Alfons Navarro1, Lily Yu2, Margo Y. Chen2
1Human Anatomy and Embryology Unit, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 2TCR Editorial Office, AME Publishing Company
Correspondence to: Margo Y. Chen. TCR Editorial Office, AME Publishing Company. Email: tcr@amepc.org.
Editor’s note
Translational Cancer Research (TCR) has published a number of special series in recent years, receiving overwhelming responses from academic readers around the world. Our success cannot be achieved without the contribution of our distinguished guest editors. This year TCR launched a new column, “Interviews with Guest Editors”, to better present our guest editors and to further promote the special series. We also hope to express our heartfelt gratitude for their tremendous effort and to further uncover the stories behind the special series.
The special series “Clinic and Therapeutic Potential of Non-coding RNAs in Cancer”(1) led by Dr. Alfons Navarro (Figure 1), Dr. Joan Josep Castellano and Dr. Marina Díaz-Beyá has attracted many readers since its publication. This special series aimed to explore todays knowledge about the potential role of ncRNAs in the clinic, especially in the liquid biopsy field, and intends to shed light into the future questions to be raised on this matter. At this moment, we are honored to have an interview with Dr. Navarro to share his scientific career experience and insights on this special series.
Figure 1 Dr. Alfons Navarro
Expert introduction
Alfons Navarro, PhD is a molecular biologist with a longstanding interest in the role of non-coding RNAs in cancer and human embryology. He graduated in Biology in 2002 and obtained his PhD (cum laude) from the University of Barcelona in 2008 with a dissertation entitled “Comparative analysis of miRNA expression in embryonic colon development, colorectal cancer, and Hodgkin's lymphoma.”. In 2010, he conducted post-doctoral research on microRNAs in cancer at the Comprehensive Cancer Center at Ohio State University under the supervision of Dr. Carlo M. Croce. Since 2012, Dr. Navarro has been a Professor of Human Anatomy and Embryology at the University of Barcelona. Due to his great interest in bioinformatics, he obtained a master's degree in Bioinformatics and Biostatistics from the Open University of Catalonia in 2016.
Dr. Navarro's research has primarily focused on non-coding RNAs in solid and hematologic cancers, including colorectal cancer, non-small-cell lung cancer, Hodgkin lymphoma, acute myeloid leukemia, and multiple myeloma. He has published over 80 articles and directed 14 doctoral theses. Additionally, he has worked on extracellular vesicles and patient-derived tumor organoids. Dr. Navarro has participated in 16 research projects, with three as principal investigator, and signed several contracts with international private companies. He has also served as editor for several journals, including Plos One, Frontiers in Oncology, Discover Oncology, Cancers, Non-coding RNA Investigation and Translational Cancer Research. Furthermore, he actively review articles in more than 10 international journals and has participated as a project evaluator and panel member for national and international agencies.
Dr. Navarro's multiple publications in high-profile journals and his presentations at national and international meetings have earned him recognition as a leading investigator in the field of microRNAs in cancer. Since 2021, he has directed the Molecular Oncology and Embryology lab at the Faculty of Medicine and Health Sciences of the University of Barcelona.
Interview
TCR: As a reputable expert in non-coding RNAs in cancer, what drove you into this field in the first place?
Dr. Navarro: In 2006, I was working on my thesis on pharmacogenomics in different tumor models. My thesis director, Dr. Mariano Monzo, asked me to attend a seminar about a new group of non-coding RNAs and the methodology available to quantify them. I initially went without too much interest, only with the aim of summarizing the seminar to my mentor. However, I came back excited about the new molecules and their importance in cancer research, and with a lot of ideas on how to study them in our cancer models. These new molecules were microRNAs. I immediately started working on the study of microRNAs in different tumor models for which we had patient samples available, including colorectal cancer and Hodgkin lymphoma. With the agreement of my director, I decided to change my thesis project and focus it on the study of microRNAs in cancer. A year later, we published a first collaborative work on microRNAs in colorectal cancer(2). In 2008, I gave an oral presentation on microRNAs in Hodgkin lymphoma at the American Society of Hematology Congress, and the results were published in Blood later the same year (3). Later that year, we published a second article comparing the microRNA profiles between colon embryogenesis and colorectal cancer, identifying microRNAs with stem cell potential. The article was published in Cell Research (4), and our research was featured on the cover image of the journal issue where our article was published. That was the starting point of my love affair with non-coding RNAs.
