LABORATORY OF NEURAL TUMORS
Principal Investigator (Name, MD/PhD)
Miguel F. Segura
Adrià Molero Valencuela, PhD Researcher
Ainara Magdaleno Cazón, Tehcnician
Ariadna Boloix Amenós, Postdoctoral Researcher
Carlos Jiménez Jiménez, Postdoctoral Researcher
María José Pérez García, Postdoctoral Researcher & Project Manager
Roberta Antonelli, Postdoctoral Researcher
Clinical Associated Researchers
Lucas Moreno, MD PhD. Expertise in drug development and clinical trials.
Anna Llort, MD PhD. Expertise in pediatric brain tumors
Constantino Sábado, MD. Expertise in Hepatoblastoma
Pediatric cancer has specific features that define it as an entity that in the majority of cases is certainly different than adult tumors; i.e. etiology, biology, response to treatment and prognosis are really different. The implementation of multimodal treatments (i.e. combinations of chemotherapies, radiotherapies, biological agents…) in the lasts 20 years has enabled the raise patient survival around 80%. Although the global survival of pediatric cancer is around 80%, patients with some types of tumors present a much lower survival. Moreover, almost two-thirds of patients who survive suffer severe side effects due to the treatment. Therefore, the development of therapies to treat 20% of patients who do not survive and to reduce toxicity of current treatments avoiding long-term side effects is extremely necessary.
Pediatric tumors of the nervous system are the most common solid malignant neoplasms of childhood cancer and the leading cause of cancer-related death in children. The main objective of my laboratory is to implement the use of epigenetic therapies, that is, therapies against gene expression modulators that, in turn, regulate several genes, pathways or cellular processes, without affecting the DNA sequence. The laboratory focus on neuroblastoma, a pediatric solid tumor of the peripheral nervous system, and on pediatric brain tumor of the central nervous system pediatric such as ependymoma, medulloblastoma or high-grade glioma among others.
RESEARCH STRATEGY AND SCOPE
The research strategy of the Neural Tumors Lab is based on the following research lines:
Development of RNA-based therapies for pediatric tumors
RNA-based therapies may represent a paradigm shift for the treatment of neuroblastoma, or cancer in general, because they have the potential to act on the entire transcriptome, thus expanding the number of drug targets, since they could modulate both RNA coding (2% of the total genome that is transcribed) and non-coding RNAs (80% of the genome that is transcribed). Within RNA-based therapies, the most advanced molecules from a clinical development point of view are small RNAs (e.g. siRNA or microRNA). Moreover, they will be safer therapies, since their mechanism of action will not induce permanent effects, especially in healthy cells. One of the working hypothesis of this line is that the microRNAs (miRNAs) deregulation is contributing to the metastatic and chemoresistant behavior of high-risk neuroblastoma and miRNA(s) levels restoration represents an attractive novel therapeutic approach.
Exploiting epigenetic vulnerabilities in metastatic neuroblastoma
Metastatic relapse is the major cause of death in neuroblastoma. The liver, bone and bone marrow and lymph nodes are among the most common metastatic sites of neuroblastoma patients, which constitute a “reservoir” of tumor cells that persistently reside in patients following local and systemic cancer therapy. Their elimination continues to represent the most difficult challenges for neuroblastoma patients. Our hypothesis is that metastatic cells can colonize distant organs thanks to the re-organization of their epigenetic landscape. Results of the last five years of the laboratory clearly shows that chromatin remodelers may play significant role in the aggressiveness of neuroblastoma. Therefore, in this cell line we are i) Characterizing the epigenetic landscape of metastatic neuroblastoma; ii) Characterizing the transcriptomic map of chromatin remodelers (i.e. SWI/SNF)-regulated genes in neuroblastoma metastasis; iii) Developing of an epigenetic therapy based on the inhibition of chromatin remodeling complexes; iv) Developing more sensitive tools to diagnose and target neuroblastoma metastasis.
