Primary brain tumors represent 5% of all cancers in most western countries. In Spain, the incidence per 100.000 population range from 4.4 to 8.5 cases. The annual incidence of this tumor in Spain is about 6 cases per 100.000 population, near 2400 new cases each year. Glioblastoma (GBM). GBM is the most common and lethal primary malignant tumor of the central nervous system. Although a transient response to therapy is observed, tumor recurrence is inevitable and occurs within tissue that has received cytotoxic therapy, which suggests that a subpopulation of resistant cells (with stem cell features) is responsible for tumor regrowth. Unravelling the cellular composition and molecular pathways of gliomas are essential for therapeutic breakthroughs.

Peripheral nerve sheath tumors (PNSTs). Malignant PNSTs (MPNSTs) are rare tumors that often occur in patients with neurofibromatosis type 1. Accurate pathologic diagnosis remains a challenge in many cases. The understanding of the molecular pathogenesis of MPNST represents the best opportunity to develop new strategies for management of patients with this disease. Neurofibromatosis (NF). Progress in molecular biology and the development of mouse models are helping to elucidate the etiology of NF1 and NF2 and its clinical manifestations. Furthermore, these advances are raising the prospect of therapeutic intervention for these complex and distressing diseases.

The annual incidence of childhood cancer in Spain is 155.3 cases per million children. 57% of these tumours are solid (incidence of 88.6 per million), which is more than 570 new cases per year. In spite of the advances in the therapy of childhood cancer - thought that there is no prevention, therapy is the basis of the war against this condition – still cancer is the first disease-related cause of death before 20 years of age. In Spain, cancer is the cause of about 25% of deaths in childhood and 15% in adolescence, with solid tumours being responsible of 55-60% of these deaths.

Endometrial Cancer (EC) is ranked as the most common gynecologic malignancy of the female genital tract and the fourth most common neoplasia in women after breast, colorectal and lung cancer. Data from Spain (Globocan 2002) estimates that about 4500 new cases of EC will be diagnosed in 2012 (age-adjusted incidence: 10.4 per 100.000 population), but only about 1000 deaths are expected. According to these statistics, EC is considered to be a type of cancer with relatively good prognosis, since it is usually detected in its initial stages by the presentation of disease-related symptoms. In the early stages, EC is confined to the endometrium and can be treated by hysterectomy with or without adjuvant treatment resulting in survival rates around 96% at five-year time. However, still 30% of EC cases are diagnosed in regional or distant stages, and are related to lower survival rates, 67% and 16%, respectively. EC is made up of a biologically and histologically diverse group of neoplasms that are characterized by having different pathogeneses.

Spain has excellent research groups in the three WPs of the program, as shown in the section “scientific and technological background”. There are excellent connections with the main clinical cooperative groups and scientific societies, both National or international, as stated in the letters of support listed in the section “functional structure of the program”, and available upon request. In addition, the Spanish National Registry of Childhood Tumours includes all the paediatric oncology units of Spain and the collaboration of the regional population-based registries. Currently, it covers 93% of all childhood cancer in Spain.

Careful discussion on the synergies found between groups of this program helped to find several common objectives for the whole program, and several specific objectives for each particular WP, Tasks, deliverables, deadlines, involved and responsible are identified for each of them. Common objectives of the program. Establishment of platforms and common methodologies, including sharing samples and writing common SOPs (2 for each Objective) which will be shared within the RTICC. These will include:

