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Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies. This work was supported by Instituto de Salud Carlos III_FEDER (PI17/00464 and CB16/12/00361), by the Consejería de Salud, Junta de Andalucía (PI-0013-2018), and by Fundación María García Estrada.

Wilms tumour (WT) is the most common renal tumour in children. Most WT patients respond to chemotherapy, but subsets of tumours develop resistance to chemotherapeutic agents, which is a major obstacle in their successful treatment. Multidrug resistance transporters play a crucial role in the development of resistance in cancer due to the efflux of anticancer agents out of cells. The aim of this study was to explore several human multidrug resistance transporters in 46 WT and 40 nonneoplastic control tissues (normal kidney) from patients selected after chemotherapy treatment SIOP 93–01, SIOP 2001. Our data showed that the majority of the studied multidrug resistance transporters were downregulated or unchanged between tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues. MDR3 and MRP1 overexpression correlated with highrisk tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the time of disease-free survival was significantly shorter in patients with high transcript levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT treatment, probably by alteration of an unspecific drug excretion system. Besides, within the blastemal subtype, we observed patients with low MDR3 expression were significantly associated with a better outcome than patients with high MDR3 expression. We could define two types of blastemal WT associated with different disease outcomes, enabling the stratification of blastemal WT patients based on the expression levels of the multidrug resistance transporter MDR3. Ministerio de Economía y Competitividad PI1401466, RD06/0020/0059, PI1100018, CD06/00001 Red Tematica de Investigacion Cooperativa en Cancer RD12/0036/0017 Unión Europea FP7-HEALTH- 2011-two-stage, Project ID 278742 EUROSARC Instituto de Salud Carlos III FIS PI13/02282

Resumen del trabajo presentado a la EACR-OECI Conference: "Precision Medicine for Cancer", celebrada en Neumünster Abbey (Luxemburgo) del 1 al 4 de marzo de 2015.-- et al., An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cáncer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV prometer. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 reciplent mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventivo and therapeutic strategies.

Resumen del póster presentado al VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas, celebrado en el Centro de Investigación del Cáncer (CIC-IBMCC) del 21 al 22 de mayo de 2015.-- et al., Este póster ha ganado el 1er premio en el Concurso de Pósters de Oncología Básica y Traslacional en Oncología para Jóvenes Investigadores, celebrado durante el VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas., An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cancer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV promoter. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 recipient mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventive and therapeutic strategies.

Wilms tumor (WT) is an embryonal malignant neoplasm of the kidney that accounts for 6–7% of all childhood cancers. WT seems to derive from multipotent embryonic renal stem cells that have failed to differentiate properly. Since mechanisms underlying WT tumorigenesis remain largely unknown, the aim of this study was to explore the expression of embryonic stem cell (ESC) markers in samples of WT patients after chemotherapy treatment SIOP protocol, as the gene expression patterns of ESC are like those of most cancer cells. We found that expression of ESC markers is heterogeneous, and depends on histological WT components. Interestingly, among ESC markers, HMGA2 was expressed significantly stronger in the blastemal component than in the stromal and the normal kidney. Moreover, two subsets of patients of WT blastemal type were identified, depending on the expression levels of HMGA2. High HMGA2 expression levels were significantly associated with a higher proliferation rate (p=0.0345) and worse patient prognosis (p=0.0289). The expression of HMGA2 was a stage-independent factor of clinical outcome in blastemal WT patients. Our multivariate analyses demonstrated the association between LIN28B–LET7A–HMGA2 expression, and the positive correlation between HMGA2 and SLUG expression (p=0.0358) in blastemal WT components. In addition, patients with a poor prognosis and high HMGA2 expression presented high levels of MDR3 (multidrug resistance transporter). Our findings suggest that HMGA2 plays a prominent role in the pathogenesis of a subset of blastemal WT, strongly associated with relapse and resistance to chemotherapy., LHP and DJGD are supported by Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0017). CS is supported by a contract from Nicolás Monardes Program, Consejería de Salud, Junta de Andalucía. Research in Enrique de Alava’s lab is supported by the Ministry of Economy and Competitiveness of Spain-FEDER (CIBERONC, PI1700464, RD06/0020/0059, FMGE) and the European Commission (FP7-HEALTH-2011-two-stage, Project ID 278742 EUROSARC). DJGD is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016). Research in Carmen Sáez’s lab is also supported by research grants from the Instituto de Salud Carlos III, FIS PI13/02282.

Ewing sarcoma (ES) is an aggressive tumor defined by EWSR1 gene fusions that behave as an oncogene. Here we demonstrate that RING1B is highly expressed in primary ES tumors, and its expression is independent of the fusion oncogene. RING1B-depleted ES cells display an expression profile enriched in genes functionally involved in hematological development but RING1B depletion does not induce cellular differentiation. In ES cells, RING1B directly binds the SCN8A sodium channel promoter and its depletion results in enhanced Nav1.6 expression and function. The signaling pathway most significantly modulated by RING1B is NF-κB. RING1B depletion results in enhanced p105/p50 expression, which sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. Reduced NaV1.6 function protects ES cells from apoptotic cell death by maintaining low NF-κB levels. Our findings identify RING1B as a trait of the cell-of-origin and provide a potential targetable vulnerability., IHM is a Miguel Servet investigator (Instituto de Salud Carlos III, ISCIII). This work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncologia de Catalunya and by grants from ISCIII-FEDER (PS09/00973; RIC RD12/0042/0014, Red HERACLES), Ministerio de Economía y Competitividad (MEC) (SAF2012-31089 and SAF2015-69762-R), FEDER Funds and by the Asociación Española Contra el Cáncer (AECC). E.Á.’s lab is supported by the AECC, MEC-FEDER (RD12/0036/0017, PT13/0010/0056, RTC-2014-2102-1, ISCIII Sara Borrell CD06/00001, PI12/03102, PI14/01466), the European FP7 Projects EuroSARC (FP7-HEALTH-2011-two-stage, Project 278742 EUROSARC), Euroewing (FP7-HEALTH.2013.2.4.1-1, Project 602856), Fundación Memoria de DM Solorzano Barruso, Fundación Cris contra el Cáncer, Pablo Ugarte Foundation, and Fundación M. García Estrada. O.M.T. is funded by ISCIII-FEDER (CES12/021) and the AECC. AMC is funded by the European FP7 projects (FP7/2007-2013) under a Marie Curie International Reintegration Grant (PIRG-08- GA-2010-276998) and ISCIII-FEDER (CP13/00189). The Ewing group at the Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, is supported by the AECC and the generous donations from Pablo Ugarte Foundation.