Participation in drug development in pediatric solid tumors (e.g. Neuroblastoma, Hepatoblastoma, Brain Tumors)
We are interested in testing the therapeutic potential of new synthetic or natural compounds which can represent clear advantages (i.e. increased effectiveness, reduced toxicities) compared to traditional chemotherapy. We have a clinically representative panel of pediatric solid tumor cell lines and preclinical mouse models to test the efficacy and safety of new drugs aimed to improve the efficacy and safety of currently available treatments. Currently, we are evaluating the therapeutic potential of ABTL0812 in pediatric tumors, both preclinically but also in a “first in child” Phase I clinical trial. Additionally, we are also pursuing the evaluation of the therapeutic potential of the KIF11 inhibitor 4SC-205 in pediatric tumors.
Identification of new treatments for pediatric brain tumors (i.e. Ependymoma)
Pediatric tumors of the central nervous system (CNS) are the most common solid malignancies in children, second only to hematologic malignancies, and are the leading cause of cancer-related deaths. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. One of the most advanced epigenetic therapies, only second to DNA methyl-transferase inhibitors, is the use of histone deacetylase inhibitors (HDACi). However, while shown to be effective in certain tumor types, their use in brain tumors did not yielded the expected results, probably because these drugs were not specifically designed to reach sealed tissues such as the brain. This research line constitutes a truly translational approach to further enhance the possibility of using HDACi in the treatment of brain tumors such as, but not restricted to, Ependymoma. Here, we are also elaborating a roadmap for the implementation of immunotherapies in pediatric brain tumors and characterizing the role of the tumor microenvironment in tumor growth and aggressiveness.
ONGOING COMPETITIVE PROJECTS:
-Ref. PI20/00530 (AES ISCiii 2021-2023). PI: Miguel F. Segura. Nanotools for the treatment of metastatic neuroblastoma.
Summary: Metastatic relapse is the major cause of death in NB, where there remains a lack of therapies to target this stage of the disease. Therefore, understanding how NB cells invade, arrive at the metastatic niche and adapt to the new environment at the metastatic site, will help in designing more effective therapies to control the development and metastasis in NB. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that interfere with the translation of coding messenger RNAs (mRNAs) in a sequence-specific manner. In NB, over- or under-expression of specific miRNAs correlates with stage, progression (i.e. relapse / metastasis) and patient outcome. Particularly, miR-323a-5p was shown to be downregulated in NB metastasis and its restoration impaired tumor growth in vitro and in vivo.
MiRNA-based therapies face a major challenge, i.e. the limitations associated with their clinical administration, such as inefficient biodistribution and specific targeting of tissues. Conjugation of miRNA with nanostructured materials can improve targeting to specific tissues and reduce potential side-effects. The aim of this project is to test a new miRNA-based nanoformulation for the treatment of metastatic neuroblastoma.
Ref. DTS20/00018 (AES ISCiii 2021-2022). PI: Miguel F. Segura. Quatsomes as a novel nanomaterial platform for nucleic acids delivery.
Summary: RNA-based therapies against cancer have proved to show great potential since they are able to target all the transcriptome (coding and non-coding mRNAs), thereby expanding significantly the number of therapeutic targets.
The most therapeutically-advanced molecules in RNA-based therapies are microRNA (miRNA), endogenous noncoding small RNA that interfere with the translation and stability of RNA (coding and non-coding) in a sequence-specific manner. However, the application of these small molecules for treating human disease faces a major challenge, i.e. the limitations associated with their clinical administration such as inefficient biodistribution and specific targeting of tissues.
The aim of this project is to optimize our QS-miRNA nanoformulation for the treatment of high-risk neuroblastoma, an incurable pediatric tumor that demands new therapeutic approaches. Ours will consist on functionalizing QS-miRNA complexes with stealth polymers and specific targeting peptides which will reduce QSmiRNA complex aggregation, enhance blood circulation time and increase specificity towards neuroblastoma tumors.
Ref. ICI21/00076 (AES ISCiii 2022-2025). PI: Lucas Moreno. Scientific Officer: Miguel F. Segura. A phase I trial of ABTL0812 in paediatric patients with advanced cancer including neuroblastoma.
