Colon cancer is the third most common cancer and the second cause of cancer death in developed countries. Colorectal cancer (CRC), when men and women are considered together, is the most frequent cancer in Spain, where every year more than 19,000 new cases are diagnosed. Nowadays, the life-time cumulative risk is about 6% and overall 5-year survival is around 50%, but this depends enormously on the stage at diagnosis. Prognosis is very poor for stage IV (20%), and these patients are treated with different lines of chemotherapy and targeted therapies than involve anti VEGF and EGFR treatments which are very expensive to the health care system. Pancreatic ductal adenocarcinoma is one of the most aggressive cancers and remains a largely incurable disease. It represents about 10% of all gastrointestinal malignancies, and it is the fourth leading cause of cancer death overall. It is the tumor in which less progress has been made at the clinical level in the last 50 years. Gastric cancer is currently the 5th leading cause of cancer-related death in both sexes, with rates of 12.94 and 5.65 in men and women, respectively in Spain with important geographic differences: some Spanish regions present mortality rates that are much higher than the European mean, while others show rates among the lowest in the continent. + more...
Progress in the knowledge of the molecular basis of tumorigenesis. In the last 25 years knowledge of the molecular and cellular basis of GI cancer has dramatically improved being more profound in colorectal cancer when compared to other GI tumors. We have learnt a lot about the highly penetrant cancer genes but are still lagging behind in low susceptibility genes and their interaction with environmental/lifestyle factors. Coming from a very simplistic genetic approach focused in cancer point mutations we have added increased levels of complexity at the DNA level: allele dosage, copy number and structural variation, epigenetic changes; at the RNA level: expression profiles, splice variants, microRNAs, other non coding RNAs, and at the protein level, post-translational modifications. We now conceive cancer as a heterogeneous disease also at intra-tumoral cell level with many evidences supporting the existence of cells with properties of stem cells (called cancer stem cells). Their characterization is one of the hottes tissues in cancer research. The importance of tumor heterogeneity is further highlighted by the realization that stroma plays a critical role in tumor biology conditioning tumor behavior.
Challenges and opportunities in cancer biomarkers research. The focus of this program is to foster the use of cancer biomarkers in the routine clinical setting. Current molecular biology techniques allow to easily generate many hypothesis of candidate biomarkers for diagnosis, prognosis or therapeutic response. Cumulated knowledge on molecular hallmarks of cancer offers the possibility of detecting mutations in stool, plasma or urine, altered methylation patterns, circulating tumor DNA, micro-RNAs (miRNAs) or proteins, among others. However, most of the biomarker studies suffer from serious drawbacks in design and are usually underpowered to evaluate its clinical usefulness.
Biomarkers in risk assessment and early diagnosis: Molecular diagnosis at germline and somatic level is an integral part of the genetic counseling process. Detection of mutations in highly penetrant genes is an excellent example of successful personalized cancer medicine. However, they also show their limitations including false positive and negative results or difficulties in the interpretation of functional impact. The use of somatic alterations in diagnostic algorithms has shown their potential. When cancer is suspected, non invasive early diagnosis in biological fluids such as stools or pancreatic juice can complement standard routine screening or diagnostic tools.
Biomarkers in prognosis: So far the usefulness of biomarkers in the prognostic setting of is small in GI cancers. In early stage colorectal cancer, in spite of correlation with a more aggressive behaviour, the routine use of KRAS, TP53and BRAF mutations is not supported. MSI is the only prognostic molecular biomarker that has been sufficiently validated in independent and prospective studies where multivariate analysis including other relevant clinicopathological risk factors was performed, but it is clinically useful only in stage II, where it can help decide on the indication of adjuvant chemotherapy. Several studies have examined prognostic expression profiles in stage II and III CRC rendering promising results (73-81). However its clinical utility is uncertain or has not been confirmed so far. Inadequate sample size and lack of external validation are common limitations of these studies.
