes to the prometastatic effect of HER2-induced senescent cells.

Throughout 2015 we have also 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 have identified IL-6 as one of the main contributors of this senescent secretome. Furthermore, we have investigated whether the patterns of HER2 gene amplification are related to resistance to current treatments against HER2-positive breast cancer. In contrast to other tumor types, we have shown in both clinical and preclinical samples that loss of one pattern of gene amplification is not necessary for acquired resistance.

Our group continues to collaborate with other VHIO teams, particularly with our Tumor Biomarkers Group led by Josep Villanueva, to characterize how senescent cells remodel the extracellular environment.

Strategic Goals / Growth Factors Group

  1. Develop novel therapeutic strategies to treat HER2-positive tumors and identify mechanisms of resistance to current therapies.
  2. Characterize the role of premature senescence in breast cancer progression and treatment.
  3. Study the involvement of the immune system in cancer progression.
  4. Evaluate the activity of novel therapeutic strategies in our panels of breast and pancreatic patientderived xenografts.
  5. Continue to develop a pancreatic cancer research program in close collaboration with VHIO’s Clinical Research Program, directed by Josep Tabernero.

Highlights 2015 / Growth Factors Group

  1. Our group has shown that senescent cells contribute to tumor growth by providing cytokines to proliferating cells.
  2. We have further explored the pro-metastatic effect of the secretome of HER2-induced senescent breast cancer cells, establishing the critical contribution of cell-surface proteolytic remodeling.
  3. In contrast to other tumors models, we have reported that the different patterns of amplification of the gene encoding HER2 are not related to acquired resistance to anti-HER2 treatments in breast cancer.
  4. Our paper Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy, J Natl Cancer Inst. 2014 Sep 24;106(11), was awarded the 2015 annual prized for collaborative research in oncology by the Red Temática de Investigación Cooperativa en Cáncer (RTICC).
  5. his same manuscript was also selected by the prestigious journal Cancer Discovery for a News in Brief review: Chemotherapy Helps Overcome Trastuzumab Resistance.

PI Paper Pick / Growth Factors Group

Morancho B, Martínez-Barriocanal Á, Villanueva J, Arribas J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 2015;17:106.

Vicario R, Peg V, Morancho B, Zacarias-Fluck M, Zhang J, Martínez-Barriocanal Á, Navarro Jiménez A, Aura C, Burgues O, Lluch A, Cortés J, Nuciforo P, Rubio IT, Marangoni E, Deeds J, Boehm M, Schlegel R, Tabernero J, Mosher R, Arribas J. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies. PLoS One. 2015;10(6):e0129876.

Zacarias-Fluck MF, Morancho B, Vicario R, Luque Garcia A, Escorihuela M, Villanueva J, Rubio IT, Arribas J. Effect of cellular senescence on the growth of HER2-positive breast cancers. J Natl Cancer Inst. 2015;107(5).

Publications / Growth Factors Group

  1. Morancho B, Martínez-Barriocanal Á, Villanueva J, Arribas J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 2015 Aug 12;17:106.
  2. Vicario R, Peg V, Morancho B, Zacarias-Fluck M, Zhang J, Martínez-Barriocanal Á, Navarro Jiménez A, Aura C, Burgues O, Lluch A, Cortés J, Nuciforo P, Rubio IT, Marangoni E, Deeds J, Boehm M, Schlegel R, Tabernero J, Mosher R, Arribas J. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies. PLoS One. 2015 Jun 15;10(6):e0129876.
  3. Zacarias-Fluck MF, Morancho B, Vicario R, Luque Garcia A, Escorihuela M, Villanueva J, Rubio IT, Arribas J. Effect of cellular senescence on the growth of HER2-positive breast cancers. J Natl Cancer Inst. 2015 May 13;107(5).
  4. Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 2015 Apr 15;75(8):1675-81.
  5. Scaltriti M, Nuciforo P, Bradbury I, Sperinde J, Agbor-Tarh D, Campbell C, Chenna A, Winslow J, Serra V, Parra JL, Prudkin L, Jimenez J, Aura C, Harbeck N, Pusztai L, Ellis C, Eidtmann H, Arribas J, Cortes J, de Azambuja E, Piccart M, Baselga J. High HER2 expression correlates with response to the combination of lapatinib and trastuzumab. Clin Cancer Res. 2015 Feb 1;21(3):569-76.