Summary: Childhood cancer is the first cause of death due to disease in children. New drugs are needed to increase cure rates and reduce long-term sequelae of survivors. More than half of children with high-risk tumors such as metastatic neuroblastoma or sarcomas, or those with refractory or relapsed disease will not achieve a long-term cure. Most current therapies target cell division and proliferation by inducing DNA damage and programmed cell death. However, aggressive tumors often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumor cell death, particularly in combination, will provide new therapeutic opportunities for these patients. ABTL0812 is a first-in-class oral targeted anticancer compound that produces autophagy-mediated cytotoxicity selectively in cancer cells. It induces endoplasmic reticular stress (ER-stress) and blocks the AKT/mTOR pathway, resulting in cancer cell death. Our preclinical data indicate that ABTL0812 is effective in models of neuroblastoma (NB), even in cells that are resistant to multiple drugs. In NB, ABTL0812 further induces the associated unfolded protein response (UPR), which results in autophagy-dependent apoptosis and decreases the expression of MYCN, a key oncogenic driver of NB. Additionally, our preclinical studies suggest that ABTL0812 can potentiate the antitumor activity of chemotherapies and differentiating agents. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients. Based on our group's preclinical work, ABTL0812 received orphan drug designation (ODD) by the FDA (15-4893) and EMA (EU/3/15/1485) agencies for neuroblastoma in 2015. ABTL0812 is currently in Phase II clinical development stage for adult tumors (pancreatic cancer) after successfully completing phase I, demonstrating safety and activity. This project arising from our group's preclinical work has the following aims: 1) to conduct a “first- in-child” clinical trial with ABTL0812, 2) to demonstrate the added value of combining ABTL0812 with immunotherapeutics and conventional chemotherapeutics3) to conduct an ambitious translational study to identify pharmacodynamic, predictive, prognostic and radiomic biomarkers. The clinical trial will evaluate ABTL0812 as single agent, in combination with irinotecan-temozolomide chemotherapy and with immunotherapy, i.e. anti-PD1, anti-GD2 or antiangiogenic therapies, to be decided based on preclinical work embedded into this project. The project addresses several objectives of the Strategic Action for Health of this call and priority actions of AES2021 such as development of new drugs for treatment of rare and severe diseases and drugs with ODD. Furthermore, this study is aligned with the neuroblastoma drug development strategy aimed at finding to target MYCN, one of the key drivers of aggressive pediatric tumors such as neuroblastoma.
SELECTED PUBLICATIONS (Top 10):
1.- Segura MF, Soriano A, Roma J, Piskareva O, Jiménez C, Boloix A, Fletcher JI, Haber M, Gray JC, Cerdá-Alberich L, Martínez de Las Heras B, Cañete A, Gallego S, Moreno L. Methodological advances in the discovery of novel neuroblastoma therapeutics. Expert Opin Drug Discov. 2022 Feb;17(2):167-179. doi: 10.1080/17460441.2022.2002297. Epub 2021 Nov 22. PMID: 34807782.
2.- Boloix A, Feiner-Gracia N, Köber M, Repetto J, Pascarella R, Soriano A, Masanas M, Segovia N, Vargas-Nadal G, Merlo-Mas J, Danino D, Abutbul-Ionita I, Foradada L, Roma J, Córdoba A, Sala S, de Toledo JS, Gallego S, Veciana J, Albertazzi L, Segura MF*, Ventosa N*. Engineering pH-Sensitive Stable Nanovesicles for Delivery of MicroRNA Therapeutics. Small. 2022 Jan;18(3):e2101959. doi: 10.1002/smll.202101959. Epub 2021 Nov 16. PMID: 34786859. (*corresponding authors).
3.- Masanas M, Masiá N, Suárez-Cabrera L, Olivan M, Soriano A, Majem B, Devis-Jauregui L, Burgos-Panadero R, Jiménez C, Rodriguez-Sodupe P, Boloix A, Toledano I, Guillén G, Navarro A, Llobet-Navas D, Villanueva A, Sánchez de Toledo J, Roma J, Noguera R, Moreno L, Krauss R, Gallego S, Santamaria A*, Segura MF*. The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic neuroblastoma models. Clin Transl Med. 2021 Oct;11(10):e533. doi: 10.1002/ctm2.533. PMID: 34709738; PMCID: PMC8516339. (*corresponding authors).
