CFAH SARCOMA TRANSLATIONAL RESEARCH GROUP – VHIO – Vall d'Hebron Institute of Oncology

SARCOMA TRANSLATIONAL RESEARCH GROUP

PRECLINICAL & TRANSLATIONAL RESEARCH
Sarcoma Translational Research Group

CÉSAR SERRANO
Principal Investigator
Biosketch

Sarcoma encompasses >70 entities of mesenchymal origin, constituting 1-2% of all cancers. From a biological perspective sarcomas can be classified into two broad categories: genomically simple sarcomas driven by simple genetic alterations, such as translocations or specific activating mutations; and tumors with complex and unbalanced genomic aberrations. Each of these categories includes diverse sarcomas subtypes showing often profound differences in their molecular makeup, course of disease and therapeutic approach.

Our group focuses on the study of sarcomas with oncogenic dependency on specific drivers of disease. Among them, gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm and constitutes a paradigmatic model to study oncogene addiction and identify structural and functional mechanisms for drug response and drug resistance.

Ongoing aim efforts aim at a deeper biological understanding of GIST and other sarcomas in order to advance drug development. One of the major hurdles with a direct impact on patients’ outcomes, concerns the heterogeneity of mechanisms of resistance. Our overarching goal is therefore to identify crucial molecules and signaling mechanisms in GIST biology that can serve as therapeutic vulnerabilities.

We also continue to validate a core set of molecules co-regulated by KIT downstream pathways and identified through extensive whole transcriptome studies across several clinically representative human GIST models. Our group is particularly interested in those with pro-survival function to better understand cellular adaptation to driver inhibition, which may eventually be novel therapeutic targets.

Our goal is to have a true impact clinically by improving the daily treatment and care of our sarcoma patients. We are proud to report that our Sarcoma Multidisciplinary Unit has been designated as an Expert National Sarcoma Center by the Spanish Ministry of Health, and thus constitutes an optimal setting to translate cancer discovery into true clinical outcomes.


STRATEGIC GOALS

  • Identification of critical molecular mediators of oncogenic signaling in sarcomas.
  • Characterization of response and resistance mechanisms to targeted therapies in sarcomas.
  • Preclinical modelling and validation of therapeutic strategies to translate at the clinical level.

HIGHLIGHTS

  • We have recently determined the molecular basis for the limited clinical benefit of TKIs in imatinib-resistant GIST.
  • Our group has led high-level studies towards the clinical implementation of liquid biopsy in GIST patients.
  • César Serrano has been involved in the international consortiums that have led to the approvals of ripretinib and avapritinib in GIST.
  • We are actively engaged with sarcoma patients and advocacy groups. For example, Dr. Serrano coordinates the annual symposium of sarcoma patients in Spain. Additionally, the clinical and translational sarcoma teams at VHIO/Vall d’Hebron Hospital have starred in the documentary “#Backstage: Hablemos de un sarcoma”.

TEAM

  • Principal Investigator
    • César Serrano
  • Pre-Doctoral Fellows
    • Alfonso García Valverde
    • David Gómez Peregrina
    • Iván Olivares Rivas
    • Daniel Pilco Janeta
  • Student
    • Marc Segarra Mondéjar
  • Technician
    • Jordi Rosell Aluja. (Lab Technician)

 


Most Relevant Scientific Publications

  • Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019 Mar;120(6):612-620.
  • Serrano C, García-Del-Muro X, Valverde C, Sebio A, Durán J, Manzano A, Pajares I, Hindi N, Landolfi S, Jiménez L, Rubió-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Díaz-Beveridge R, Martínez-Marín V, Vicente-Baz D, Vivancos A, Hernández-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. 2019 May;24(5):680-687.
  • George S, Serrano C, Hensley ML, Ray-Coquard I. Soft Tissue and Uterine Leiomyosarcoma. J Clin Oncol. 2018 Jan 10;36(2):144-150.
  • Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, Serrano C, Eilers G, Zhu M, Ketzer J, Wardwell S, Ning Y, Song Y, Kohlmann A, Wang F, Clackson T, Heinrich MC, Fletcher JA, Bauer S, Rivera VM. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014 Nov 15;20(22):5745-5755.
  • George S, Barysauskas C, Serrano C, Oduyebo T, Rauh-Hain JA, Del Carmen MG, Demetri GD, Muto MG. Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma. Cancer. 2014 Oct 15;120(20):3154-8.
  • Serrano C, Wang Y, Mariño-Enríquez A, Lee JC, Ravegnini G, Morgan JA, Bertagnolli MM, Beadling C, Demetri GD, Corless CL, Heinrich MC, Fletcher JA. KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol. 2015 Aug 1;33(22):e93-6.

