The “Molecular Mechanisms of Cancer” Program, referred to hereafter as MMoC, is a reformatted version of a similar coordinated effort that was active during the second funding cycle of the RTICC (years 2007-2012). The redesigned version of this program was made taken into consideration two independent parameters: (i) The need of incorporating new, highly productive cancer groups in research topics of interest to the MMoC Program. This led to the incorporation of three new partners upon the emission of a competitive call and subsequent scientific evaluation (Drs. C. Lopez-Otin, A. Lopez-Guillermo, and G. Thomas). (ii) According to the call from the funding agency, the need of fulfilling the requirement of a maximum of 15 independent groups in the program. These criteria have led to: (ii.a) The consolidation of previously independent participants into larger research groups (i.e., B. Alarcon/M.L. Toribio, A. Aranda/P. Santisteban, O. Bachs/A. Bigas/L. Espinosa, A.C. Carrera/I. Merida, P. Crespo/J. Leon, A. Munoz/J.M. Rojas). (ii.b) The transfer of 26 groups highly specialized in single tumors to other RTICC research programs. (ii.c) The elimination of 5 groups that, due to either lack of productivity or poor implication in the previous RTICC research activities, were not considered to be of high priority to the MMoC program. (ii.d) The continuation of 11 groups based on the external annual evaluations made by the ISCIII. Due to all these rearrangements, the new MMoC program has been reduced from 60 to 15 research groups.

Despite those changes, the central philosophy of this program has not changed. The main goals of the new MMoC Program are: (i) Obtaining a better view of the basic signaling and regulatory mechanisms that contribute to primary tumorigenesis, metastasis and the therapeutic response of a large number of different tumor types. (ii) Translating this information into the identification of biomarkers, diagnostic/prognostic protein/gene signatures, and therapeutic targets for specific tumors. (iii) Serving as basic technical/experimental platform to help the research avenues of the rest of RTICC programs.

The aim of the MMoC is to approach key issues in cancer biology and treatments with a holistic, innovative, and clinical-oriented manner. In this regard, we are interested on biological programs that have direct impact on primary tumors, fully established metastasis, dormant metastatic cancer cells, therapeutic response, and disease recurrence. To this end, we plan to use the combined power of genome sequencing and high-throughput techniques (genomics, proteomics, cellomic screenings) to identify new regulatory elements and biological programs that contribute to the tumorigenic process and its final clinical outcome (WP1). We have experience in this type of work, since groups of our program have already made important inroads towards the discovery of new driver oncogenic mutations in tumors (E. Campo, C. López-Otín, A. López-Guillermo) as well as in the elucidation of unexpected biological programs triggered by early signaling transducers (B. Alarcón, X.R. Bustelo, A.C. Carrera, P. Crespo, E. Santos, G. Thomas), cell cycle inhibitors (O. Bachs), and ligand-stimulated transcriptional factors (A. Aranda, A. Muñoz, P. Fernández-Salguero). This preliminary work has resulted in the identification of new gene signatures with diagnostic value (F. Bonilla, X.R. Bustelo, E. Campo, C. López-Otín, A. López-Guillermo) as well as in the identification of new therapeutic targets for specific tumor types such as melanoma (P. Fernández-Salguero), breast cancer (X.R. Bustelo, B. Alarcón), chronic lymphocytic leukemia (E. Campo, C. López-Otín, A. López-Guillermo) and colorectal tumors (F. Bonilla, A. Muñoz).We also want to use as main research criteria the clinical impact of the selected targets and molecular signatures identified in our studies (WP1, WP2). This will be achieved following different experimental avenues. Firstly, we will favor the use of inducible approaches (i.e., chemically induced shRNA constructs and knock-in mice) to inactivate the targets under study in defined stages of tumor development. Secondly, we will make use of knock-in strains that will mimic accurately the possible use of drugs in a clinical setting (i.e., chemically inducible knock-in mice that would express catalytically-inactive versions in either a systemic or tissue-specific manner). Some of these inducible knock-in strains have been already developed by some MMoC partners (X.R. Bustelo, P. Crespo, E. Santos, G. Thomas). We also aim at developing new inhibitory approaches to block the activity of nodal oncogenic molecules (WP3). For example, groups of the MMoC program are working in the development of new family inhibitors for Erk (P. Crespo),PI3Ks (A.C. Carrera), GTPases (B. Alarcón, X.R. Bustelo), or the undifferentiated state of cancer cells (P. Crespo /J. León). New immunotherapy-based approaches have been also designed (B. Alarcón, A.C. Carrera). Finally, we want to use as main criteria the clinical interest of the new targets/signatures identified. For that purpose, we will focus our attention in targets that can be druggable in a clinical- and pharmacological-amenable manner (i.e., enzymes, surface molecules). Furthermore, we have designed an entire work package (WP4) to analyze the clinical relevance of our experimental data, find ways to translate those advancements to the bench-side, and for the development of new diagnostic kits. In addition to the “discovery” phase of our research, the MMoC program also wants to serve as a common experimental/technological platform that could help the research activities of the rest of RTICC programs. It is important to note that most members of the MMoC program have set up collaborations during the last RTICC funding period (2007-2012), as evidenced by the number of collaborative publications, projects, and patents that have been generated in the last RICC funding period. This will ensure that the cooperative work within the MMoC will be fully implemented from the beginning of the next funding cycle.

