Cima Universidad de Navarra (Spain) researchers lead an international study that has generated preclinical models that mimic the development and evolution of this blood cancer in patients.
These models will allow the design of more effective and personalized therapies for multiple myeloma, the second most frequent hematological cancer.
Nature Medicine publishes this study that opens a pathway for research into other non-curable tumors.
Leukemia, will open the doors to the development of new therapeutic RNA-based strategies for multiple myeloma, the second most common cancer of the blood
March 29, 2023. An international group of researchers, led by Dr. José Ángel Martínez-Climent at the Cima University of Navarra, has created mouse avatars of patients with multiple myeloma to study and develop personalized treatments against this blood cancer, the second most frequent hematological cancer and incurable in most cases. These artificial mice can mimic the genetic and immunological diversity of the origin and evolution of this disease in patients. This advance will allow researchers to design more effective and personalized therapies for multiple myeloma.
Nature Medicine publishes this study that opens a pathway for research into other non-curable hematological and solid tumors.
Hospitals, research centers, and biotechnology and pharmaceutical companies from Spain, Switzerland, United States, and Japan have also participated in this multicenter study. The leading researchers of the project are part of the Cancer Center Clínica Universidad de Navarra and belong to the Centro de Investigación Biomédica en Red en Cáncer (CIBERONC) and the Instituto de Investigación Sanitaria de Navarra (IdiSNA)
A multiple myeloma “catalog” to improve its treatment
Multiple myeloma is a blood cancer that occurs in the bone marrow. It is caused by the proliferation of plasma cells, immune cells responsible for producing antibodies. It is a heterogeneous disease, meaning that it can present in different ways and have different responses to treatment.
To meet the medical need for new treatments to cure the disease, the researchers have used genetic engineering and multi-omic cellular and molecular technologies to analyze more than 500 genetically heterogeneous mice that develop multiple myeloma and tumor cells from more than 1,000 patients with the disease. These samples are from patients attended in the Hematologic Cancer Area of the Cancer Center Clínica Universidad de Navarra. Thanks to this analysis, “we have generated artificial mice that accurately reflect key aspects of the origin and development of multiple myeloma in humans. This allows us to study the progression of the disease, test therapeutic alternatives and predict the response to combinations of immunotherapy drugs in the clinic,” says Marta Larrayoz, a researcher in the Hemato-Oncology Program at Cima University of Navarra and first author of the study.
Significant implications for patients
Researchers must be able to contrast and validate the information provided by preclinical models with patient data to advance laboratory work. “Thanks to our ongoing collaboration with the hematologists at the Cancer Center Clínica Universidad de Navarra, we have identified in our mouse models of multiple myeloma a correlation between the genetic and
immunological traits of each tumor and its selective response to preclinical therapies,” says José Ángel Martínez-Climent, principal investigator and coordinator of the study, also belongs to the Cima Hemato-Oncology Program.
This research will allow researchers to anticipate treatment outcomes with next-generation immunotherapies and mimic in the laboratory clinical situations associated with the worst outcomes, such as high-risk multiple myeloma, extramedullary disease, or acquired therapeutic resistance. “This scenario offers us opportunities to advance in the investigation of new therapeutic strategies and to optimize the design of future immunotherapy clinical trials,” says Martínez-Climent. In addition, “we are testing novel therapies in experimental models at stages of the disease where multiple myeloma cells might be most vulnerable, particularly in early precursor conditions or in the minimal residual disease state (after treatment, when few tumor cells remain). To do this, we have established numerous scientific collaborations with pharmaceutical companies developing clinical trials in this disease to carry out these same trials in our mice”.
The ultimate goal, say the researchers, “is to transfer the discoveries from the laboratory to the clinic and that research initiatives such as ours can be extrapolated to other hematological malignancies and solid tumors that remain incurable with currently available treatments.”
This work has received funding through the imCORE Network, the Ministry of Health, the Ministry of Science and Innovation, the Carlos III Health Institute (co-financed with ERDF funds), the Paula and Rodger Riney Foundation, and the Arnal Planelles Foundation. It has also received support from other public and private institutions, such as Iberdrola, through the Spanish Association Against Cancer within its call for “Accelerator Grants” (EDITOR Project).
Caption: Cima and the Cancer Center Clínica Universidad de Navarra researchers. In front: Teresa Lozano, Maddalen Jiménez, Jon Celay, Marta Larráyoz, José Ángel Martínez Climent, Mª José García Barchino and Amaia Etxebeste. Behind: Juan José Lasarte, Vicente Fresquet, Sergio Roa, Cristina Pérez, Pablo Sarobe, Felipe Prósper, Bruno Paiva, Jesús San Miguel and Xabier Agirre.