All Publications

  • Serrano C, Leal A, Kuang Y, Morgan JA, Barysauskas CM, Phallen J, Triplett O, Mariño-Enríquez A, Wagner AJ, Demetri GD, Velculescu VE, Paweletz CP, Fletcher JA, George S. Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Dec 15;25(24):7287-7293.
  • Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu MJ, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary KIT mutations in imatinib-resistant gastrointestinal stromal tumors. Br J Cancer. 2019 Mar;120(6):612-620.
  • Serrano C, García-Del-Muro X, Valverde C, Sebio A, Durán J, Manzano A, Pajares I, Hindi N, Landolfi S, Jiménez L, Rubió-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Díaz-Beveridge R, Martínez-Marín V, Vicente-Baz D, Vivancos A, Hernández-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. 2019 May;24(5):680-687.
  • Serrano C, García-Del-Muro X, Valverde C, Sebio A, Durán J, Manzano A, Pajares I, Hindi N, Landolfi S, Jiménez L, Rubió-Casadevall J, Estival A, Lavernia J, Safont MJ, Pericay C, Díaz-Beveridge R, Martínez-Marín V, Vicente-Baz D, Vivancos A, Hernández-Losa J, Arribas J, Carles J. Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib. Oncologist. 2019 May;24(5):680-687.
  • Ravegnini G, Serrano C, Simeon V, Sammarini G, Nannini M, Roversi E, Urbini M, Ferrè F, Ricci R, Tarantino G, Pantaleo MA, Hrelia P, Angelini S. The rs17084733 variant in the KIT 3′ UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumour: a sponge-like mechanism conferring disease susceptibility. Epigenetics. 2019 Apr 13:1-13.
  • Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, Yu C, Mannan AM, Rubin BP, Demetri GD, Raut CP, Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2019 Mar;120(6):612-620.
  • Ravegnini G, Sammarini G, Serrano C, Nannini M, Pantaleo MA, Hrelia P, Angelini S. Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors. Ther Adv Med Oncol. 2019 Mar 1;11:1758835919831902.
  • Serrano-Candelas E, Ainsua-Enrich E, Navinés-Ferrer A, Rodrigues P, García-Valverde A, Bazzocco S, Macaya I, Arribas J, Serrano C, Sayós J, Arango D, Martin M. Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth. Mol Oncol. 2018 Aug;12(8):1383-1397.
  • Moura DS, Ramos R, Fernandez-Serra A, Serrano T, Cruz J, Alvarez-Alegret R, Ortiz-Duran R, Vicioso L, Gomez-Dorronsoro ML, Garcia Del Muro X, Martinez-Trufero J, Rubio-Casadevall J, Sevilla I, Lainez N, Gutierrez A, Serrano C, Lopez-Alvarez M, Hindi N, Taron M, López-Guerrero JA, Martin-Broto J. Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients. Oncotarget. 2018 Apr 3;9(25):17576-17588.
  • George S, Serrano C, Hensley ML, Ray-Coquard I. Soft Tissue and Uterine Leiomyosarcoma. J Clin Oncol. 2018 Jan 10;36(2):144-150.
  • Serrano C, George S, Valverde C, Olivares D, García-Valverde A, Suárez C, Morales-Barrera R, Carles J. Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors. Target Oncol. 2017 Jun;12(3):277-288.
  • Poveda A, García Del Muro X, López-Guerrero JA, Cubedo R, Martínez V, Romero I, Serrano C, Valverde C, Martín-Broto J; GEIS (Grupo Español de Investigación en Sarcomas/Spanish Group for Sarcoma Research). GEIS guidelines for gastrointestinal sarcomas (GIST). Cancer Treat Rev. 2017 Apr;55:107-119.
  • Martin-Broto J, Martinez-Marín V, Serrano C, Hindi N, López-Guerrero JA, Bisculoa M, Ramos-Asensio R, Vallejo-Benítez A, Marcilla-Plaza D, González-Cámpora R. Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis. Clin Transl Oncol. 2017 May;19(5):536-545.
  • Poveda A, Martinez V, Serrano C, Sevilla I, Lecumberri MJ, de Beveridge RD, Estival A, Vicente D, Rubió J, Martin-Broto J. SEOM Clinical Guideline for gastrointestinal sarcomas (GIST) (2016). Clin Transl Oncol. 2016 Dec;18(12):1221-1228.
  • Serrano C, Romagosa C, Hernández-Losa J, Simonetti S, Valverde C, Moliné T, Somoza R, Pérez M, Vélez R, Vergés R, Domínguez R, Carles J, Ramón Y Cajal S. RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas. Cancer. 2016 Jan 1;122(1):99-107.
  • Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, Serrano C, Eilers G, Zhu M, Ketzer J, Wardwell S, Ning Y, Song Y, Kohlmann A, Wang F, Clackson T, Heinrich MC, Fletcher JA, Bauer S, Rivera VM. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014 Nov 15;20(22):5745-5755.
  • George S, Barysauskas C, Serrano C, Oduyebo T, Rauh-Hain JA, Del Carmen MG, Demetri GD, Muto MG. Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma. Cancer. 2014 Oct 15;120(20):3154-8.
  • Serrano C, George S. Recent advances in the treatment of gastrointestinal stromal tumors. her Adv Med Oncol. 2014 May;6(3):115-27.
  • Serrano C, Wang Y, Mariño-Enríquez A, Lee JC, Ravegnini G, Morgan JA, Bertagnolli MM, Beadling C, Demetri GD, Corless CL, Heinrich MC, Fletcher JA. KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol. 2015 Aug 1;33(22):e93-6.
  • Serrano C, Nucci MR, Tirumani SH, Raut CP, George S. Hormone dependency in metastatic low-grade leiomyosarcoma following uterine smooth muscle tumour of uncertain malignant potential. BMJ Case Rep. 2014 Mar 27;2014.
  • Simonetti S, Serrano C, Hernández-Losa J, Bagué S, Orellana R, Valverde C, Lleonart ME, Aizpurua M, Carles J, Ramón y Cajal S, Romagosa C. Schwannomas, benign tumors with a senescent phenotype. Histol Histopathol. 2014 Jun;29(6):721-30.
  • Serrano C, George S. Leiomyosarcoma. Hematol Oncol Clin North Am. 2013 Oct;27(5):957-74.
  • Serrano C, Simonetti S, Hernández-Losa J, Valverde C, Carrato C, Bagué S, Orellana R, Somoza R, Moliné T, Carles J, Huguet P, Romagosa C, Ramón y Cajal S. BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours. Histopathology. 2013 Feb;62(3):499-504.
  • Morales-Barrera R, Bellmunt J, Suárez C, Valverde C, Guix M, Serrano C, Gallén M, Carles J. Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function. Eur J Cancer. 2012 Aug;48(12):1816-21.
  • Serrano C, Morales R, Suárez C, Núñez I, Valverde C, Rodón J, Humbert J, Padrós O, Carles J. Emerging therapies for urothelial cancer. Cancer Treat Rev. 2012 Jun;38(4):311-7.
  • Serrano C, Cortés J, De Mattos-Arruda L, Bellet M, Gómez P, Saura C, Pérez J, Vidal M, Muñoz-Couselo E, Carreras MJ, Sánchez-Ollé G, Tabernero J, Baselga J, Di Cosimo S. Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol. 2012 Apr;23(4):897-902.
  • Serrano C, Alonso J, Gómez-Mariano G, Aguirre E, Diez O, Gadea N, Bosch N, Balmaña J, Graña B. Low penetrance hereditary retinoblastoma in a family: what should we consider in the genetic counselling process and follow up? Fam Cancer. 2011 Sep;10(3):617-21.
  • Cedrés S, Quispe I, Martínez P, Longo M, Rodríguez E, Serrano C, Muñoz E, Pallisa E, Felip E. Computed tomography (CT) predicts accurately the pathologic tumour size in stage I non-small-cell lung cancer (NSCLC). Clin Transl Oncol. 2010 Dec;12(12):829-35.
  • Serrano C, García Á, Brana I, Pérez-Benavente A, Oaknin A. Angiosarcoma of the ovary: is it always a lethal disease? J Clin Oncol. 2010 Nov 20;28(33):e675-7.
  • Serrano C, Markman B, Tabernero J. Integration of anti-epidermal growth factor receptor therapies with cytotoxic chemotherapy. Cancer J. 2010 May-Jun;16(3):226-34.
  • Serrano C, Suárez C, Andreu J, Carles J. Acute aortic dissection during sorafenib-containing therapy. Ann Oncol. 2010 Jan;21(1):181-2.
  • Prat A, Serrano C, Valverde C, Calvo E. Acute severe hypothyroidism induced by sunitinib. Radiother Oncol. 2008 Oct;89(1):124-5.
  • Prat A, Martínez P, Serrano C, Montero MA, Andreu J, Cortés J. Acute lung injury associated with docetaxel and bevacizumab. Clin Oncol (R Coll Radiol). 2007 Dec;19(10):803-5.
  • Serrano C, Mackintosh C, Herrero D, Martins AS, de Alava E, Hernández T, Pérez-Fontán J, Abad M, Pérez A, Serrano E, Bullón A, Orfao A. Imatinib is not a potential alternative treatment for uterine leiomyosarcoma. Clin Cancer Res. 2005 Jul 1;11(13):4977-9.