Dr Ernest Moles Meler

Dr Ernest Moles Meler

Conjoint Lecturer

PhD, University of Barcelona (UB, Spain), 2015

MSc with Honours, University of Barcelona (Spain), 2010

BSc, University of Lleida (Spain), 2009.

Medicine & Health
School of Clinical Medicine

Dr. Ernest Moles is a multidisciplinary investigator with extensive expertise in the fields of precision-nanomedicine, immunotherapy and oncology. Through his research at IBEC (Spain, 2010-2017), he developed >20 antibody-nanoparticle conjugates for management of difficult-to-treat paediatric blood diseases. Findings resulted in 12 publications at highly-regarded nanomedicine journals (J.Control Release-2015/2016,Biomaterials-2017; 50% as first or corresponding author). His research has influenced others to develop nanomaterials against HIV and cancer (Biomolec Chemistry,2020,18,9639-9652, Acta Pharmacologica Sinica,2021,42:1516-1523). Dr. Moles joined CCI in 2017, applying his translational capacity to engineer targeted nanotherapeutics for the treatment of cancer. Through UNSW-RIS 2019/2020 infrastructure funds ($923k), he established nanomedicine-dedicated infrastructure, the first of its kind at CCI/UNSW, through which he developed advanced chemo- & RNA-based lipid nanotherapeutics for the treatment of aggressive leukaemia (Pharmaceutics,2021,13:1681, Sci Transl Med,2023,15:eabm1262) and paediatric brain cancers (ongoing studies on DIPG & GBM through RNA Institute seed grant and Moderna Global programme). Contributions within the nanomedicine field are further evidenced by being cited in reviews of highly-regarded journals (Adv Drug Delivery Reviews,2020,154-155:151-162, Nature Nanotechnology,2021,16:369-384), an invited editorial contribution to Nature Biomedical Engineering (2019,3:248-250). Leadership in his field is further evidenced by the award of a prestigious US Moderna Global Fellowship (2023-2025).

