Director, Translational Research Program
“The secret behind the swift translation and application of cancer science and medicine is the two-way collaboration and dialect between researchers and clinical investigators in a multidisciplinary setting. It is thanks to our team science that translational and clinical research at VHIO are tightly connected, enabling us to deliver on the promise of precision medicine for an increasing number of our patients. Rapidly transforming cancer discovery into real benefits can and will only continue to happen through the pooling of expertise from bench to bedside and back.”
Josep Lluis Parra-Palau
Our group focuses on the study of brain tumors: primary tumors and brain metastasis. These are some of the most aggressive cancers and advancing progress within this field is consequently crucial.
In brain tumors, as in many other malignancies, evolving heterogeneity represents one of the most important challenges that are currently hampering our efforts aimed at more effectively treating cancer. We are studying genomic heterogeneity at the level of genomic alterations.
Tumors are composed of a mosaic of cell subclones that differ in their genomic alterations. We explore this genomic diversity present in glioblastoma and are analyzing intratumor genomic heterogeneity as it evolves over time in response to therapy. Following Darwinian selection rules, the cellular subclones enriched in response to treatment are those that will confer resistance and facilitate the identification of novel therapeutic targets to counter tumor resistance and relapse.
We have identified some of the candidate genes responsible for disease recurrence and are designing therapeutic approaches to prevent the reappearance of brain tumors. Moreover, in order to track, assess and better understand their evolving genomic heterogeneity, we are studying cell-free circulating tumor DNA in fluids from patients with brain tumors. Tumors shed DNA into the blood stream and the sequencing of this circulating DNA enables the accurate, less invasive molecular characterization of tumors, and these blood-based markers facilitate a more precise diagnosis, monitoring and identification of actionable gene mutations.
Finally, we study the role of the tumor microenvironment which, in the case of brain cancers, plays a critical role in cancer progression. Tackling the tumor microenvironment might be a way of attacking cancer independently of its heterogeneity. By eliminating the niche where cancer resides and thrives should help us to develop more effective anti-cancer compounds.
Figure: Studying brain tumors from all angles.
Seoane J. Division hierarchy leads to cell heterogeneity. Nature. 2017 Sep 14;549(7671):164-166.
Huber-Ruano I, Raventos C, Cuartas I, Sánchez-Jaro C, Wosikowski K, Janicot M, Seoane J. An Antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages. Ann Oncol. 2017 Sep 1;28(9):2278-2285
Seoane J, Gomis RR. TGFβ Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb Perspect Biol. 2017 Dec 1;9(12).
Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Apr;17(4):254-268.
Héctor G. Palmer
We aim to better understand the molecular mechanisms that confer tumors the capacity to self-renew, resist therapy, relapse and metastasize – all definitive factors in the survival of patients. We are dedicated to studying the consequences of intratumoral cell heterogeneity for tumor evolution and patient survival. Among the various cell populations that construct heterogeneous tumors, Cancer Stem Cells (CSC) are at the apex of a differentiation process within the cancerous tissue -- somewhat reminiscent of the hierarchy present in the normal tissue from which they originate. CSC can also compose the small reservoir of drug-resistant cells that trigger relapse after chemotherapy-induced remission, or give rise to distant metastasis. It is therefore becoming increasingly evident that the failure to eradicate cancer stem cells can promote tumor regrowth.
Our studies mainly focus on colorectal cancer. At molecular level we are analyzing the role of oncogenic pathways controlling the fate of Colon Cancer Stem Cells (CoCSC). RAS/PI3K/AKT, Wnt/beta-catenin and Notch pathways are drivers of cancer stem cell fate and lead to disease progression in many tumor types. Over recent years we have described a novel mechanism of resistance to PI3K and AKT inhibitory drugs conferred by beta-catenin in colorectal cancer. This is of great relevance since many patients in clinical studies do not respond to these therapies, and no molecular explanation behind such resistance had previously been described.