Projects / Growth Factors Group

  1. Nuevas Estrategias para Tratar el Cáncer de Mama Positivo para HER2.
  2. Terapias contra Tumores de Mama Positivos para p95HER2 y Senescencia Celular Inducida por p95HER2.
  3. 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.
  4. Immune profiles during breast cancer treatment. Indication of biomarkers of sensitivity/resistance.
  5. Overcoming heterogeneity in gastrointestinal stromal tumors: early detection of resistant subpopulations for tyrosin kinase inhibitor rotation.
  1. Targeting Oncogene-Induced Senescence in Breast Cancer.
  2. Immunoterapia contra tumores de mama positivos para p95HER2.
  3. Targeting Oncogene-Induced Senescence in Breast Cancer.
  4. Inmunoterapia contra tumores de mama positivos para p95HER2.
  5. Clinical Impact of Intratumor heterogeneity in metastasic breast cancer.

Mouse Models of Cancer Therapies Group / Laura Soucek

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Principal Investigator
Laura Soucek

Staff Scientist
Jonathan Whitfield

Post-Doctoral Fellow
Marie-Eve Beaulieu

Graduate Students
Toni Jauset González
Sandra Martínez
Daniel Massó Vallés

Technician
Érika Serrano del Pozo

Summary / Mouse Models of Cancer Therapies Group

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. Of note, our project was awarded a national prize for Innovation and Peptomyc obtained a ‘seal of excellence’ for an SME Instrument Phase I by the European Commission, under the scope of H2020.

We are currently validating our new therapeutic strategy in the 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, metastatic breast cancer). Glioblastoma in particular is the focus of our recently obtained grant for biomedical studies awarded by the BBVA Foundation.

In parallel, we have been pre-clinically validating new therapeutic strategies against components of the tumor microenvironment. One of these has been particularly successful, resulting in a paper published in Cancer Research: Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma, Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L. Cancer Res. 2015 Apr 15;75(8):1675-81), which led to new clinical trials for pancreatic cancer patients.

In recognition of research of excellence, Laura Soucek, ICREA Professor since 2014, was this year appointed as Associate Professor of the Universidad Autónoma de Barcelona.

Strategic Goals / Mouse Models of Cancer Therapies Group

  1. Design and characterization of new cell penetrating peptides for cancer therapy.
  2. Pre-clinical validation of a new generation of Omomyc-based peptides as a therapeutic strategy in breast, brain, and lung cancer.
  3. Define the role of Myc inflammatory effectors in pancreatic tumorigenesis and tumor maintenance.
  4. Preclinical validation of Myc inhibition in breast cancer metastasis.

Highlights 2015 / Mouse Models of Cancer Therapies Group

  1. Peptomyc was awarded a “Seal of Excellence” for a SME Instrument Phase I by the European Commission within the Horizon 2020 Program.
  2. We showed BTK inhibition as an effective strategy to reduce fibrosis in pancreatic cancer (Massó-Vallés et al., Cancer Research 2015).
  3. Laura Soucek was awarded a FERO fellowship for a nanotechnology project aiming at treating metastatic breast cancer with Omomyc-based nanoparticles.
  4. The Soucek laboratory was awarded a BBVA Foundation Grant in Biomedicine. Title: Validation of an innovative anti-Myc therapy in glioblastoma.

PI Paper Pick / Mouse Models of Cancer Therapies Group

Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L. Ibrutinib exerts potentantifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 2015;75(8):1675-1681.

Cecconi F, Soucek L, Taub DD, Ziparo E. Live or Die: Choice Mechanisms in Stressed Cells. Mediators Inflamm. 2015;2015:454863.

William H. Goodson III, Leroy Lowe, David O. Carpenter, Michael Gilbertson, Abdul Manaf Ali, Adela Lopez de Cerain Salsamendi, […], Laura Soucek, […], Zhiwei Hu. Assessing the Carcinogenic Potential of Low Dose Exposures to Chemical Mixtures in the Environment: The Challenge Ahead. Carcinogenesis. 2015;36 Suppl 1:S254-S296.

Stephanie C. Casey, Monica Vaccari, Fahd Al-Mulla, Rabeah Al-Temaimi, Amedeo Amedei, Mary Helen Barcellos- Hoff, Dustin Brown, Marion Chapellier, […], Sandra Ryeom, Hosni K. Salem, Ivana Scovassi, Neetu Singh, Laura Soucek, Louis Vermeulen, Jonathan R. Whitfield, Jordan Woodrick, Annamaria Colacci, William H. Bisson, and Dean W. Felsher. Assessing the Carcinogenic Potential of Environmental Chemicals: The Tumor Microenvironment. Carcinogenesis. 2015;36 Suppl 1:S160-S183.

Horizons 2016 / Mouse Models of Cancer Therapies Group

  1. Develop Myc inhibition as a viable therapeutic strategy in the clinic, beyond gene therapy, with specific focus on lung cancer.
  2. Define the role of Myc in breast cancer metastasis.