Obviously, the size of the MMoC (15 groups) does not allow to approach the myriads of regulatory elements and signaling routes that contribute to the transformed phenotype. To this end, we will concentrate our efforts on early signaling mediators (transmembrane proteins, exchange factors, protein and lipid kinases, EMT-MET mediators, cell cycle regulators, ligand-induced transcriptional factors) that are closely linked to the engagement of mitogenic, cytoskeletal, metabolic, and transcriptomal programs in many cancer cell types and tumor-associated normal cells that play ancillary roles in the tumorigenic process (i.e., myofibroblasts, lymphocytes). The reasons for the selection of these routes are four-fold: (i) All these proteins coordinate the activation of large signaling and transcriptomal programs that have a wide impact on the biology of the cancer cells and, therefore, are very important for the discovery of new therapeutic targets, inhibitory strategies, and diagnostic tools. (ii) It will increase the success of the cooperative research activity within the MMoC, since the groups have extensive and complementary expertise in those routes. (iii) Previous collaborative work of MMoC members have already discovered functional interconnections among all the aforementioned biological routes, a fact that will favor the multicentric and multifaceted study of those complex biological programs. (iv) As indicated above, preliminary studies conducted by MMoC members have identified targets that are ready for immediate study, thus favoring the productivity of the program from the beginning of the new RTICC funding cycle.

Given the horizontal nature of our program, our work will be directed to the elucidation of signaling routes and biological programs that are operative in high-incidence tumor types. However, to emphasize the interconnectivity with other RTICC groups, most of the functional studies will be directed towards the tumor types preferentially investigated in the other RTICC programs. Our own research can also indirectly benefit from the collaboration with clinical and basic scientist of other RTICC programs, as evidenced by the extensive network of collaborations that we have set up during the last RTICC period.

1. Obtaining a better view of the basic signaling mechanisms that contribute, either intrinsically or extrinsically to the cancer cell, to primary tumorigenesis, metastasis, and the therapeutic response of different tumor types.
2. Translating this information into the identification of biomarkers, diagnostic transcriptomal/proteomic/metabolomic signatures, and therapeutic targets for specific tumors.
3. Serve as basic experimental/technical platform to help the research avenues of the rest of RTICC programs.