1. WP1. Collection of tumor samples, cell lines and nucleic acids.
2. WP2. Screening of new compounds in in vitro tumor models.
• Task 2.1. The role of PARP1 inhibitors and NEDD8 inhibitors will be further explored in Ewing sarcoma models.
• Task 2.2. The pathway of NOTCH and Hedgehog will be explored in rhabdomyosarcoma models.
• Task 2.3. Inhibitors of TGF-beta, mTOR, eif4E will be explored in GBM.
• Task 2.4. Inhibitors of HER3 will be tested in PNST.
• Task 2.5. Optimization and development of new models for testing the effects of drugs in endometrial tumorigenesis (cell cultures and tumor cell explants, 3D cultures, mice models (PTEN +/-, conditional/inducible PTEN-/-, xenotransplants, orthotopic transplants); Evaluation of drugs targeting genes involved in endometrial carcinoma development and progression.
3. WP3. Development of tumor xenografts in immunodeficient mice.
• Task 3.1: Tumor xenografts of GBM, PNST, NF1-associated tumors.
• Task 3.2: Ewing sarcoma, and neuroblastoma.
4. WP4. Investigation of genetic and epigenetic alterations for identifying diagnostic and prognostic molecular markers.
   • Task 4.1. aCGH analysis validated by FISH and immunohistochemistry (IHC) with tissue microarrays (TMA).
   • Task 4.2. expression profiling by cDNA arrays, validated by RT-PCR and IHC in TMA;
   • Task 4.3. Gene interaction network analysis
   • Task 4.4. miRNA analysis by RT-PCR in low density arrays, and methylation analysis of miRNACpG islands
   • Task 4.5. Exome sequencing of different EC samples (primary tumors, metastatic tumors, tumor cell lines under different conditions
   • Task 4.6 Validation of results by functional analysis with cell lines and explants (knock-down and overexpression).

As it is evident from the description of the previous contributions of the groups that form the Program, innovation will be an important part of our future activities. Most specific research objectives deal with the development and validation of new diagnostic, prognostic or predictive biomarkers of strong innovative potential. Moreover, the common objectives of the program should produce new SOPs, and new clinical guidelines, which will, in turn, better the standard of clinical care of our National Health Care System.

Up to 11 patents have been filed by members of the program in the last 4 years; two of them have been licensed and are currently under exploitation. The institutions participating in this Program have the appropriate technology transfer departments to secure a correct management of the intellectual properties generated by our groups. We will potentiate the creation of technology-based enterprises based on our results, such as Transbiomed (see Group J. Reventos).

In the present RTIC proposal this program was designed to cover three different areas of cancer research which pose a significant amount of mortality and morbidity in special demographic groups (children, women), although are usually underfinanced and out of the main focus of the pharma industry. This program includes research on tumors of the nervous system, pediatric solid tumors, and gynaecological tumors, with emphasis in endometrial carcinoma .The program on “other tumors and pediatric tumors” is composed of 14 research groups. They include the most active clinical and translational research groups in Spain in the field of pediatric solid tumors, central/Peripherals nervous system and uterine cancer, according to their recent (5 years) publications record, grant support and international recognition. The program has an optimal balance between Basic and Clinical-Epidemiological Research groups (3 vs 11 respectively), and all the groups are active in translational research projects.

There a number of global synergies inherent to the conception of this Program. All clinical researchers included in groups JLFL, JS, CL, JSDT, SN, JP, XMG, JPA will contribute to create a powerful bioresource of well-annotated nervous system, pediatric and endometrial carcinoma samples with long-term follow-up for crossed external validations of prognostic markers. In addition, we count with support of the National Biobank Network. For the purpose of predictive value prospective recruitment will be a key issue; several groups are involved in prospective clinical trials (JS, CL, JSDT, SN, JP, XMG, JPA). Importantly, all the coordinators of the main childhood national cooperative trials are included in the proposal (JSDT, JGC, SN groups). In addition, all groups are led/contain pathologists expert in tissue validation of genomics findings; this allowing the implementation of robust and cheap assays to detect biomarkers on routine clinical samples; to support this, we also got a letter of support from the President of the Spanish Academy of Pathology. We therefore foresee a combined approach using ad-hoc retrospective series as a first step and prospectively collected series as external validation tools. Cross validations of the above mentioned markers between distinct centers are envisioned. All clinical data and documents linked to samples will be available for the study assessment/audit. This commitment creates a critical link among clinical researchers aimed to foster the relationship with basic and translational researchers of the program (XR, JLFL, JGC).Primarily, the establishment of this RTIC will help to foster synergies within each individual Group and in, a second step, within the Program. The fact that both basic and clinical researchers have strong international ties will further enhance the value of this joint bioresource. Lastly and importantly, to foster integration between all three WPs, four ambitious common objectives have been designed.