Publications / Mouse Models of Cancer Therapies Group

  1. Live or Die: Choice Mechanisms in Stressed Cells. Cecconi F, Soucek L, Taub DD, Ziparo E. Mediators Inflamm. 2015;2015:454863. doi: 10.1155/2015/454863. Epub 2015 Oct 8.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609861/pdf/MI2015-454863.pdf
  2. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Goodson WH 3rd, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci A, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams G, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi AI, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP Sr, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D'Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar PK, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Sing Leung P, Nangia-Makker P, Cheng QS, Robey RB, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Abd Hamid R, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell WK, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z. Carcinogenesis. 2015 Jun;36 Suppl 1:S254-96. doi: 10.1093/carcin/bgv039.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480130/pdf/bgv039.pdf
  3. The effect of environmental chemicals on the tumor microenvironment. Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, Brown DG, Chapellier M, Christopher J, Curran CS, Forte S, Hamid RA, Heneberg P, Koch DC, Krishnakumar PK, Laconi E, Maguer-Satta V, Marongiu F, Memeo L, Mondello C, Raju J, Roman J, Roy R, Ryan EP, Ryeom S, Salem HK, Scovassi AI, Singh N, Soucek L, Vermeulen L, Whitfield JR, Woodrick J, Colacci A, Bisson WH, Felsher DW. Carcinogenesis. 2015 Jun;36 Suppl 1:S160-83. doi: 10.1093/carcin/bgv035.
    http://carcin.oxfordjournals.org/content/36/Suppl_1/S160.full.pdf+html
  4. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L. Cancer Res. 2015 Apr 15;75(8):1675-81. doi: 10.1158/0008-5472.CAN-14-2852.
    http://cancerres.aacrjournals.org/content/75/8/1675.full.pdf+html
  5. The estrogen receptor fusion system in mouse models: a reversible switch. Whitfield J, Littlewood T, Evan GI, Soucek L.Cold Spring Harb Protoc. 2015 Mar 2;2015(3):227-34. doi: 10.1101/pdb.top069815. PMID: 25734072
  6. Tamoxifen administration to mice. Whitfield J, Littlewood T, Soucek L. Cold Spring Harb Protoc. 2015 Mar 2;2015(3):269-71. doi: 10.1101/pdb.prot077966. PMID: 25734062

Projects / Mouse Models of Cancer Therapies Group

New Project:

  1. BBVA Foundation Grant in Biomedicine. Title: Validation of an innovative anti-Myc therapy in glioblastoma. 2015-2017.

Ongoing:

  1. Grant for Emerging Research Group of Catalunya from the Agency for Management of University and Research Grants (AGAUR). 2014-2016.
  1. ERC Consolidator Grant. Title: Pushing Myc inhibition towards the clinic. 2014-2019.
  2. Instituto de Salud Carlos III: Proyectos FIS de Investigación en Salud. Title: Advancing Myc inhibition towards the clinic for the treatment of lung cancer. 2014-2017.
  3. Worldwide Cancer Research Grant. Title: Advancing Myc inhibition towards the clinic: characterization of an Omomyc cell-penetrating peptide. 2013-2016.

Awards / Mouse Models of Cancer Therapies Group

  1. The Soucek laboratory was awarded a BBVA Foundation Grant in Biomedicine. Title: Validation of an innovative anti-Myc therapy in glioblastoma
  2. The group was also awarded first prize in the Competition for Innovation by the Vall d´Hebron Institute of Research (VHIR), Barcelona, Spain. Title: Pushing Myc inhibition to the clinic using cell penetrating peptides. The project aims at developing a new therapeutic option for patients with cancer by targeting the Myc protein with an inhibitor peptide, Omomyc, a new pharmaceutical entity.
  3. Peptomyc was awarded a ´Seal of Excellence´ for an SME Instrument Phase I by the European Commission within the Horizon2020 Program.
  4. Laura was awarded a FERO fellowship for a nanotechnology project aiming at treating metastatic breast cancer with Omomyc-based nanoparticles.
  5. Marie-Eve Beaulieu, postdoctoral fellow in our lab, was awarded a prize for the best presentation at the 15th ASEICA International Congress (Seville, Spain, 21 – 23 October).
  6. Jonathan Whitfield, Staff Scientist in the Soucek lab, was awarded a fellowship to attend and present at the joint VHIO/Weizmann Institute of Science Joint Conference on Cell Communication in Translational Research, 22 – 23 January, 2015, Rehovot, Israel
  7. Daniel Massó, PhD student in the laboratory, was awarded best poster prize at the 9th Scientific Session of the Vall d’Hebron Research Institute (VHIR). Title: Targeting Myc in Breast Cancer Metastasis.
  8. Toni Jauset, PhD student in the laboratory, was awarded the poster prize at XII Scientific Session of Biochemistry and Molecular Biology of Universidad Autónoma de Barcelona. Title: Myc inhibition is an effective strategy against multiple subtypes of NSCLC.