Our findings will facilitate the selection of ‘sensitive’ patients based on their expression of particular biomarkers predicting drug-response. We are currently focusing on a new generation of EGFR, Wnt/beta-catenin and Notch inhibitors in close collaboration with several major pharmaceutical companies, and have already experimentally evidenced the efficacy and mechanisms of action of these drugs in pre-clinical models of colorectal cancer with patient-derived xenografts. This marks an important milestone within the field; for decades colorectal cancer had been described as a paradigmatic tumor addicted to the oncogenic Wnt/beta-catenin pathway.
We also seek to identify the molecular determinants of response to these anti-cancer therapies that could consequently become robust biomarkers for the selection of ‘sensitive’ patients as well as better guide the design of future clinical trials. Some of these predictive biomarkers are mutations affecting components of the Wnt/beta-catenin pathway, whose identification can be perfectly standardized in clinical practice for patient selection.
Our collaboration with the Vall d'Hebron University Hospital's Medical Oncology Department, led by Josep Tabernero, as well as partnerships with pharmaceutical companies, will accelerate the translation of our findings into clinical practice, and hopefully revert the long-stalled scenario of CRC drugs.
Our group has developed a collection of PDX models derived from primary tumors or liver metastasis of more than 150 CRC patients. Most recently, we have also generated around 50 clinical trial associated xenografts (CTAX) from patients enrolled in these studies. During this past year we have also been developing translational research projects focusing on lung cancer, hepatocarcinomas and neuroendocrine tumors. We are generating PDX models, evaluating mechanisms of drug action, treatment resistance and sensitivity to novel therapeutic strategies tested in clinical trials.
Figure: Labeling dormant tumor cells. A. Lentivirus to label slow cycling cancer cells. B. Cells with chromatin labeled with H2BeGFP. C. Tumor organoid labeled with H2BeGFP to identify slow cycling cancer cells resistant to chemotherapy. D. A pulse chase labelling marks slow cycling cancer cells with low proliferation and differentiation and high self-renewal.
Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumägi A, Arjama M, Danielsen SA, Kryeziu K, Elez E, Tabernero J, Guinney J, Palmer HG, Nesbakken A, Kallioniemi O, Dienstmann R, Lothe RA. Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. Clin Cancer Res. Epub 2017 Dec 14.
Martinez-Marti A, Felip E, Matito J, Mereu E, Navarro A, Cedrés S, Pardo N, Martinez de Castro A, Remon J, Miquel JM, Guillaumet-Adkins A, Nadal E, Rodriguez-Esteban G, Arqués O, Fasani R, Nuciforo P, Heyn H, Villanueva A, Palmer HG, Vivancos A. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2017 Oct 1;28(10):2451-2457.
Byrne AT, Alférez DG, Amant F, Annibali D, Arribas J, Biankin AV, Bruna A, Budinská E, Caldas C, Chang DK, Clarke RB, Clevers H, Coukos G, Dangles-Marie V, Eckhardt SG, Gonzalez-Suarez E, Hermans E, Hidalgo M, Jarzabek MA, de Jong S, Jonkers J, Kemper K, Lanfrancone L, Mælandsmo GM, Marangoni E, Marine JC, Medico E, Norum JH, Palmer HG, Peeper DS, Pelicci PG, Piris-Gimenez A, Roman-Roman S, Rueda OM, Seoane J, Serra V, Soucek L, Vanhecke D, Villanueva A, Vinolo E, Bertotti A, Trusolino L. Interrogating open issues in cancer medicine with patient-derived xenografts. Nat Rev Cancer. 2017 Sep 15;17(10):632.
Dienstmann R, Elez E, Argiles G, Matos I, Sanz-Garcia E, Ortiz C, Macarulla T, Capdevila J, Alsina M, Sauri T, Verdaguer H, Vilaro M, Ruiz-Pace F, Viaplana C, Garcia A, Landolfi S, Palmer HG, Nuciforo P, Rodon J, Vivancos A, Tabernero J. Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights. Mol Oncol. 2017 Sep;11(9):1263-1272.