Nat Med (2023). Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma. Larrayoz, M., Garcia-Barchino, M.J., Celay, J. et al. Nat Med 29, 632–645 (2023). https://doi.org/10.1038/s41591-022-02178-3(Read more)
About Cima Universidad de Navarra
Cima Universidad de Navarra is a biomedical research institute of the Universidad de Navarra. The purpose of our more than 400 scientists is to carry out translational research of excellence based on novel biological knowledge and oriented to find therapeutic solutions to patients’ needs.
To translate preclinical research results into clinical applications, Cima has a Translational and Innovation unit that establishes collaborations with biotechnology and pharmaceutical companies that convert scientific knowledge into new treatments for patients. In addition, we specialize in developing novel therapies, such as immunotherapy and gene therapy, and cancer research, whose activity is integrated into the Cancer Center Clínica Universidad de Navarra.
The EDITOR project, a collaboration of 13 research institutions from the UK, Spain and Italy, is entering it´s final year. Thorugh out the four years of this project, there has been bast scientific achievements with one main focuse: Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable haematological malignancies.
The overall goal of the project is to better characterise the early stages of these cancers and the cancer cells that persist after treatment (MRD cells). The project will produce resources to accelerate research in the early detection and intervention of these blood cancers. Our aim is to focus on treating the cause of the disease through the advancement of precision therapies and treatments that manage MRD, instead of waiting for a relapse (https://editorproject.com/the-project-hematological-diseases/).
You can find below a summary of the Scientific achievements on each of the diseases we have focused on the EDITOR project:
Researchers at the Clinica Universidad de Navarra and CIMA Universidad de Navarra are leading an international study which has revealed a novel set of genes specific to multiple myeloma which condition its manifestation and development
The research also shows that the expression of these genes allows for better classification of patients with this disease in terms of survival
The finding, published in Leukemia, will open the doors to the development of new therapeutic RNA-based strategies for multiple myeloma, the second most common cancer of the blood
Pamplona (Spain), February 22, 2021. Researchers at Clinica and CIMA of the Universidad de Navarra are leading an international study which has revealed a new set of genes specific to multiple myeloma which condition its manifestation and development. This discovery has identified 40,511 new non-coding genes (up to now called junk genes) involved in the evolution of this cancer of the blood.
The study also shows that the expression of the genes, together with the genetic alterations connected with a negative prognosis in patients with multiple myeloma, allows for better classification of the survival results.
The results of this work have been published in Leukemia, one of the most prestigious international scientific journals in the field of hematology, and opens the door to new RNA-based therapeutic strategies for multiple myeloma, the second most frequent hematologic cancer.
The group led by Dr. Iñaki Martín-Subero from the Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS) in Barcelona, and the group led by Dr. Ari Melnick, from the Weill Cornell Medical College in New York, among other institutions, have participated in the research.
The RNA molecule which ‘translates’ multiple myeloma
Multiple myeloma is an incurable disease originating in the bone marrow. Its biological heterogeneity makes its clinical management challenging. Recent oncological research has focused on some molecules involved in the regulation of the genome and gene expression. Specifically, this research has deciphered a type of specific long non-coding RNAs (lncRNAs), which has allowed the researchers to identify new genes with a key role in the origin and workings of the cancer cells.
“The initial study for detection and definition of the complete lncRNAs transcriptome was carried out in samples from 38 multiple myeloma patients proving their functionality in the disease. We have also shown its potential as a biomarker by analyzing the most complete series of patients with multiple myeloma to date, the so-called CoMMPass study”, said Dr. Xabier Agirre, a researcher in the Hemato-Oncology Area at CIMA.
Clinically, “we have shown that the expression of lncRNAs, together with the negative-prognosis genetic alterations in patients with multiple myeloma, offers much better sub-stratification of patients regarding survival”, affirmed Dr. Felipe Prósper, co-director of the Hemato-Oncology Program at CIMA and the Hematology Service of the Clinica Universidad de Navarra.
As stated by the researchers, this advance shows that there are many other key genes for the development of this disease, which may be interesting therapeutic targets to open the doors to novel therapies based on the specific RNAs of multiple myeloma.