Laura Soucek is currently a Reviewer for Anti-cancer Drugs, BBA (Biochimica et Biophysica Acta), BioEssays, Cancer Immunology and Immunotherapy, Cancer Research, Cancer Treatment Review, Clinical Cancer Research, Current Pharmaceutical Design, Developmental Dynamics, Drug Discovery Today, Gastroenterology Research and Practice, International Journal of Biological Sciences, IJEP (International Journal of Experimental Pathology), Journal of Experimental and Clinical Cancer Research, Molecular Biology and Evolution, Nature, Nature Cell Biology, Nature Communications, Nature Medicine, Oncogene, Oncogenesis, “Oncology” books, iConcept Press Ltd, Plos One, Therapeutic Advances in Chronic Disease, Tumor Biology. Laura Soucek is currently a Scientific Editor for the journal Cancer Discovery.

VHIO´s Mouse Models of Cancer Therapies in the media: examples of National and International news coverage:

Laura and her group also featured in the annual FERO Foundation´s video, presented at the annual FERO fundraising dinner in Barcelona:

Special coverage of the FERO video in the Spanish periodical La Vanguardia:

Tumor Biomarkers Group / Josep Villanueva

Imagen

Principal Investigator
Josep Villanueva

Post-Doctoral Fellows
Mercè Juliachs
Olga Méndez

Technician
Mireia Pujals

Summary / Tumor Biomarkers Group

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, and 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 such changes are translated into differential protein secretion, which can also potentially be exploited 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.

Proteomic technologies facilitate a genome-scale hunt for tumor-specific biomarkers and drug targets and could therefore revolutionize early detection and molecular characterization of cancer through noninvasive methods. The methodological focus of our group centers on quantitatively profiling the secreted sub-proteome (‘secretome’) of cells. 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.

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 nonclassical 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 this to advance biomarker and drug target discovery.

Strategic Goals / Tumor Biomarkers Group

  1. 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.
  2. Discovery of secreted signaling pathway-based tumor biomarkers and therapeutic targets using quantitative proteomics.
  3. Characterize the influence of non-classical secretion during tumorigenesis, particularly in tumor invasion and metastasis.

Highlights 2015 / Tumor Biomarkers Group

  1. In a recent review, Méndez O, Villanueva J. Challenges and opportunities for cell line secretomes in cancer proteomics. Proteomics Clin Appl. 2015, our group has presented an overview of the main technical and biological issues related to cell line secretome analysis, where we discussed both the challenges and opportunities for its use in tumor biomarker discovery.

PI Paper Pick / Tumor Biomarkers Group

Méndez O, Villanueva J. Challenges and opportunities for cell line secretomes in cancer proteomics. Proteomics Clin Appl. 2015;9(3-4):348-357.

Zacarias Fluck M, Morancho B, Vicario R, Luque-García A, Ferrer-Ramón C, Escorihuela M, Villanueva J, Rubio I, Arribas J. Effect of cellular senescence on the growth of HER2-positive breast cancers. J Natl Cancer Inst. 2015;107(5).

Morancho B, Martínez-Barriocanal Á, Villanueva J, Arribas J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 2015;17:106.

Horizons 2016 / Tumor Biomarkers Group

  1. Expand our secretome studies to characterize the influence of non-classical secretion in different aspects of tumor progression.
  2. Continue to characterize the invasive secretome in breast cancer with a focus on identifying new drug targets.

Publications / Tumor Biomarkers Group

  1. Méndez O, Villanueva J.Challenges and opportunities for cell line secretomes in cancer proteomics. Proteomics Clin Appl. 2015, Apr;9(3-4):348-57. doi: 10.1002/prca.201400131. Epub 2015 Feb 10. Review.
  2. Zacarias Fluck M, Morancho B, Vicario R, Luque-García A, Ferrer-Ramón C, Escorihuela M, Villanueva J, Rubio I, Arribas J. Cellular senescence supports the growth of HER2-positive breast cancers. J Natl Cancer Inst. 2015 May 13;107(5). pii: djv020. doi: 10.1093/jnci/djv020.
  3. Morancho B, Martínez-Barriocanal Á, Villanueva J, Arribas J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 2015 Aug 12;17:106. doi: 10.1186/s13058-015-0619-7.

Projects / Tumor Biomarkers Group

  1. Tumor Invasion-based Secretomes for Cancer Biomarker Discovery
    Agency: SNS FIS
    Duration: 01/01/2013 - 31/12/2015
    Principal Investigator: Josep Villanueva
  1. 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