Director, Preclinical Research Program
“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.”
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.
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.
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.
Enrique Javier Arenas
Luis Alfonso Garcia
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.
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.
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.
Daniel Massó Vallés
Toni Jauset González
Sandra Martínez Martín
Virginia Castillo Cano
Laia Foradada Felíp
Génesis Martín Fernandez
Meritxell Sánchez Hervás
Erika Serrano del Pozo
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).
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.
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.
Juan Manuel Duran
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.
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.