iParaCyts project - Evaluating the therapeutic potential of immunosuppressive paracrine cytokines in the tumor microenvironment of metastatic lesions
Our consortium proposes the integrated study of immunosuppressive cytokines expressed in liver metastatic lesions. While most of the studies in immuno-oncology are focused on primary tumors, the majority of patients treated with immunotherapies suffer from disseminated metastatic disease and, in many instances, liver metastasis. Liver metastases are common, confer dismal prognosis, constitute a clear unmet medical need, and are strongly associated with resistance to immunotherapy. We will study 5 highly relevant cytokines (TGFβ, TNFα, IL8, LIF and GDF15) in liver metastasis. The reasons for this choice are: (a) Evidence for integrated regulation of this cytokine network; (b) the expertise of the members of the consortium; (c) inhibitory compounds against these targets are undergoing early clinical development in our institutions and serial biopsies from liver metastases are and will become available. We hypothesize based on preliminary data that these 5 paracrine cytokines are crucial to promote tumor escape from the immune system in liver metastases, with potential redundancies when considering them as therapeutic targets. Our aims are: (a) Epidemiology of the cytokines in human liver metastases. (b) Effect of the inhibition of the cytokines on tumor growth and the cancer immune response. (c) Study of the tumor immune landscape in patients treated with inhibitors of these cytokines in the context of clinical trials. Our studies will focus on patient-derived samples as well as syngeneic animal models of liver metastasis. Importantly, pre- and on-treatment biopsies from liver lesions in early phase clinical trials testing inhibitory compounds will be studied.
Our project will evaluate the 5 immunosuppressive cytokines as therapeutic targets in isolation or in potential synergistic treatment combinations, identify predictive biomarkers of response to the blockade of the cytokines, and discover novel therapeutic targets for the treatment of liver metastasis.
- Joan Seoane, Fundación Hospital Universitario Vall d’Hebron – Fundación Privada Institut d’Investigació Oncològica de Vall d’Hebron (VHIO), Spain
- Ignacio Melero, Fundación Instituto de Investigación Sanitaria de Navarra, Spain
- Bruno Ségui, Cancer Research Center of Toulouse -INSERM (Institut National de la santé et de la recherche médicale), France
- Jörg Wischhusen, University Hospital Wuerzburg, Germany
- Gianluigi Giannelli, Ente Ospedaliero Specializzato in Gastroenterologia "Saverio de Bellis", Italy
- Pinar Pir, Gebze Technical University, Turkey
An interview with young Principal Investigator, Dr. Pinar Pir*, partner in the iParaCyts project, funded under the co-funded Joint Transnational Call 2021 of TRANSCAN-3
Dr. Pinar is a Principal Investigator of the Pirism Lab, Department of Bioengineering, Gebze Technical University, Turkey
How did you know about JTC 2021 TRANSCAN-3 call?
Although I was aware of the TRANSCAN-3 calls via announcement emails from TUBITAK (Editor’s note: TUBITAK is the funding agency from Turkey, partner of TRANSCAN-3), I did not have collaborators to initiate a consortium myself, hence I never attempted to apply for these calls. A former colleague, Dr. Vera Pancaldi was already involved in the first stage of a project proposal to TRANSCAN-3 together with Prof. Bruno Ségui, and she noticed that a team working purely on bioinformatics could contribute to both project design and to the data analysis throughout the project. She introduced me to Prof. Ségui, we exchanged few emails about my potential contribution to the project, and eventually, I joined the consortium after meeting Prof. Joan Seoane and other consortium members.
What is the added value of the participation of an emerging group in TRANSCAN-3 projects?
As a computational biology group in a technical university, Gebze Technical University (GTU), we do not have access to Next Generation Sequencing (NGS) facilities or clinical samples. Without collaboration with hospitals and experimental groups, we cannot have access to any unpublished data, and therefore our work is confined to applying novel analysis methods to published data shared in the databases.
In Turkey, the use of NGS technologies is still expensive compared to other countries and local funding is limited to about 50K euros per project, hence even if we collaborate with hospitals and experimental groups, the volume of the data produced in our projects have a limited impact in the field. Taking part in a TRANSCAN-3 project will help us overcome most of these difficulties, the consortium will have a larger total budget towards our goal, we will have access to novel clinical data, and contribute to novel discoveries in the field. These opportunities will motivate the whole team and the outputs of this project will have a positive impact on their future careers.
As an emerging group, we have little experience in taking part in international projects. Although I worked in international projects as a postdoc previously, taking part in such a project as a Principal Investigator (PI) will allow me to gain expertise in leading a sub-team within a larger consortium. My group will also gain expertise in working with international researchers. Further, the outputs of this project will help us get wider recognition for our work and perhaps lead to future collaborations.