TCR: Could you briefly describe the key regulatory mechanisms of non-coding RNAs in cancer therapy?
Dr. Navarro: The key regulatory mechanisms of non-coding RNAs in cancer therapy are diverse and depend on the specific type of non-coding RNA being targeted. However, for the purpose of this response, let me focus on the role of microRNAs, which are the best-studied group of non-coding RNAs in cancer therapy.
MicroRNAs are small non-coding RNAs that function by inhibiting protein translation in a sequence-dependent manner. They bind to the 3'UTR region of target mRNAs through sequence complementary binding, and when microRNAs become deregulated in pathology, a broad spectrum of targets can be affected. This can be both a benefit and a challenge in therapy, as one microRNA can modulate an entire cellular pathway, but can also have off-target effects due to its ability to target multiple genes.
When using microRNAs in therapy, the first thing to consider is whether the microRNA needs to be upregulated or downregulated. Depending on the pathology and the specific microRNA, it may act as a pathological suppressor or driver, and we need to either reconstitute or suppress its expression, respectively.
Different strategies can be used to modify microRNA levels in the cell, such as the use of anti-microRNAs or microRNA mimics. Anti-microRNAs are small RNA molecules that can bind to and inhibit the function of specific microRNAs, leading to a decrease in their levels. An example of a clinical trial for an anti-miRNA is An example of a clinical trial for a microRNA mimic is a phase I trial that evaluated MRG-106, an anti-miR-155, in patients with cutaneous T-cell lymphoma. The trial showed promising results, with MRG-106 leading to significant reductions in tumor burden and increased progression-free survival.
MicroRNA mimics, on the other hand, are synthetic RNA molecules that mimic the function of endogenous microRNAs and can be transfected into the cell to increase the levels of a particular microRNA. An example of a clinical trial using a microRNA mimic is a phase I trial that evaluated MRX34, a liposomal nanoparticle containing a miR-34 mimic, in patients with advanced solid tumors. MiR-34a was a microRNA extensively analyzed and even our group identified that miR-34a had a role as relapse biomarker in resected lung cancer patients (5). Unfortunately, the MRX34 trial was suspended due to immune-related adverse events, but it highlighted the potential of microRNA mimics as therapeutic agents.
In addition to these direct approaches, indirect strategies for regulating microRNA expression can also be used, such as the use of epigenetic modulators that can alter the expression of microRNA genes.
It's worth noting that while microRNAs are the best studied group of non-coding RNAs in cancer therapy, other types of non-coding RNAs, such as lncRNAs and circRNAs, also play important roles in cancer and can be targeted using similar approaches as those used for microRNAs.
Furthermore, other regulatory mechanisms of non-coding RNAs in cancer therapy include epigenetic regulation, post-transcriptional regulation, modulation of signaling pathways, modulation of immune response, and exosome-mediated communication. Understanding these mechanisms can also help to identify potential targets for cancer therapy.
TCR: Some non-coding RNAs have been confirmed or are under development as biomarkers or targeted drugs for cancer immunotherapy. Could you please give a review on how these non-coding RNAs were discovered and validated?
Dr. Navarro: The discovery and validation of non-coding RNAs (ncRNAs) as biomarkers and targeted drugs for cancer immunotherapy have been a significant area of research in recent years. Some examples include from miRNAs to lncRNAs: miR-155 have been shown to enhance the immune response to cancer cells and improve the efficacy of immunotherapy by CTLA-4 blockade; lncRNA NEAT1 has been shown to enhance the immune response to cancer cells and improve the efficacy of immunotherapy by PD-1 blockade. These are only two examples of a long list of non-coding RNA described to regulate immunotherapy response by different mechanisms. In the discovery and validation of these ncRNAs as biomarkers and targeted drugs for cancer immunotherapy typically involve several steps. First, high-throughput technologies such as RNA-seq, expression arrays or qPCR based arrays are used to identify differentially expressed ncRNAs in patients responding vs resistance to immunotherapy treatment. Next, the functional role of the identified ncRNAs is evaluated using in vitro and in vivo experiments. Finally, clinical studies are conducted to validate the clinical utility of the identified ncRNAs as biomarkers or therapeutic targets for cancer immunotherapy.