Biomarkers in prediction of response. There are three targeted agents, bevacizumab, cetuximab, and panitumumab, currently approved for use by the US FDA in advanced colorectal cancer. Despite their widespread use, they have had only limited clinical usefulness with mCRC. KRAS mutations are the only marker that is clearly used for the prediction of resistance to cetuximab or panitumumab. Further clinical research is required into the development of predictive biomarkers that can help identify the subset of patients who would benefit most from their use, as well as the optimal cytotoxic chemotherapy regimen with which they should be combined and their sequence. For the last twenty years we have remarkably increased our understanding of the molecular biology of cancer. This should open an opportunity to develop new biomarkers that help us refine clinical management, but clinical applicability has been shown elusive. The lack of standardization for both technical/technological (internal) and clinical (external) validation procedures of new prognostic and predictive biomarkers may partly explain this slow transition into the clinic. The Colon and Gastrointestinal Cancer Program within RETIC aims at providing a strong resource to speed up the discovery and validation of relevant biomarkers that can improve the management of GI cancer patients.
The overarching goal of this project is to foster the discovery and especially, the validation and
implementation of novel biomarkers in the management of colorectal and gastrointestinal cancer patients. The objectives of the program will be:
We will do so by joining under the same Program leading groups in basic and translational science with acknowledged clinical researchers. The work plan to achieve the aims is described in the format of work packages.
EXCELLENCE, INNOVATION AND TECHNOLOGY TRANSFER
The present program merges efforts of key leaders in epidemiological, basic, translational and clinical research in gastrointestinal cancer in Spain. Altogether, researchers of the program show an impressive record in funds raised and publication output in the field (see description of the groups). This is a brand new program aimed at creating a common framework for all participants. With clear and reasonably ambitious aims we aim to further potentiate the intrinsic capacities of all the groups. A significant fraction of the groups are already active in clinical innovation having implemented new organizative strategies in patient management. Also, a relevant number of patents have been filed and even successful promotion of spin-off (VCN Biosciences) has been achieved.
FUNCTIONAL STRUCTURE OF THE PROGRAMME
WP1 Discovery of new biomarkers in gastrointestinal tumorigenesis
WP2 Development of relevant preclinical in vitro and in vivo models
WP3. Personalized risk assessment in GI hereditary cancer syndromes
WP4. Validation of novel prognostic markers
WP5. Validation of predictive markers of resistance and sensitivity to conventional and targeted therapies
Prediction of response to anti-EGFR therapies
There a number of global synergies inherent to the conception and execution of this Program. All clinical researchers E Diaz-Rubio, J Tabernero, A Carrato, L Paz-Ares, F Bonilla, E Aranda, J Albanell and G Capella will contribute to create a powerful bioresource of well-annotated colorectal, gastric and pancreatic samples with long-term follow-up for crossed external validations of prognostic markers. For the purpose of predictive value prospective recruitment will be a key issue. We 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 (E Batlle, M Esteller, F Mollinedo, A Garcia de Herreros, E Santos, FX Real). A definitive synergy will be established among the clinical and translational Groups. Clinical trials will be performed with the participation of most medical oncologists. Biological samples will be obtained to be studied by the basic and translational research investigators. The clinical parameters of efficacy (response rate, progression-free survival and overall survival) and treatment toxicities will be correlated with the genetic alterations observed, to identify prognostic and predictive factors. These results will represent an advantage for selecting a specific and more efficacious treatment for the different groups of patients. The fact that both basic and clinical researchers have strong international ties will further enhance the value of this joint bioresource.