How do you think international consortia can help emerging groups to develop their careers?
The benefits of emerging groups can be in many ways. One would be the opportunity to take part in a project with a potentially big impact in the field, rather than working on smaller projects that will lead to smaller contributions. The students/postdocs in emerging groups usually have limited access to funds for training, but a consortium can provide them with opportunities to get training from other members of the consortium.
Finally, both the PI and the other group members can find the opportunity to extend their scientific network which may lead to future collaborations, even after decades. One example would be the collaboration between Dr. Pancaldi and myself, which goes back to the times when both of us were postdocs. We met in the EpiGeneSys Consortium in 2012, and although we never worked in the same institution, we always kept in touch, met up at conferences, and collaborated in organising joint workshops or applying to calls such as TRANSCAN-3. I believe that, taking part in such consortia will help my group members to build similar long-lasting and fruitful scientific networks.
How do you envision TRANSCAN projects’ success in the patients' treatment?
TRANSCAN projects will allow consortium members to jointly collect samples from many types of cancer and produce data on these samples. The output of the projects will shed light on active molecular mechanisms of these cancer types, and lead to the proposal of drug targets and drug candidates to be tested. Eventually, the data will be publicly available, and other researchers will access to these data and apply their novel methods on the data to extract additional biological information. All in all, the whole field will be learning more on mechanisms of cancer and have novel drug candidates to be taken into clinical trials. Therefore, I believe that the new data and knowledge produced in TRANSCAN projects will lead to improved and perhaps personalized treatment options for patients in the near future.
How did you get interested in looking for solutions in cancer research?
I worked on yeast, bacteria and stem cells as a PhD student and a postdoctoral researcher in computational biology. In 2016, I was invited to take part in a collaborative project by Prof. Devrim Gözüaçık and Prof. Tunahan Çakır based in Turkey where the effect of cellular dormancy on the emergence of metastasis was to be studied in cell lines and mouse models. While working on the project, I was fascinated by the mechanisms involved in dormancy and I realized how important it is to understand these mechanisms and to prevent metastasis to be able to save lives. Since then, the majority of my projects focuses on better understanding cancer and its microenvironment. Sadly, many people I know are suffering from cancer and few of them passed away shortly after they were diagnosed with metastasis, including Dr. Andrew Sims, who was a colleague and collaborator since we were postdocs in Manchester, he worked on cancer himself. His loss motivated me even further to focus on cancer research.
This TRANSCAN-3 project will bring my work closer to translational medicine and perhaps will help save lives in the future. It feels like a new chapter in my career, for the first time I will be directly involved in the analysis of clinical samples together with experienced clinicians who already made a difference in the field.
Do you think the collaboration among different countries in this type of consortia will accelerate the transfer of results to the patient?
I do believe that these international collaborations will accelerate the transfer of results to the clinic as expertise from groups located in different countries can be synergistically integrated to produce more comprehensive outputs rather than confining the efforts to groups located in one institution or country. Outputs of a project with partners from multiple countries will be more effectively disseminated and followed up by more researchers or perhaps R&D companies, who will take the finding to the next stage of drug development.
How do you think TRANSCAN-3 can reach a higher number of emerging groups?
Joining a consortium is usually mediated by previous contacts, where mutual trust is already established. Hence the emerging groups would need such contacts to be able to join consortia built by more experienced researchers. If the PI of the emerging group has previously worked in a research group with many collaborations, having such contacts is perhaps much easier. But in some cases, the PI maybe changed their field of research recently or worked in groups with no collaborations; in these cases, they would have no existing contacts to help them find a consortium to join. I believe COST (European Cooperation in Science and Technology) actions provide good opportunities to meet new collaborators in the same field. Also, consortia such as EpiGeneSys does not provide any funding to most participants but provide the networking environment in a relatively informal setting. I personally find it difficult to meet people in conferences with hundreds of participants, but it is much easier to make contacts if there are only 30-50 participants. I think events with a focus on a specific field such as cancer research should be both encouraged and funded by funding bodies so that young PIs and group members can build their scientific networks effectively. It is crucial that travel grants for young researchers are available for attending such events. I am aware that online platforms are also very effective on building such networks without any financial burden. For instance, some of my students meet with new people on LinkedIn and start collaborating online on a project of their interest. But I still find face-to-face interactions and informal social settings more fruitful in building long-lasting collaborations. Perhaps, I am too old to be a ‘young researcher’ after all.