This research has been carried out within the framework of the Instituto de Investigación Sanitaria de Navarra (IdiSNA) and the Centro de Investigación Biomédica en la Red de Cáncer (CIBERONC). It has had the support of Iberdrola, through the Asociación Española contra el Cáncer (AECC) and its Accelerator Awards with the joint participation of Cancer Research UK and the Fondazione AIRC per la Ricerca sul Cancro (AIRC). It is also funded by: the European Union within the Blue Print Epigenome project, the Multiple Myeloma Research Foundation, the Spanish Ministry of Science and Innovation, the Ramón Areces Foundation, the Navarrese Government and other public and private institutions.
The results of this work are part of the doctoral thesis of Arantxa Carrasco-León, a CIMA researcher into Hemato-Oncology.
Caption: (from right to left): Felipe Prósper and Xabi Agirre together with the main authors of the article Arantxa Carrasco-León and Teresa Ezponda and other researchers of the Hemato-Onoclogy Program at CIMA.
Leukemia (2021). Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma. Carrasco-Leon, A., Ezponda, T., Meydan, C. et al. DOI: 10.1038/s41375-021-01147-y (Read more)
The 2020 has been a year marked by the pandemic. The global health crisis has slowed down, or even paralysed, the scientific activity of biomedical research centres, especially in Europe.
In this context, the laboratories involved in the Editor project have continued to work on the knowledge of haematological diseases at the rate that the pandemic has allowed, resuming their practically usual research activity in the second half of the year.
In March, a general meeting of the Steering Board took place by videoconference. There they updated the status of the project and progress. In the second half of the year, the researchers practically resumed their scientific activity. Since then, all hubs celebrated a specific meeting for each haematological disease: multiple myeloma (MM) or amyloidosis (AL), follicular lymphoma (FL), myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).
These scientific meetings, held -also by videoconference- in the last four-month period of the year, were organised to deepen the advancement of research by strengthening collaborations and promoting new relationships between teams from Spain, Italy and the United Kingdom. Thus, in addition to sharing the latest advances and presenting the challenges to be faced in the next year, these meetings aimed to reinforce one of the general objectives of the project: to promote young talent.
An opportunity to advance knowledge of hematologic diseases with scientific leaders in the field
The scientific meetings were developed through brief presentations by the members of each disease group, where the leading role fell to junior researchers. Hannah Armes (UK), Martina Sarchi (Italy), Càtia Simões (Spain) or Connor Knight (UK) are some young researchers who have wanted to share their experience and the challenges of participating in the project.
(Pamplona, Spain, August 20, 2020) — A joint research by groups of the EDITOR Accelerator Award have discovered a molecular trait that is shared by myeloma patients.
Multiple myeloma is a greatly heterogeneous disease, both from biological and clinical perspectives. In spite of this heterogeneity, several groups of the EDITOR accelerator award have discovered a molecular trait that is shared by myeloma patients. The study has been led by the groups of Xabier Agirre and Felipe Prosper from the CIMA of Pamplona and Iñaki Martin-Subero from the Hospital Clinic of Barcelona, also with the participation of Jesus San Miguel, coordinator of the EDITOR project. The article, recently published in Genome Research, is entitled “Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma”. Using a multi-epigenomics approach and integrative computational analyses as well as detailed functional experiments, the authors identified the existence of a core epigenomic landscape underlying MM pathogenesis. This chromatin landscape is mostly characterized by the widespread activation of regulatory elements that remain inactive in normal cells. Such activation, seems to be mediated by the action of specific TF families, affecting genes particularly involved in preventing cell death associated with cellular stress, such as TXN and PRDM5. As chromatin activation seems to be a feature of myeloma patients as a whole, these findings suggests that drugs reverting this epigenetic process may be appropriate as a backbone treatment for this aggressive disease. (Read more)
(WASHINGTON, April 29, 2020) — In a special report published today in the journal Blood, an international working group of experts in myelodysplastic syndromes (MDS) proposes – for the first time – the recognition of a distinct subtype of MDS based on the presence of a nonheritable genetic mutation that causes the disease. The mutation is found in approximately one in every five patients with MDS.
