ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Valentina Zuco is first author on ‘ Effects of irinotecan plus trabectedin on a desmoplastic small round cell tumor patient-derived xenograft’, published in DMM. Valentina is a scientist in the lab of Nadia Zaffaroni at Fondazione IRCCS Istituto Tumori, Milan, Italy, investigating patient-derived tumor models to identify new therapeutic strategies for patients with rare cancers to be translated into clinical trials.
Valentina Zuco
How would you explain the main findings of your paper to non-scientific family and friends?
Desmoplastic small round cell tumor (DSRCT) is an aggressive and ultra-rare sarcoma that mainly affects male patients of pediatric age as well as adolescents and young adults. Clinical trials testing new therapeutic options are very challenging in rare cancers such as DSRCT, and preclinical investigations comparing new anticancer agents with currently used drugs are particularly relevant. Patient-derived xenografts (PDXs), which are obtained by directly implanting freshly resected tumor pieces into immunocompromised mice, preserve the original cell morphology and molecular characteristics of the originating clinical tumors. We generated a PDX of a DSRCT, which represents one of the very few patient-derived models of DSRCT worldwide. We aimed at testing drugs that could be available in the clinical practice for patients with sarcomas, a family of tumors that encompasses DSRCT, to generate preclinical findings that could be translated in the design of a clinical trial practice in the short term. Indeed, DSRCT has very limited therapeutic options, and most patients die from their disease. We showed that irinotecan, an alkylating agent used on sarcomas at pediatric age, could have effectiveness in DSRCT. Tumor responses achieved with this drug could be enhanced by the addition of either eribulin or trabectedin, two other drugs available for the treatment of sarcomas that did show some activity in small clinical studies on DSRCT. Indeed, the combination of irinotecan plus trabectedin was successfully tested in two patients as a third-line treatment, with evidence of activity by pediatric oncologists of our Institution. A clinical trial will be performed to test this combination in patients with DSRCT within the Italian Sarcoma Group, the national network for research and treatment of sarcoma in Italy.
What are the potential implications of these results for your field of research?
This study emphasizes the importance of patient-derived preclinical (PDX) models to explore new treatments in rare cancer such as DSRCT, where disease rarity challenges the successful conduct of clinical trials that compare different treatment strategies. Our findings led to the design of a phase II single-arm clinical trial in DSRCT that will investigate the combination of irinotecan plus lurbinectedin, a novel synthetic agent derived from trabectedin with a similar mechanism of action.
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
We performed our experiments in a PDX model of DSRCT. PDXs are translatable preclinical models, which retain the main characteristics of their paired clinical tumors. Our PDX of DSRCT maintained not only the same tissue architecture, cell morphology and differentiation histomorphology, but also the genomic and transcriptomic profile of the originating tumor, including the expression of the pathognomonic EWSR1::WT1 gene fusion. For these reasons, our DSRCT PDX model appears to be particularly suitable for directly comparing standard-of-care agents and newer therapies in DSRCT, where the level of clinical evidence for existing therapies is low and comparative prospective clinical trials are lacking, mainly due to disease rarity. In the past decade, preclinical pharmacological studies on DSRCT have mainly been performed following xenotransplantation of a DSRCT cell line into immunocompromised mice, and, only recently, have DSRCT PDXs been generated and used to evaluate the therapeutic potential of anticancer agents such as NTRK3 and EGFR inhibitors. The main drawback of this model is the inability to provide information on the cross-talk between tumor cells and the tumor microenvironment (TME). Whether treatment strategies for DSRCT modulate the TME remains difficult to model and investigate.
“It was an encouraging surprise to observe that irinotecan plus trabectedin combination induced a complete response in mice […]”
Ki-67 immunostaining (top) and Haematoxylin and Eosin staining (bottom) in residual tumor specimens from a mouse. A histopathological analysis was performed in animals sacrificed at the end of the experiment (i.e. 86 days) to assess whether the absence of palpable tumors in mice treated with the irinotecan-trabectedin combination was associated with a pathological complete response. Residual tumors were detected in only two of four tissue specimens. The image of residual tumor shows no evidence of proliferation (no Ki-67-positive cells) and the presence of histiocytosis.
Ki-67 immunostaining (top) and Haematoxylin and Eosin staining (bottom) in residual tumor specimens from a mouse. A histopathological analysis was performed in animals sacrificed at the end of the experiment (i.e. 86 days) to assess whether the absence of palpable tumors in mice treated with the irinotecan-trabectedin combination was associated with a pathological complete response. Residual tumors were detected in only two of four tissue specimens. The image of residual tumor shows no evidence of proliferation (no Ki-67-positive cells) and the presence of histiocytosis.
What has surprised you the most while conducting your research?
It was an encouraging surprise to observe that irinotecan plus trabectedin combination induced a complete response in mice, consisting of the absence of palpable tumor, associated with a pathological complete remission in most of the tumors. In addition, the efficacy of the combined treatment was not associated with weight loss and toxic death in mice.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
Networking is needed in research on rare cancers to speed up research findings and consequently to lead to better patient outcomes in a short time. Sharing data and tumor models could be key to advancement in the field of DSRCT. I truly hope to increase interactions with other scientists and teams working on DSRCT in the near future, also to increase the chances for preclinical research on DSRCT to be adequately funded.
“[…] the development of innovative and effective treatments requires close collaboration between preclinical researchers and surgical, medical and radiation oncologists.”
What changes do you think could improve the professional lives of scientists?
I believe that the development of innovative and effective treatments requires close collaboration between preclinical researchers and surgical, medical and radiation oncologists. I am part of a team working on soft-tissue sarcoma that includes a different array of expertise, including scientists, pathologists and oncologists of different background. The interplay of these professionals could improve the knowledge of soft-tissue sarcoma and the preclinical discovery of new treatments to be moved forward in clinical trials and clinical practice.
What's next for you?
We aim at further developing our work in ultra-rare sarcomas including DSRCT. The next step will be to evaluate the combination of irinotecan plus lurbinectedin, a novel synthetic agent derived from trabectedin with a similar mechanism of action. We are also willing to provide further insights into the mechanisms of action of these two drugs when combined together. We are also interested in extending our investigations on irinotecan in other sarcomas, including adult-type sarcomas.
Valentina Zuco's contact details: Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
E-mail: [email protected]
