"At VHIO we aim to deliver on the promise of precision oncology by translating discovery into more effective treatments for patients as quickly as possible."
Leticia de Mattos
Davis Torrejón Castro
Josep Lluís 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 critical.
One of the most important challenges in cancer is the heterogeneity of tumors, which we are studying at both the level of genomic alterations and that of cell differentiation state.
Tumors are composed by a mosaic of cell subclones that differ in their genomic alterations. We are studying genomic diversity present in glioblastoma and how intratumor genomic heterogeneity evolves over time in response to treatment. Following Darwinian selection rules, the cellular subclones enriched in response to treatment are those that will confer resistance to treatment and facilitate the identification of novel therapeutic targets to counter tumor resistance and relapse.
Besides the genomic intratumor diversity, cells within tumors although having the same genomic alterations might present differences in the epigenomic state. In particular, we are analyzing a subpopulation of undifferentiated cells responsible for tumor initiation and relapse. These cells have stem cell-like characteristics and are known as cancer-initiating cells (CICs) or cancer stem cells. CICs are considered to be responsible for the initiation, recurrence and chemo- and radio-resistance of tumors and therefore represent crucial therapeutic targets. Advancing our understanding of the molecular mechanisms involved in these cells is consequently paramount. We aim to identify novel markers for CICs, obtain new insights into the signaling pathways and molecular mechanisms involved in CICs, and design novel therapeutic approaches to target them.
Finally, due to genomic intratumor heterogeneity, we are interested in developing non-invasive methods to assess the genomic alterations present in tumors. We are studying cell-free circulating tumor DNA in fluids from patients with brain tumors. Tumors shed DNA into the blood stream and the subsequent sequencing of the circulating DNA enables the accurate, noninvasive molecular characterization of tumors. These circulating markers facilitate the diagnosis, monitoring and identification of actionable gene mutations of tumors.
De Mattos-Arruda L, Mayor R, Ng CKY, Weigelt B, Martínez-Ricarte F, Torrejon D, Oliveira M, Arias A, Raventos C, Tang J, Guerini-Rocco E, Martínez-Sáez E, Lois S, Marín O, de la Cruz X, Piscuoglio S, Towers R, Vivancos A, Peg V, Ramon y Cajal S, Carles J, Rodon J, González-Cao M, Tabernero J, Felip E, Sahuquillo J, Berger MF, Cortes J, Reis-Filho JS, Seoane J. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.
Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG 2nd, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015;5(11):1164-1177.
Iyengar PV, Jaynes P, Rodon L, Lama D, Law KP, Lim YP, Verma C, Seoane J, Eichhorn PJ. USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. Sci Rep. 2015;5:14733.
Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly AL, Sokalingum Pillay N, Desaiah D, Estrem ST, Paz-Ares L, Holdoff M, Blakeley J, Lahn MM, Baselga J. First-in-Human Dose Study of the Novel Transforming Growth Factor-b Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma. Clin Cancer Res. 2015;21(3):553-560.
Participation in Research Contracts:
Grantor: Fundación para la Investigación del Cáncer de la Universidad de Salamanca (FICUS) y el Centro de Investigación del Cáncer (CIC).
IV Premio Nacional Doctores Diz Pintado. January 2015.
Héctor G. Palmer
Our main interest is to better understand the molecular mechanisms that confer tumors the ability 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 different cell populations that build an heterogeneous tumor, 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 are responsible for relapse after chemotherapy-induced remission, or give rise to distant metastasis. It is therefore becoming evident that therapies failing to eliminate cancer stem cells may allow re-growth of the tumor.
Colorectal cancer is our prime focus of study. At molecular level, we are analyzing the role of those oncogenic pathways that control the fate of Colon Cancer Stem Cells (CoCSC). RAS/PI3K/AKT and Wnt/beta-catenin pathways are two drivers of cancer stem cell fate and lead to progression across 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 clinical relevance since many patients in clinical trials are not responding to these drugs and no molecular explanation behind resistance had previously been evidenced. These 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 Wnt/betacatenin inhibitory drugs in close collaboration with several major pharmaceutical companies and have already produced experimental evidence on 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 in the field – for decades colorectal cancer was described as a paradigmatic tumor addicted to the oncogenic Wnt/beta-catenin pathway. We also work on identifying the molecular determinants of response to these drugs that could become robust biomarkers to select ‘sensitive’ patients and 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 Medical Oncology Service at the Vall d’Hebron University Hospital and pharmaceutical companies will accelerate the translation of our findings into clinical practice and hopefully revert the long-stalled scenario of CRC therapies.
Our group has developed a collection of patient-derived xenograft (PDX) models from more than 100 CRC patients. They are derived from primary tumors or liver metastasis. More recently we have also generated around 30 clinical trial associated xenografts (CTAX) from patients enrolled in clinical studies. All these models faithfully recapitulate original patient tumors and, most importantly, their response to treatments, becoming the gold standard for studying mechanisms of drug-resistance or sensitivity.
Arques O, Chicote I, Puig I, Tenbaum SP, Argiles G, Dienstmann R, Fernandez N, Caratu G, Matito J, Silberschmidt D, Rodon J, Landolfi S, Prat A, Espin E, Charco R, Nuciforo P, Vivancos A, Shao W, Tabernero J, Palmer HG. Tankyrase inhibition blocks Wnt/b-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res. 2016;22(3):644-656. Epub 2015 Jul 29.
García-García C; Rivas M; Ibrahim Y; Calvo MT; Grueso J; Antón P; Aura C; Jessen K; Dienstmann R; Palmer HG; Tabernero J; Scaltriti M; Baselga J; Serra V. Sensitivity to MEK and mTORC1/2 inhibition in colorectal cancer is dictated by TP53 mutational status. Clin Cancer Res. 2015;21(24):5499-5510.
Barbáchano A; Pereira F; Segura M; Ordoñez-Morán P; González-Sancho JM; Fernández-Barral A; Hanniford D; Martínez N; Real FX; Palmer HG; Rojas JM; Hernando E; Muñoz A. SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150. Oncogene. 2015;5:14733. Epub 2015 Oct 12.
Herrero A, Pinto A, Colón-Bolea P, Casar B, Jones M, Agudo-Ibáñez L, Vidal R, Tenbaum SP, Nuciforo P, Valdizán EM, Horvath Z, Orfi L, Pineda-Lucena A, Bony E, Keri G, Rivas G, Pazos A, Gozalbes R, Palmer HG, Hurlstone A, Crespo P. Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell. 2015;28(2):170-182.
FERO Foundation Fellowship: Personalized genetic studies to investigate drug-resistance and relapse in colon cancer - Unmasking hiding resistant clones.
Title: METHODS OF TREATING COLORECTAL CANCERS HARBORING UPSTREAM WNT PATHWAY MUTATIONS.
Patent Office: United States Patent and Trademark Office. Application Number: 62/119,939.
Patentee: Novartis AG
Profit entity: Novartis AG
Inventors: Linda BAGDASARIAN, Feng CONG, Savina JAEGER, Margaret Elise MCLAUGHLIN, Ronald MEYER, Andrea MYERS, Michael Ross PALMER, Youzhen WANG, Stephen David WOOLFENDEN, Ana VIVANCOS, Héctor PALMER .