IOR Bellinzona, new frontiers of research in biomedicine
Institutional Communication Service
10 September 2018
An international research team at the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana) in Bellinzona, led by Dr. Andrea Alimonti, has discovered an innovative method to contain the evolution of prostate cancer. The study was published in the leading scientific journal Nature, in June. We spoke to Arianna Calcinotto, young researcher at the IOR and first author of the study, who is responsible for this discovery, and to Dr. Alimonti, who is also professor at the USI Faculty of Biomedical Sciences, for insights on biomedical research in Ticino.
Dr. Calcinotto, tell us more about your findings and what inspired you and your colleagues to devise this new immunotherapy concept.
It is a general understanding that to fight cancer we need to harness the immune system, as most of the immunotherapy drugs currently under evaluation work by stimulating the immune system to recognize and kill the cancer cells. Previous trials using immunotherapy in prostate cancer have been unsuccessful. This information brought us to investigate whether the immune response could play a different role in this type of tumour. Prostate cancer treatments usually fail after time as resistance to therapy develops, a condition known as castration-resistant prostate cancer (CRPC). Because this condition is one of the most common causes of cancer-related mortality in men, we decided to investigate the role of the immune cells in the development of this specific phase of resistance for this common disease.
For decades, oncologists and researchers were unanimous in believing that the target to strike in order to stop this phenomenon were the male hormones (androgens and testosterone, which fuel the tumour's growth); without these, in fact, the prostate cancer cells start to die off. Later, however, those cells fight back and manage to survive, even without their essential nutrient. How the tumour managed to withstand the lack of androgens and come back stronger than ever has been, up to now, a mystery. Working with partners in the United Kingdom and in Italy, we found elevated levels of the protein interleukin-23 (IL-23) in the blood and in the tumours of most patients resistant to antiandrogen therapy. We noticed moreover that the release of IL-23 in the tumour is caused by a particular type of immune cell (called myeloid cells), which make it treatment resistant – like a "dark force" – by allowing the survival and proliferation of the prostate cancer cells.
The next step will now be to run clinical trials and identify the antibody that can selectively block IL-23. Our research will be the basis for a promising clinical study in prostate cancer patients, similar to research underway for the treatment of disorders such as psoriasis, which is very well tolerated by patients.
You are the first author of the study; could you explain what your role was in the overall team effort?
The first author of the study is the leader of the project, having therefore the responsibility to conceive the project and design, and interpret the results obtained. The first author has also more practical duties, such as performing the experiments and orchestrating the results obtained by the work team and the external collaborators. All these important steps needed for the good trial of the project are shared with a work team and supervised by the head of the lab. I am really glad that the major contributors of the study were women. We built up a very productive and cohesive team, a key element for the success of the project. The ability to create and work within a network of researchers is fundamental for the development of a large project, such as this one, either because each group brings its own technological expertise, or because it has access to a larger number of patients. Collaborations are often developed thanks to the contacts made during scientific conferences, where research projects are presented. In those situations, it is quite common to end up talking about research interests with colleagues, typically during the coffee breaks or at the breakout sessions. But collaborations are created also with colleagues with whom you have worked in the past, who have since acquired new skills.
Do you believe that this discovery could actually change the course of diseases still thought to be incurable?
Prostate cancer causes more than 300,000 deaths annually worldwide. The current standard of care for advanced-stage prostate cancer is androgen depletion (an antihormone therapy) by chemical means. However, this almost invariably provides only a temporary halt to the disease.
When cancer progression resumes despite low androgen levels developing CRPC condition, no efficient clinical options are available, so there is still a need for additional clinical strategies. We believe that our work will have important clinical implications and advances our understanding of the biological processes that underlie castration resistance. Antibodies that block IL-23 are approved for clinical use to treat autoimmune conditions, which clears the way for them to be tested as a possible treatment for CRPC patients. We aim to run a clinical trial to assess if anti-IL-23 antibodies can improve the standard of care treatment and revert therapy-resistance in patients affected by metastatic CRPC. Our findings also raise the question of whether immune cells might contribute to the progression of other sorts of cancer in which growth is driven by hormone-receptor signalling such as breast and ovarian cancers. In the long run, I would like to focus my efforts on understanding the spectrum of interactions in the tumour microenvironment also in different tumour context. I believe that these discoveries will pave the way to new therapeutic options and illuminate a novel concept of immunotherapy for cancer.
Your career path has brought you on both sides of the Atlantic. Why did you eventually land at the IOR, in the small city of Bellinzona?
After my PhD training at San Raffaele Scientific Institute (IT) and Mayo Clinic (USA), I felt the need to increase my professional experience by moving to another competitive and cutting-edge research institute. I strongly believe that a change of location during the training period of a scientist is a benefit for the career, providing opportunities to meet people and create several research networks. During my scouting to find a good lab to broaden my knowledge in basic and applied science, a professor in Milan advised me about the group headed by Andrea Alimonti in Bellinzona. When I came for my interview, I was impressed by the outstanding science carried out by the Alimonti lab and the impact of international collaborations that the lab had. Furthermore, even if IOR is a relatively small institute, it has nothing to spite to bigger research institutes all over the world. The state-of-the-art core facilities at the IOR, the collaborative culture and inter-disciplinary dialog fostered within the institute, coupled with the outstanding scientific environment offered in Switzerland, enable to conduct outstanding scientific research. Thus, I concluded that attending a Postdoctoral position at Alimonti’s group would have been an excellent opportunity for me to acquire the professional skills and experience needed to become distinctive and a leader in the field of cancer immunology. Last but not least, Ticino has from its side the beauty of its nature and weather. There are few places in the world in which we can work in the lab without feeling to be turned into a lab rat.
Prof. Alimonti, how do you see the future of biomedical research in the Canton Ticino, in comparison to the ‘big players’, for instance in the U.S.?
This year has been an astonishing year for our research team and for the IOR. We have published in less than 4 months two papers in Nature Genetics and Nature, two of the most important scientific journals in the world and inspired novel clinical trials for the therapy of prostate cancer patients. As IOR, we have also published another paper on Nature Medicine, whereas the Institute for Research in Biomedicine in Bellinzona (IRB, also affiliated to USI) published two papers on Nature. Overall, I felt extremely positive about the research environment in Ticino. This is only the tip of the iceberg since many other papers are published every year from IOR and IRB. When I travel and I say that I come from Bellinzona, my colleagues tell me: “I know the place. It is a small city but you guys do great research over there”, and they conclude with a smile, saying, “you are almost more productive there than in Zurich”. I agree with these remarks and I feel extremely pleased. Between IOR and IRB, in Bellinzona we are a small community of nearly 200 scientists that is coping with relatively limited resources compared to other research centers in the North part of Switzerland, who can benefit from large amounts of public and private funding. I do not know if there is a secret behind this success or if this year we have been just lucky, but I am convinced nevertheless that biomedical research could be a driver of a future economic growth in Ticino. What others have done over the past two decades now needs to be brought to the next level. Only in this way will we succeed in competing and possibly beat the “big players”. The building of the new campus in Bellinzona, a structure that from early 2021 will bring the IOR, the IRB and of the NSI (Neurocentro della Svizzera italiana) under the same roof, is a milestone that confirms the relevance of biomedical research in the Canton Ticino. The new centre will clearly provide opportunities for synergies and growth, and I trust that our public Institutions will continue to guarantee its support by investing in this important sector of economic and social development.
Originally published in Ticino Welcome magazine (nr. 059, September-November 2018, pp. 26-28)