Additional sinergies are also evident: (i) Up to 4 researchers (L Paz-Ares, R García-Carbonero, J Tabernero, M. Esteller and G. Capella) have strong ongoing research programs using xenografts that complement to each other in a nice manner. Other researchers such as E Batlle (colorectal) and F Mollinedo (pancreatic) will benefit from this expertise. (ii) At least three groups (F Bonilla and G Capella- DG Mollevi and F Mollinedo) work in the role of microenvironment using distinct approaches that may eventually converge in elucidating the role of stroma in resistance to drug therapies in GI cancer. (iii) Three groups (G Capella, E Diaz-Rubio and A Carrato) are active in Hereditary GI (colorectal and pancreatic) Cancer research and are undertaking complementary approaches to tackle this disease.(iv) Four groups (FX Real, A Carrato, CA González, M Esteller and G Capella) show an excellent track in collaboration in epidemiological studies on risk assessment in average risk population using distinct epidemiological cohorts. (v) the advanced characterization of tumors and circulating cells by E Batlle and M Esteller will open several opportunities for interaction with clinical researchers such as E Diaz-Rubio or J Tabernero; (vi) J Tabernero, F Bonilla and G Capella are currently undertaking complementary approaches to study circulating DNA and exosomes.
ADDED VALUE OF THE RESEARCH GROUPS
G Capella contribution to the network goes with his acknowledged expertise in hereditary cancer where he has made significant contributions in their diagnostic algorithms, the development of new techniques for typing circulating DNA and evaluating its clinical usefulness and his pioneering work in the development of personalized xenografts back to1990. He has also led projects to discover prognostic and predictive genetic profiles in the therapeutic field, and has a solid background in managing joint projects and research organizations which supports his role as coordinator.
Clinical translational research. E Díaz-Rubio contributes with a succesful multidisciplinary group enriches the programme thanks to its experience and presence in the RTICS since the beginning of its creation (2003-2012). He is pioneering work in stratifying patients using molecular markers (i.e. CTC) and exemplifies, together with E Aranda, A. Carrato the strategic alliance of the Network with the Spanish Cooperative Group TTD. Also, his group has made leading contributions in the field of Hereditary Cancer. J Tabernero adds value through a strong clinical research background including trials both investigator-initiated and in the context of national and international cooperative groups. He also credits a successful record in new drug development with a large portfolio of first in human phase I clinical trials in solid tumors and the characterization of molecular markers in ancillary studies. A Carrato is adding an active multidisciplinary group that will enable recruiting patients into clinical trials and biomarker validation studies with an emerging translational part focused in predictive factors and in hereditary GI cancer. E Aranda is the current chairman of TTD, the Spanish Cooperative Group for Digestive Tumor set up in 1986 with the aim of becoming a cooperative group to research and develop protocols in the field of gastrointestinal tumours, with the initial premise of improving quality of care.
He is not only adding to the group his own clinical expertise but a fluent connection with an organization of 270 members of 132 clinical institutions that do not only work in Spain but collaborates in international projects with other important cooperative groups. Luis Paz-Ares and Rocío García-Carbonero are adding relevant preclinical models, an ongoing research program on predictive factors and a solid clinical research track with high recruitment rates. J Albanell and C Montagut add significant expertise in the identification of molecular markers for personalized medicine in preclinical models and its validation in the clinic. F Bonilla offers a balanced profile between basic (role of exosomes;etc) and clinical research with a track of original research in the analysis of circulating DNA.Basic translational research. M Esteller's laboratory is focused on the depiction of epigenetic signatures associated tocancer. They master the latest DNA methylation-screening technology allowing the interrogation of alterations characterizing different cancer types and stages in a genome-wide manner. His many contributions to the field of cancer epigenetics, specifically in colorectal cancer for the purpose of the Program, and his strong international dimension are key added values for the Network. The Batlle laboratory pioneers the study of the role of stem cells in the initiation and progression of colorectal cancer (CRC). Their activity, complements the expertise of the rest of the groups in this CRC network program both from the conceptual and technical points of view. Their innovative approximation to understand CRC is another essential addition to the Program. A Garcia de Herreros provides to the network its longstanding experience in the molecular pathways controlling EMT, invasion, stemness and resistance to apoptosis. This experience has also allowed gathering molecular tools, and lately also animal models, very useful for many groups working on epithelial tumorigenesis. Few groups work on pancreatic cancer in Spain. The difficulties involved in the study of this tumor are formidable. FX Real offers an innovative approach to the study of pancreatic cancer both sporadic and familial as well as access to large collections of biological samples associated with international consortia and an ample array of relevant in vitro and in vivo models of the disease. F Mollinedo adds a strong interest in pancreatic cancer together with a longterm commitment to proprietary drug discovery in this disease. E Santos has made significant contributions in ras protein activation which play a very significant role in GI tumors. Epidemiological research. CA González commitment to the Program adds a necessary epidemiological (classical and molecular) dimension to the Program and a focus in gastric cancer and pancreatic cancer. He is the coordinator of EPIC-Spain and an acknowledged researcher with strong ties with most international epidemiological consortia. Of note, FX Real nicely adds to the epidemiological side to the Program contributing with a strong record in molecular epidemiology of pancreatic cancer.