“This study represents an important step forward in the ability to diagnose MDS on the basis of genetic features, and this is paving the way to obtain a diagnosis without the need to analyze bone marrow,” said lead author Luca Malcovati, MD, of the University of Pavia Medical School in Italy. “Patients who carry this genetic variant may benefit from treatment with an approved drug, luspatercept. In addition, other potential new treatments that directly target this genetic mutation are in the early stages of development and may benefit patients in the future.” (Read more)
New MDS Subtype Proposed Based on Presence of Genetic Mutation. (Article in English, April 29th 2020)Eloy Francisco Robles Cortes2023-08-28T12:22:33+00:00
December 2019. EDITOR project, focused on improving early detection and intervention of blood cancers, has completed a year with a positive balance in its forecasts. It started in its kick-off meeting held in January 2019 at Clinica Universidad de Navarra headquarters in Madrid (Spain). During this year the 13 institutions -from Spain, Italy and the United Kingdom- that form part of this international consortium have advanced in the knowledge of monoclonal gammopathies such as multiple myeloma, leukaemia and lymphoma. For that progress, the scientists based the research on the use of the latest techniques in genomic sequencing, the development of new humanized animal models of these diseases, and the compilation of large patient samples.a.
Among the scientific advances of the project, researchers have implemented protocols for advance genomics. Therefore, they used techniques such as RNA-sequencing or massively parallel single-cell RNA-sequencing based on small cell populations selected through high sensitivity fluorescence-activated cell sorting, a specialized type of flow cytometry. “The results obtained with these techniques are changing our understanding of myelomagenesis and clonal heterogeneity, and that could have an impact on the development of new therapeutic strategies,” says Dr Jesús San Miguel, Director of Clinical and Translational Medicine at Universidad de Navarra and the lead investigator. (Read more)
Advanced genomics, design of new animal models and patient sample collection: EDITOR project goals during 2019 (December 22th 2020)Eloy Francisco Robles Cortes2023-08-28T12:22:34+00:00
March 2020. The Steering Board from the EDITOR project, an international early detection and intervention of blood cancer research, held its third scientific meeting by videoconference. Clinica Universidad de Navarra (Spain) organised this meeting in which 36 researchers attended. They represented the 13 research institutions from the United Kingdom, Italy and Spain that are part of the project. Also, there were representatives from the financing institutions (CRUK and AECC) and the multiple myeloma patient association. Due to the COVID-19 pandemia the meeting, initially planned to take place in Madrid, was replaced by a virtual meeting with the same agenda.
Dr Jesús San Miguel, Director of Clinical and Translational Medicine at the Universidad de Navarra and the lead investigator, introduced the session remembering the mission of the project and updating the progress achieved during its first year. Among them, he highlighted the design of new tools for cell detection and characterisation, the development of antibodies panels, the establishment of new protocols and the design of improved mouse models. Subsequently, there were sessions dedicated to the advances in each disease. Thus, they were focused on multiple myeloma (MM) or amyloidosis (AL), follicular lymphoma (FL), myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). The last presentation was about the development of computational biology systems for the identification of new therapeutic targets and the design of personalised therapies for the treatment of these haematological malignancies. (Read more)
BCI researchers are lead members of an international team to be funded by an Accelerator Award, which will bring together scientists from the UK, Spain and Italy in a bid to improve early detection and intervention of blood cancers. The award of £4.8M over 5 years, funded through a partnership between Cancer Research UK (CRUK), AIRC and FC AECC, encourages cross-institutional collaboration to unite resources and expertise to accelerate progress in cancer research.
The Accelerator Award, led by Prof Jesus San Miguel, Director of Clinical and Translational Medicine at the University of Navarra, Spain, will support research into three types of blood cancer: follicular lymphoma, multiple myeloma and acute myeloid leukaemia, with each country acting as a specialist hub (across 13 centres) for one of these diseases. The three cancer types share similar features of progression, and the team hope to develop integrative models of how they evolve from a pre-malignant (or minimal residual disease) stage to malignant disease, and how best to target these cancers at their most vulnerable. (Read more)
Accelerator Award to improve early detection and intervention of blood cancers (Oct. 9th 2018)Eloy Francisco Robles Cortes2023-08-28T12:22:34+00:00
A new international Accelerator Award is funding researchers from the UK, Spain and Italy to improve early detection and intervention of haematological malignancies. The team is working together to develop disease models and produce data for studying blood cancers at an earlier stage. We talked to the lead investigator, Professor Jesus San Miguel – the Director of Clinical and Translational Medicine and Vice-Dean of the Medical Faculty at the University of Navarra – to learn about how they are combining their expertise to accelerate early detection for blood cancers. (Read more)
Detecting blood cancers earlier than ever before. CRUK interviewa Dr. Jesús San Miguel (Sept. 13th 2018)Eloy Francisco Robles Cortes2023-08-28T12:22:34+00:00