Location
Children's Cancer Institute, Level 1 Lowy Cancer Research Centre
  • Journal articles | 2023
    2023, 'Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia', , http://dx.doi.org/10.1126/scitranslmed.abm1262
    Journal articles | 2022
    Karsa M; Ronca E; Bongers A; Mariana A; Moles E; Failes TW; Arndt GM; Cheung LC; Kotecha RS; Kavallaris M; Haber M; Norris MD; Henderson MJ; Xiao L; Somers K; Moles Meler E, 2022, 'Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia', Frontiers in Oncology, 11, pp. 779859, http://dx.doi.org/10.3389/fonc.2021.779859
    Journal articles | 2021
    Connerty P; Moles E; de Bock CE; Jayatilleke N; Smith JL; Meshinchi S; Mayoh C; Kavallaris M; Lock RB; Moles Meler E, 2021, 'Development of siRNA-loaded lipid nanoparticles targeting long non-coding RNA LINC01257 as a novel and safe therapeutic approach for t(8;21) pediatric acute myeloid leukemia', Pharmaceutics, 13, pp. 1681, http://dx.doi.org/10.3390/pharmaceutics13101681
    Journal articles | 2020
    Lantero E; Belavilas-Trovas A; Biosca A; Recolons P; Moles E; Sulleiro E; Zarzuela F; Ávalos-Padilla Y; Ramírez M; Fernàndez-Busquets X, 2020, 'Development of DNA Aptamers Against Plasmodium falciparum Blood Stages Using Cell-Systematic Evolution of Ligands by EXponential Enrichment', Journal of biomedical nanotechnology, 16, pp. 315 - 334, http://dx.doi.org/10.1166/jbn.2020.2901
    Journal articles | 2019
    Biosca A; Dirscherl L; Moles E; Imperial S; Fernàndez-Busquets X, 2019, 'An immunopegliposome for targeted antimalarial combination therapy at the nanoscale', Pharmaceutics, 11, http://dx.doi.org/10.3390/pharmaceutics11070341
    Journal articles | 2019
    Moles E; Kavallaris M; Fernàndez-Busquets X, 2019, 'Modeling the distribution of diprotic basic drugs in liposomal systems: Perspectives on malaria nanotherapy', Frontiers in Pharmacology, 10, http://dx.doi.org/10.3389/fphar.2019.01064
    Journal articles | 2019
    Moles E; Kavallaris M, 2019, 'A potent targeted cancer nanotherapeutic', Nature Biomedical Engineering, 3, pp. 248 - 250, http://dx.doi.org/10.1038/s41551-019-0390-7
    Journal articles | 2018
    Quiliano M; Pabón A; Moles E; Bonilla-Ramirez L; Fabing I; Fong KY; Nieto-Aco DA; Wright DW; Pizarro JC; Vettorazzi A; López de Cerain A; Deharo E; Fernández-Busquets X; Garavito G; Aldana I; Galiano S, 2018, 'Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery', European Journal of Medicinal Chemistry, 152, pp. 489 - 514, http://dx.doi.org/10.1016/j.ejmech.2018.04.038
    Journal articles | 2017
    Moles E; Galiano S; Gomes A; Quiliano M; Teixeira C; Aldana I; Gomes P; Fernàndez-Busquets X, 2017, 'ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model', Biomaterials, 145, pp. 178 - 191, http://dx.doi.org/10.1016/j.biomaterials.2017.08.020
    Journal articles | 2017
    Moles E; Marcos J; Imperial S; Pozo OJ; Fernàndez-Busquets X, 2017, '2-picolylamine derivatization for high sensitivity detection of abscisic acid in apicomplexan blood-infecting parasites', Talanta, 168, pp. 130 - 135, http://dx.doi.org/10.1016/j.talanta.2017.03.030
    Journal articles | 2016
    Ch'ng JH; Moll K; Quintana MDP; Chan SCL; Masters E; Moles E; Liu J; Eriksson AB; Wahlgren M, 2016, 'Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications', Scientific Reports, 6, http://dx.doi.org/10.1038/srep29317
    Journal articles | 2016
    Moles E; Moll K; Ch'ng JH; Parini P; Wahlgren M; Fernàndez-Busquets X, 2016, 'Development of drug-loaded immunoliposomes for the selective targeting and elimination of rosetting Plasmodium falciparum-infected red blood cells', Journal of Controlled Release, 241, pp. 57 - 67, http://dx.doi.org/10.1016/j.jconrel.2016.09.006
    Journal articles | 2015
    Moles E; Fernandez-Busquets X, 2015, 'Loading antimalarial drugs into noninfected red blood cells: An undesirable roommate for Plasmodium', Future Medicinal Chemistry, 7, pp. 837 - 840, http://dx.doi.org/10.4155/fmc.15.35
    Journal articles | 2015
    Moles E; Urbán P; Jiménez-Díaz MB; Viera-Morilla S; Angulo-Barturen I; Busquets MA; Fernàndez-Busquets X, 2015, 'Immunoliposome-mediated drug delivery to Plasmodium-infected and non-infected red blood cells as a dual therapeutic/prophylactic antimalarial strategy', Journal of Controlled Release, 210, pp. 217 - 229, http://dx.doi.org/10.1016/j.jconrel.2015.05.284
    Journal articles | 2015
    Moles E; Valle-Delgado JJ; Urbán P; Azcárate IG; Bautista JM; Selva J; Egea G; Ventura S; Fernàndez-Busquets X, 2015, 'Possible roles of amyloids in malaria pathophysiology', Future Science OA, 1, http://dx.doi.org/10.4155/fso.15.43
    Journal articles | 2014
    Marques J; Moles E; Urbán P; Prohens R; Busquets MA; Sevrin C; Grandfils C; Fernàndez-Busquets X, 2014, 'Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells', Nanomedicine: Nanotechnology, Biology, and Medicine, 10, pp. 1719 - 1728, http://dx.doi.org/10.1016/j.nano.2014.06.002
    Journal articles | 2014
    Movellan J; Urbán P; Moles E; de la Fuente JM; Sierra T; Serrano JL; Fernàndez-Busquets X, 2014, 'Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs', Biomaterials, 35, pp. 7940 - 7950, http://dx.doi.org/10.1016/j.biomaterials.2014.05.061
    Journal articles | 2012
    Urbán P; Valle-Delgado JJ; Moles E; Marques J; Díez C; Fernàndez-Busquets X, 2012, 'Nanotools for the delivery of antimicrobial peptides', Current Drug Targets, 13, pp. 1158 - 1172, http://dx.doi.org/10.2174/138945012802002302