MANAGEMENT OF THE PROGRAM
Gabriel Capellá will be the coordinator of the program and a member of the executive board of the RTICC. The IP of each group will be part of the Executive Board of the Program having designated WP coordinators that will facilitate the day-to-day supervision of the Program. We will recommend to the IPs of the groups funded by other programmes to delegate his presence in the members of the group experts in GI cancer. The Executive board will meet yearly taking advantage of the annual meeting of the RTICC. Tasks and responsibilities of the coordinator will be to assure integration of the WP’s and to supervise and assess compliance with deliverables of the different activities. Considering the number of groups, the past experience in cooperation among themselves as well as the agreed work plan, the Program should be manageable. The quality of the groups, the critical mass achieved and our previous experience within RTICC or similar networks are additional factors that will facilitate the daily work within RTICC.
There are many ongoing interactions between members of the Program. All clinical researchers (E Diaz-Rubio, J. Tabernero, A Carrato, E Aranda, F Bonilla, L Paz-Ares, J Albanell and G Capellá) either bilaterally or within the context of TTD. Also, since a proportion of the groups were already belonging to the previous Network connections were already in place. E. Diaz- Rubio was the leader of the Translational Programme of the RTICC and so coordinating preclinical, translational and clinical projects. Also, together with this group of researchers he has participated in the elaboration of many clinical guidelines. G. Capella collaborates with E Diaz-Rubio in Hereditary Cancer and with many other members in the validation of prognostic signatures. He has been also collaborating with M Esteller in the use of preclinical models and the validation of a panel of methylation markers in non invasive diagnosis of colorectal cancer, a work that has lead to the filing of a patent. M Esteller and J Tabernero collaborate within the COLTHERES consortium, in the identification of DNA methylation, genotyping and other alterations including full “omics” approaches associated to EGFR-resistance of colorectal cancer patients. In collaboration with Dr CA Gonzalez, and as part of a multicentre FIS project, Dr Esteller's laboratory is defining epigenetic signatures characterizing precursor lesions of gastric cancer. The group of FX Real collaborates closely with A. Carrato and CA González in the study of genetic susceptibility to pancreatic cancer; with E. Batlle in the study of transcriptional networks regulating endoderm differentiation and GI stemcells; and with G. Capellá in markers of GI cancer risk and outcome. The Batlle lab and the Capellá lab have recently started a collaboration aimed to validate the expression of colon stem cell signatures in CRC samples. F Bonilla collaborates with A García Herreros and A Muñoz, belonging to other Programs within the Network, in the study of the role of activation of tumoral stroma and its role in colorectal tumorigenesis. A García Herreros is also collaborating with J Albanell, with the goal of validating in tumors the relevance of laboratory findings in the clinical setting. He also interacts with E Santos in order to validate the impact of these observations.