The number of groups included in the program (14 groups) is much larger than the minimum (6 groups) required by the call. This number is also more than enough to carry out the three different areas of cancer research proposed. The size and scientific excellence indicators of each one of the groups show clearly that the necessary critical mass is present in our Program. Most of the groups include a much larger number of senior scientists than the minimum required by grant call (minimum of 4 staff scientists). We have also the necessary critical mass of the different specialities. For example, we include the three most recognized gynecological pathologists in Spain, the seven pediatric oncologists with more translational scientific production, and leading all of the National Therapeutic Protocols in pediatric solid tumors, which are very necessary to achieve successfully several of the scientific aims. We include the Spanish scientist who has published more extensively about glioblastoma multiforme pathogenesis, and the most internationally recognized Spanish epidemiologists in the field of gynaecologic and solid pediatric tumors, respectively.

Dr. Enrique de Alava will be the coordinator of the program. Also, the coordinator of the program will be member of the executive board of the RTICC. The IP of each group will be part of the Executive Board of the Program. We will recommend to the IPs of the groups funded by other programs to delegate his representation to the Program to the member of their groups more directly involved in the work packages. The intellectual property issues that may be related to collaborative projects will be dealt and discussed when necessary at the Executive Board meetings.

Each of the partners adds specific value to the consortium. Dr. Seoane has optimal experience on preclinical models to study central nervous system cancer. Dr. Fernández Luna adds deep expertise on signaling pathways in glial tumors. Drs. Lázaro and Ramón y Cajal are leading experts on the research on peripheral nerve tumors, as well as on its genetic determinants. Dr. Ramón y Cajal is a leading Molecular Pathologist in our country, and holds extensive experience in clinical trials and predictive Biomarkers. Dr. Sánchez de Toledo and his Group coordinate the National protocols on rhabdomyosarcoma, retinoblastoma and osteosarcoma; he is the leading pediatric oncologist of the country in terms of cases treated. Dr. de Alava, program coordinator, is a sarcoma pathologist whose Group has hybrid interests between the clinics and Basic research; he is the president of the scientific council of the Spanish Academy of Pathology. Dr. Navarro is the director of the Spanish Reference Laboratory for pathologic and biologic studies of Neuroblastoma, and Dr. Noguera shares this interest with her expertise on the European program of quality control in Neuroblastic tumors (ENQUA). Dr. Garcia Castro coordinates a big multidisciplinary group including leading clinicians in the major hospitals in Madrid, linking them to a strong research facility at ISCIII. Dr. Peris is the chairman of the Spanish National Registry of Childhood Tumours, while Dr. Bosch is the leading European epidemiologist with interest in gynecological tumors. Dr. Reventós leads the reference basic research laboratory on hormone-dependent tumors; besides endometrial cancer, synergies could be established in other tumors such as prostate carcinoma; he is a founder of Transbiomed, a company with the mission to translate the results into products for therapy and diagnosis. Dr. Prat, Dr. Matías Guíu, and Dr. Palacios are chairmen of key Pathology services and a European reference on the pathology of gynecological cancer in general.

We have got letters of support to this program from different scientific societies and cooperative groups. In case this proposal gets funded specific agreements will be signed between the General Coordinator of RTICC and these entities.

• Spanish Society of Pathology
• Spanish National Biobank Network
• International Gynecological cancer Society
• International Society of Gynecologic Pathologists
• EuroEwing/Ewing2008 protocol (European Ewing sarcoma protocol)
• Co-director, Children cancer Research Institute, Vienna (coordinator of International Neuroblastoma Trials)
• GEICO (Grupo Español de investigación en cáncer de ovario) (Spanish Cooperative group on ovary cancer research)
• Sociedad Española de Neurocirugía (Spanish Society of Neurosurgery)

We want to focus and foster this synergistic work towards the resolution of a number of very ambitious scientific goals which have two main characteristics in common: a) they are clear and well defined urgent unmet medical needs of three relevant population subgroups: children, posmenopausal women, and the elderly; and b) they cannot be accomplished at the single-group level but require to be addressed through multi institutional and multidisciplinary collaboration.