We expect a high level of scientific and technical innovation from the work contemplated in the MMoC program. From a scientific point of view, our studies have been designed to tackle important biological issues that have not been yet properly solved in the cancer field. In addition, the studies in all WPs have been designed in order to get a “fresh” look at critical signal transduction routes that contribute to cancer ontogeny, progression, and metastasis. This will result in the discovery of new biological programs and, perhaps more importantly, in the identification of new therapeutic targets. Finally, it is worth noting that the design of the work has a fully translational and clinical orientation, an underlying philosophy that will allow us to focus our attention on targets and gene/protein signatures with potential direct impacts on the cancer patient. The experimental plan, which has a strong orientation towards the study of targets and biological processes in clinical and therapeutically relevant tumor stages (i.e., fully established tumors or metastasis, the dormant state of cancer cells), will also improve the chances that our data will have a direct translational component. Last, but not least, it should be underscored that this program has large and interactive scientific groups that are international leaders in their respective fields, a feature that will ensure the success and international impact of our research. We also predict that our work will have a high potential for technological transfer. Thus, we expect that our work will result in the identification of new therapeutic targets, leads for drugs, diagnostic tools (antibodies, probes, middle-size arrays), and diagnostic/prognostic gene/protein/metabolomic signatures. This will lead to the generation of patents, commercial licenses, and the open collaboration with biopharmaceutical industry. It should be noted that some of our groups have experience in patenting and collaborations with industry, a feature that will further smoothen our prospects of success.

The responsibility for the S/T coordination at the overall program level will be with the PC through: (i) Constant monitoring of the general scientific and industrial evolution outside of the consortium at the Spanish and international level as compared to the objectives and targets monitoring of progress of research carried out in MMoC, of the work being carried out in the work packages, the results and the necessary changes to the project definition and work plan as a result of those findings, according to project milestones. (ii) Maintaining and following-up the work plan, progress monitoring, identifying and handling trouble shooting of technical or organizational problems, co-coordinating S/T and general MMoC meetings. (iii) Preparing the required reports and (if and as required) proposals for changes in the project strategy for implementation for adoption by the decision making bodies. (iv) Evaluating the S/T content of deliverables and publications produced by the project, including assessing of progress reports, new work plan and deliverables. At the WP level, the S/T coordination is ensured by the WP and Task leaders. They will be responsible for: (i) The S/T coordination of their work package. (ii) Ensuring the communication between the WP partners and with the Executive Board. (iii) Following-up decisions made by consortium management bodies concerning the WP. (iv) The timely delivery of reports and WP results to the Executive Board. (v) Alerting the EB and the PC in case of delay in the performance of the WP or in case of breach of responsibilities of any contributing WP partner. (v) Organizing the update workshops for WP members. Updates about the coordination and progress of work will be done in the context of MMoC organized workshops. These meetings will be done each semester at the WP level and, annually, at the overall MMoC level.

Given the large percentage of the work in all our WPs that will rely on high-throughput technologies, the MMoC will benefit by the presence of service units that were already set up for multicentric work in the previous RTICC period. The use of these centralized units will favor efficiency of the analysis and consistency in the data obtained from different partners. Specifically, the MMoC has the following technical platforms for the work contemplated in this project: (i)Deep sequencing unit and Whole Genome Sequencing units at the IDIBAPs (Barcelona, directed by P. Jares from E. Campo’s group). (ii) Microarray Genomics and Proteomics Unit at the CIC (Salamanca, headed by X.R. Bustelo). (iii) Proteomics Unit at IDIBAPs (Barcelona, headed by O. Bachs). (iv) Pathology Unit for high-throughput analysis of mouse tissues at the CIC (Salamanca, headed by E. de Álava, RTICC Program #7). (v) Pathology Units for human samples at both the PHUH (Madrid, headed by F. Bonilla) and the IDIBAPS/Clínic Hospital (Barcelona, headed by A. López-Guillermo). (vi) A structural unit for crystal structure determinations at the CIC (Salamanca, Spain, headed by Dr. J. de Pereda (non RTICC participant). (vii) A Drug Screening Unit at the CIC (Salamanca, headed by Dr. A. Pandiella, ). All these units have extensive experience in coordinated work in the context of the previous RTICC as well as in other initiatives such as the ProteoRed network (supported by Genoma-España Foundation and, more recently, by the Carlos III Health Institute).