IMPACT AND TRANSFER
The Colon and Gastrointestinal Cancer Program will provide a strong resource to foster the validation and implementation of novel biomarkers in the management of GI cancer patients. The objectives of the program are (i) To identify new relevant biomarkers in GI tumorigenesis; (ii) To develop relevant preclinical in vitro and in vivo models of GI cancer with a special emphasis in the identification of predictive markers; (iii) To further personalized risk assessment in hereditary GI cancer syndromes by using novel germline and somatic risk markers; (iv) To validate novel prognostic markers in GI cancer; and (v) To validate predictive markers to conventional and targeted therapies in GI cancer. The title of the project “TOWARDS A MORE PERSONALIZED CANCER MEDICINE IN GI CANCER: Individualizing risk assessment, prognosis and prediction of response using novel molecular markers” reflects that our will. This will havethree major clinical outcomes in GI cancer: (i) a refined risk assessment; (ii) a better prognostic classification; and (iii)the implementation of taylor-made treatment of cancer patients. To achieve this ambitious overarching outcome we have a gathered a powerful network of epidemiological, basic, translational and clinical researchers in GI cancer whose quality and track record ensures the success of the endeavor. Our common aims clearly reflect the current activities of researchers, their decision to collaborate in joint projects and the vision that such a high-profile objective cannot be attained playing individual games. Major outputs of the project will be: (i) the identification of new candidate markers after extensive and comprehensive profiling of tumors, the filing of corresponding patents and the publication of high impact/relevance publications in the field; (ii) the set up of novel and validated preclinical methodologies and assays that can be also intellectually protected; (iii) the identification of novel candidate cancer genes and variant with an impacts in risk assessment; (iv) the creation of distinct joint follow-up cohorts of patients (both retrospective and prospective) that will be a necessary platform for marker validation; (v) the creation of validation of kits with prognostic and/or predictive value constituted cohorts; .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 programme 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 programme will be disseminated readily at scientific meetings, both international and national. Along with high impact publications we expect patents of biomarkers in risk assessment, prognostic and predictive application. Several of the groups have long standing experience in technology transfer and clinical application of laboratory discoveries and care will be taken to protect industrial property prior to publication. Clinical researchers within the Program include all key players in phase GI cancer phase I-III trials in Spain. The intellectual property issues that may be related to collaborative projects will be dealt and discussed when necessary at the Executive Board meetings. Also we aim to design innovative clinical trials based on our discoveries. Furthermore we expect to change guidelines for clinical practice based on the knowledge generated. As a token, some examples of putative transfer and application are described. E Batlle aims at generating tools that target colorectal Colon Cancer Stem Cells. Antibodies generated against these cell types may have theranostic applications. M Esteller has already unveiled epigenetic biomarkers have already been translated into clinical application. The best known example is the analysis of MGMT promoter methylation as an indicator of chemosensitivity to alkylating agents in glioma patients (Esteller et al 2000). Similarly, DNA methylation biomarkers associated to resistance to chemotherapy in colorectal cancer will be evaluated. From a clinical perspective E Diaz-Rubio has innovated from the clinical side creating a reference lab that has introduced in the clinical routine the genotyping for anti-EGFR treatment. In the present project new additional markers assessed by him and other groups (see WP5) will be validated and introduced in the clinical setting. We anticipate that more trials such as PARSC and ULTRA that aim to stratify patients based on their genotype will be designed and eventually implemented.
SCHEME OF EVALUATION OF THE PROGRAMME
We propose an evaluation that will take into account the overall performance of the group (publications, patents, research projects, clinical trials) and the degree of achievement of the specific aims of the Program taking into account established timelines. We have already defined three broad outcomes for the Program that will be easily evaluable at the end of the project: 1. refined risk assessment in hereditary GI cancer; 2. refined prognostic assessment in GI cancer; and 3. Taylor-made treatment of cancer patients.
A number of indicators for the activity of each group are suggested.
Promotion of the Network
Methodology. Annual report on the activities of the programme to be delivered to the Coordinator and the RTICC Executive Committee. We suggest an external review every two years.
Timeline of tasks related to specific WPs
WP5. Validation of predictive markers of resistance and sensitivity to conventional and targeted therapies