The following are some examples of potential impact on urgent questions that scientists and clinicians involved in pediatric, nervous system, and gynecological cancer are currently facing. Better understanding of the genetic or epigenetic mechanisms that drive cancer progression; Learning the molecular mechanisms that underlie clonal selection and allow the tumor cells to acquire their invasive potential; Biological profiling and classification of GBM, endometrial carcinoma or pediatric sarcomas; Design of new and more successful targeted therapies to treat, not only advanced metastatic patients, but also earlier cases; Design of new treatments which, not only improve patient symptoms and prolong progression free survival but, most importantly, significantly prolong overall survival; Better understanding on how to block acquired resistance to conventional or molecular targeted treatments, a major concern and a serious drawback for every treatment developed in lung cancer; Better knowledge about the genetic and phenotypic risks markers which associate to higher susceptibility to cancer.

Along with high impact publications we expect some other technological contributions such as patents of biomarkers use for more accurate diagnosis or prediction of response, patents on new targets and new applications of compounds. Also we expect to propose some new clinical trials based on our discoveries. Furthermore we expect some no so clearly evaluable outputs such as new and improved management of several subgroups of cancer patients and new guidelines for clinical practice. We expect also to generate preclinical tools to better validate biomarkers in routine tissue samples.

Several of the groups of the program have long standing experience in technology transfer and clinical application of laboratory discoveries. A total of 11 patents have been filed by the groups in the last 4 years. Several of the partner shave experience in direct involvement in collaboration with industry both at the discovery level, through participation in phase I-III trials, or by creating new biotech companies. For example Transbiomed was founded at the end of 2007 by doctors Jaume Reventós, Andreas Doll and Miguel Abal (all included in Group JR) from the Vall d’Hebron University Hospital and Raimon Forés, executive in the biotechnology sector. TransBioMed stems from a hospital environment, with a clear translational vocation, through the development and evaluation of biomedical research, and the mission totranslate the results into products for therapy and diagnosis. Based on a multi-disciplinary team that includes doctors, researchers and financial managers, this enterprising advance in the clinical sector is supported by CIDEM via the Génesis awards. Last February they closed a round of funding valued at €1.2 millions with the venture capital firm Inveready Seed Capital.

Dissemination of this research will be made through the classical strategies based on papers published in the international literature, either in high impact general cancer or in cancer biology journals. Also, researchers of this program are usually very active with presentations in national and international meetings. Thus it is foreseen that the results of the collaborative projects of the present program will be disseminated readily at scientific meetings, both international and national. Lastly, we expect a fruitful collaboration with the well-established associations of patients with pediatric, gynecologic, and nervous system cancer, as well as private charities such as AECC (Asociación Española Contra el Cáncer). The latter has a specific program to fund projects on pediatric cancer.

The following plan includes evaluation criteria for each activity. Criteria can vary slightly between WPs depending on the previous degree of collaboration.

Nervous system

• Tumor niche and control of the immune response in gliomas. At least two manuscripts with two or more groups involved. Elaboration of a collaborative project that includes at least two groups.
• Cell migration and invasion in GBM. At least two manuscripts with two or more groups involved
• Therapeutic targets and markers of therapy response in GBM. At least four manuscripts with two or more groups involved. Financial support obtained for at least two collaborative projects.
• New therapeutic strategies in nervous system tumors. At least two manuscripts with two or more groups involved. At least two preclinical studies. At least one clinical trial could be designed.

Pediatric tumors

Short-term (2013-2014)

• 5 originals with 3 of them with 2 or more groups involved.
• One review article with more than 2 groups involved.
• All deliverables corresponding to this period.

Long-term (2014-2016)

• One review article with more than 2 groups involved.
• 6 Originals with 4 of them with more than 2 groups involved.
• A new research project with three or more groups involved.
• All deliverables corresponding to this period.

Gynecologic tumors

Short-term (2013-2014)

• One review article with more than 2 groups involved.
• • 5 Originals, 3 of them with more than 2 groups involved.
• All deliverables corresponding to this period.

Long-term (2014-2016)

• One review article with more than 2 groups involved.
• 6 Originals with 4 of them with more than 2 groups involved.
• All deliverables corresponding to this period.
• A new research project with three or more groups involved.