The type of holistic and clinical-oriented work contemplated in the MMoC Program cannot be achieved successfully unless clinical and basic labs, each providing its complementary scientific and technical background, get together in a full-time collaborative effort. This is especially acute in this case, since the data from cancer genome sequencing and high-throughput technologies generate large amounts of hits that impact in quite different biological processes and clinical parameters. Furthermore, the multiple biological read-outs contemplated in all our WPs make it impossible carrying out this type of work using a “single-lab” perspective. We believe that the group structure of our program is quite fit to achieve our scientific aims, since most groups have overlapping, but not identical fields of research that can contribute to significant advances in areas of the work that other partners cannot tackle by themselves. The close collaboration between basic and clinical labs is also of paramount importance to achieve our translational goals. The importance of this collaboration is demonstrated by our record of previous achievements during the last funding period of the RTICC. This has led already to quite few shared publications, patents, and coordinated grants. This previous experience of coordinated work, combined with the needs of the new research plan, will make these synergistic interactions much more frequent, easier and proficient in the near future. Given the quality of the new groups that have joined the program in this new application, the potential of interactions in the program is significantly expanded. It is also important to note that the MMoC program does not like to be an insulated effort. Indeed, our research is oriented towards the direct elucidation of biological programs that will be operative in many tumor types, so it is quite likely that our data will permeate into other RTICC Programs. Likewise, specific aspects of our research program can be further complemented by groups belonging to other RTICC programs. Obvious candidates among the basic labs include those headed by J. Arribas, E. Batlle, M. Esteller, A. García-Herreros, A. Pandiella, J.M. Paramio, M. Sánchez G. Capellá, L. Paz-Ares, M.A Piris, F.X. Real, and J.M. San Miguel. Many of us have already started collaborations with some of those groups, including published work. Conversely, we also want to make our scientific and technological platforms available to the rest of RTICC partners in order to speed up the “discovery” and “corroboration” phase of their biological hits. As in the case of our intra-program experience, our previous collaborative effort demonstrate that these synergistic interactions have taken place previously and, certainly, provide a firm basis for the continuation of such collaborations in the context of the new RTICC period. This synergism will be further fostered by the active participation of some MMoC partners in other RTICC programs (X.R. Bustelo, F. Bonilla).

We believe that the work contemplated in the MMoC program will have a practical impact in a number of areas:(1) A better understanding of the signaling mechanisms that regulate primary tumorigenesis, metastasis, treatment resistance and recurrence. This will result in collaborative publications in high impact journals. (2)The identification of new therapeutic targets, protein/gene signatures with diagnostic value, and anti-tumor lead drugs. This will result in collaborative publications in high impact journals, elaboration of patents, and the initiation of collaborative agreements with biopharmaceutical companies. Due to this, we have designed a specific dissemination (inside and outside the RTICC members) and transfer strategy for the research conducted by all members of the MMoC program.

The members of the MMoC program will ensure that the information generated in our program is not confined to small cooperative groups within the MMoC. To that end, a variety of activities have been planned to disseminate information about the work carried out in the MMoC and the results achieved, targeting both the public and the scientific world.(A.1) Internal dissemination activities. They will guarantee that all MMoC members and rest of RTICC partners are updated in a routine basis about the project advancement, the planning, and all other issues which are important to obtain maximum efficiency of resources and consistency of results. To that end, we will organize both management meetings and technical coordination meetings within the MMoC and RTICC to carry out this communication strategy. In addition, all the information generated within the project will be communicated to the MMoC coordinator (Dr. Santos) who, eventually, will be in charge of channeling this information to the other partners when appropriate. Confidential information will be also posted in the intranet of the RTICC webpage, as it has been done in our previous funding cycles. Finally, as in those previous cycles, we will organize meetings and workshops within the MMoC (each semester) and the general RTICC (in an annual basis). To facilitate the maximal dissemination, the latter meetings will be done in the context of larger scientific meetings, such as those organized by the Spanish Association for Cancer Research (a member of the EACR) or the Spanish Oncology Society (SEOM).(A.2) External dissemination activities. Our strategy here aims at communicating effectively with parties outside the RTICC, such as other scientist, potential users, biopharmarmaceutical companies, and the general public. The external dissemination will remain under the control of the RTICC main coordinator and the RTICC executive committee always staking into consideration the obvious limitations regarding restricted and confidential results. Non confidential information will be posted in the public area of the RTICC web page. The information generated by MMoC and some of the results of the work undertaken under the MMoC umbrella will be of general interest. Therefore, as a default rule, the outcomes of the various MMoC initiatives will be open to public access. The research results and the results of other activities (such as the standardization work and experimental protocols)will be published on-line and made accessible to all interested parties (researchers, oncologists, academics, students)through a number of dissemination actions. Results will be disseminated through a variety of "classical" vehicles such as the RTICC web page, conferences, seminars, publications in scientific (peer and non-peer reviewed) journals, publication of textbooks and articles in the specialized and in the general press, etc. Such actions will be taken individually by members of our program, by the MMoC or by the RTICC as a whole and will be planned and monitored by the MMoC and RTICC coordinators as well as the RTICC executive committee. Proper dissemination of research knowledge cannot be achieved unless the information ‘chain’ between the scientists and the ‘consumers’ of such knowledge is adequately managed, so that scientifically and ethically correct knowledge is delivered to the parties that ‘need to know’ when, where and in a form that is suitable to them. Attention will be placed on this aspect of quality contents production. Records will be produced, where possible, for tracking the knowledge dissemination actions taken under the MMoC and RTICC umbrella. Records will be collected centrally for analysis, production of statistics and indicators as appropriate and feasible, and transmitted for evaluation together with the annual report.