The discovery and validation of ncRNAs as biomarkers and targeted drugs for cancer immunotherapy have opened up new avenues for the development of personalized cancer therapies. However, more research is needed to fully understand the functional role of ncRNAs in cancer immunotherapy and to develop effective ncRNA-based therapies for cancer.
TCR: What are the controversies and uncertainties of non-coding RNAs in cancer therapy？What does the future hold for non-coding RNAs in cancer therapy？
Dr. Navarro: It's difficult to answer without focusing on a specific type of non-coding RNA. One general controversy and uncertainty surrounding non-coding RNAs in cancer therapy is the potential for off-target effects and toxicity. This has been seen in some clinical trials, where the use of microRNA mimics or anti-microRNAs has led to unexpected side effects, such as liver toxicity and immune-related adverse events. For example, a clinical trial testing an anti-microRNA for the treatment of hepatitis C virus-associated liver cancer was terminated early due to severe immune-related adverse events.
Another challenge is the specificity of non-coding RNA targeting, as many microRNAs can have multiple targets and affect various pathways. This can lead to unintended consequences and make it difficult to predict the overall effects of targeting a specific microRNA.
Despite these challenges, non-coding RNAs continue to hold promise in cancer therapy. The development of more specific and targeted delivery systems, as well as a better understanding of the underlying mechanisms of non-coding RNA regulation, may help to overcome these challenges and improve the efficacy and safety of non-coding RNA-based therapies.
TCR: Is the topic of this special series associated with any of your recent research projects? Would you please share some significant researches you are working on?
Dr. Navarro: We are currently in the early stages of developing several projects with potential therapeutic approaches. One project involves studying the non-coding RNA cargo of extracellular vesicles, while another project focuses on using patient-derived tumor organoids to evaluate the role of various non-coding RNAs in regulating cancer stem cells. Additionally, by co-culturing tumor organoids with the patient's own white blood cells, we can evaluate the response to immunotherapy in these patient-centered models.
Overall, the future of non-coding RNAs in cancer therapy is promising. We expect that our ongoing research will contribute to a better understanding of non-coding RNA function and regulation in cancer. Specifically, we aim to increase knowledge of the role of non-coding RNAs in the survival of cancer stem cells, which are often involved in treatment resistance and patient relapse.
TCR: If there is a chance to update this special series, what would you like to moderate, add or emphasize more?
Dr. Navarro: Sure. In my perspective, staying current with the rapidly evolving field of non-coding RNAs is crucial. Regular updates to the specialized series that covers the clinical and therapeutic roles of these RNAs in cancer, including less well-studied groups such as circRNAs or piwiRNAs, are essential. Additionally, with the expected increase in clinical trials using non-coding RNA-based approaches, it's important to keep track of these developments and highlight them in an updated special issue.
References
- Clinic and Therapeutic Potential of Non-coding RNAs in Cancer. Available online: https://tcr.amegroups.org/post/view/clinic-and-therapeutic-potential-of-non-coding-rnas-in-cancer
- Bandrés E, Cubedo E, Agirre X, et al. Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29.
- Navarro A, Gaya A, Martinez A, et al. MicroRNA expression profiling in classic Hodgkin lymphoma. Blood. 2008;111(5):2825-2832.
- Monzo M, Navarro A, Bandres E, et al. Overlapping expression of microRNAs in human embryonic colon and colorectal cancer. Cell Res. 2008;18(8):823-833.
- Gallardo E, Navarro A, Viñolas N, et al. miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis. 2009;30(11):1903-1909.