4.- Muñoz-Guardiola P, Casas J, Megías-Roda E, Solé S, Perez-Montoyo H, Yeste-Velasco M, Erazo T, Diéguez-Martínez N, Espinosa-Gil S, Muñoz-Pinedo C, Yoldi G, Abad JL, Segura MF, Moran T, Romeo M, Bosch-Barrera J, Oaknin A, Alfón J, Domènech C, Fabriàs G, Velasco G, Lizcano JM. The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. 2021 Jun;17(6):1349-1366. doi: 10.1080/15548627.2020.1761651. Epub 2020 May 25. PMID: 32397857; PMCID: PMC8204958.
5.- París-Coderch L, Soriano A, Jiménez C, Erazo T, Muñoz-Guardiola P, Masanas M, Antonelli R, Boloix A, Alfón J, Pérez-Montoyo H, Yeste-Velasco M, Domènech C, Roma J, Sánchez de Toledo J, Moreno L, Lizcano JM, Gallego S, Segura MF. The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis. Cell Death Dis. 2020 Sep 17;11(9):773. doi: 10.1038/s41419-020-02986-w. PMID: 32943619; PMCID: PMC7498451.
6.- Antonelli R, Jiménez C, Riley M, Servidei T, Riccardi R, Soriano A, Roma J, Martínez-Saez E, Martini M, Ruggiero A, Moreno L, Sánchez de Toledo J, Gallego S, Bové J, Hooker JM, Segura MF. CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models. Cancers (Basel). 2020 Jul 16;12(7):1922. doi: 10.3390/cancers12071922. PMID: 32708733; PMCID: PMC7409080.
7.- Qadeer ZA, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C, Soriano A, Ma A, Griffiths LM, Zeineldin M, Filipescu D, Jubierre L, Chowdhury A, Deevy O, Chen X, Finkelstein DB, Bahrami A, Stewart E, Federico S, Gallego S, Dekio F, Fowkes M, Meni D, Maris JM, Weiss WA, Roberts SS, Cheung NV, Jin J, Segura MF, Dyer MA, Bernstein E. ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures. Cancer Cell. 2019 Nov 11;36(5):512-527.e9. doi: 10.1016/j.ccell.2019.09.002. Epub 2019 Oct 17. PMID: 31631027; PMCID: PMC6851493.
8.- Soriano A, Masanas M, Boloix A, Masiá N, París-Coderch L, Piskareva O, Jiménez C, Henrich KO, Roma J, Westermann F, Stallings RL, Sábado C, de Toledo JS, Santamaria A, Gallego S, Segura MF. Functional high-throughput screening reveals miR-323a-5p and miR-342-5p as new tumor-suppressive microRNA for neuroblastoma. Cell Mol Life Sci. 2019 Jun;76(11):2231-2243. doi: 10.1007/s00018-019-03041-4. Epub 2019 Feb 15. PMID: 30770954; PMCID: PMC6502783.
9.- Jubierre L, Jiménez C, Rovira E, Soriano A, Sábado C, Gros L, Llort A, Hladun R, Roma J, Toledo JS, Gallego S, Segura MF. Targeting of epigenetic regulators in neuroblastoma. Exp Mol Med. 2018 Apr 27;50(4):51. doi: 10.1038/s12276-018-0077-2. PMID: 29700278; PMCID: PMC5938021.
10.- Jubierre L, Soriano A, Planells-Ferrer L, París-Coderch L, Tenbaum SP, Romero OA, Moubarak RS, Almazán-Moga A, Molist C, Roma J, Navarro S, Noguera R, Sánchez-Céspedes M, Comella JX, Palmer HG, Sánchez de Toledo J, Gallego S, Segura MF. BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways. Oncogene. 2016 Sep 29;35(39):5179-90. doi: 10.1038/onc.2016.50. Epub 2016 Mar 21. PMID: 26996667.
ACTIVE COLLABORATIONS WITH INDUSTRY: (Name, country)
Nanomol Technologies S.L. (Barcelona, Spain)
Ability Pharma S.L. (Barcelona, Spain)
4SC (Münich, Germany)
PAST MEMBERS: (Name, actual position)
Dra. Luz Jubierre Zapater. Currently postdoctoral researcher at MSKCC, NY, USA.
Dra. Laia París-Coderch. Currently working as Validation and GMP Junior Consultant at TDV SL.
Dra. Aroa Soriano. Currently leading the Personalized Medicine Program at Vall Hebron Hospital.
Dr. Marc Masanas. Currently enrolled in a Master Program.