In the present context, translation and exploitation are referred mainly to the use of the results that will be generated by the MMoC research activities, in particular to their conversion into clinically useful tools for the management of cancer patients and their bringing onto the market for commercial exploitation. It is likely that the research activities undertaken under the umbrella of the project will generate results with various commercial potentials. As in all collaborative work, this may raise the issues of intellectual property rights (IPRs), of protection of the property rights (patenting) and of undertaking to bring a product onto the market using an appropriate commercial vehicle (start-up, licensing).The management of exploitation of results must be obviously handled with care. Since the RTICC is not a legal entity, the generation of patent applications, patent filing and licensing will be done by the respective legal entities (i.e., Universities, CSIC, Foundations, Health Institutes). In any case, the MMoC members can receive input from the RTICC coordination team, since they have had previous experience in knowledge protection-related activities. In addition, the MMoC and RTICC coordinator will make sure that the rights of all RTICC members involved in these results are adequately protected.

In our view, the evaluation of the MMoC program has to take into consideration the following criteria:(1) An optimal time-window to allow the consolidation of the scientific collaborations and its subsequent dissemination. Due to this, we believe that the evaluation should take place in the third year of the funding period. This can be done by a standard final report, in which the groups will indicate the work done and the results obtained with the RTICC funding. An earlier evaluation can be also possible to assess the work in progress of the Program. In order to be effective, this mid-term evaluation should be conducted using the on site visit system or, alternatively, by organizing the public presentation of the ongoing work to the evaluation committee.(2) Main criteria for evaluation must consist, as in any scientific enterprise, in the quality of the scientific output generated during the period under evaluation. Given the nature of our Program, we believe that the best parameters to evaluate our work are those related to the number of publications, patents, and level of international impact of our results (i.e., invited seminars, organization of workshops, etc.). By contrast, we do not believe that the participation in either epidemiological studies or clinical trials should are adequate criteria for the evaluation of the MMoC research activity.(3) The purpose of the RTICC call is to foster the interaction among different cancer groups in Spain. Due to this, we believe that the evaluation of the scientific productivity must be limited to those items that been done only in collaboration within the RTICC framework (i.e., with other MMoC groups or with IPs involved in other RTICC programs).(4) In addition to the scientific output, the evaluation must also consider other parameters that can objectively measure network activity of our members within both the MMoC and other RTICC programs. Those may include, for example, the evaluation of the number of collaborative grants, organized workshops, or exchange of personnel.(5) As in any other scientific activity, this evaluation must be carried out using an ad hoc external scientific committee.(6) Given that the RTICC budget is oriented towards the support of scientific personnel, we believe that the final evaluation must be done with enough time (i.e., 6 months before the end of the RTICC period) in order to: (i) Avoid gaps in the support of personnel belonging to MMoC groups that were evaluated positively. (ii) Facilitate alternatives for the personnel of groups that did not pass that evaluation.