2023     Cancer Council NSW, $500k, 3 years. CIC (CIA Prof. R Lock).

2022     Moderna Global Fellowship - Moderna® Global Fellows program, $300k USD, 3 years. CIA.

2022     NHMRC Synergy grant, $5M, 5 years, CIH (CIA Prof. M Kavallaris).

2022     Neuroblastoma Australia, $175k, 2 years. CIB (CIA Prof. M Kavallaris).

2021     UNSW RNA Institute Seed Funding, $70k, 1 year. CIC (CIA Prof. M Kavallaris).

2021     UNSW Medicine EMCR Cancer Research Seed grant, $50k, 1 year. CIA (Lead Investigator).

2019     Tour de Cure 2019/2020 - Senior Research Grant, $200k, 2 years. CIC (CIA Prof. M Kavallaris).

2019     UNSW Research Infrastructure Scheme 2020, $199k, 1 year. CIA (Lead Investigator).

2018     UNSW Research Infrastructure Scheme 2019, $261k, 1 year. CIA (Lead Investigator).

2018     UNSW Research Infrastructure Scheme 2019, $463k, 1 year. CID (CIA Dr. Celine Heu, UNSW).

2021    Children’s Cancer Institute Spot Award, Children’s Cancer Institute, Australia.

2017     Doctoral studies extraordinary award for academic course 2015-2016, University of Barcelona, Spain.

2016     PhD Thesis Award Excellent Cum laude and International Mention, University of Barcelona, Spain.

2014     Training of Research Personnel (FPI) overseas fellowship, Spain. No. EEBB-I-14-08319/BIO2011-25039.

2011     Training of Research Personnel (FPI) PhD fellowship, Spain. No. BES-2012-053013/BIO2011-25039.

Jan 2023 - date. mRNA nanomedicines for brain cancer therapy.

DIPG is the deadliest of all paediatric cancers (<1 year life expectancy) and remains incurable. Chemotherapy has been vastly unsuccessful due to the limited penetrability of conventional drugs into the brain, and radiotherapy only provides a short delay in tumour growth. CAR T cell therapy is an active treatment whereby T cells are extracted from the patient and genetically reprogrammed in the laboratory to attack the cancer cells. Recent preclinical and clinical studies have demonstrated the therapeutic potential of this approach to treat DIPG. However, high costs, delays in production, along with recurrent neurotoxicity linked to the permanent changes currently introduced in the T cells have severely hampered the clinical applicability and availability of this approach. IVT mRNA delivery using injectable NPs now offers the unique opportunity to circumvent these limitations by reprogramming the T cells directly in the patient in a transitory and precisely controlled manner, improving therapeutic potency and treatment availability, whilst reducing toxicity and costs of production. The main objective of this project, supported by a Moderna global fellowship awarded to Dr. Ernest Moles, is to the investigate the efficacy of IVT mRNA technology for the in vivo controlled reprogramming of T cells to recognize and precisely treat brain DIPG tumours. This approach is explored as an alternative treatment modality to conventional CAR T cell therapy by which we expect to achieve a potent cancer remission whilst reducing side effects, and advance towards the goal of providing a cure against this incurable cancer.

2019 - date. Development of RNAi nanomedicines for treatment of high-risk neuroblastoma.

High-risk neuroblastoma has a poor survival due to treatment failure and off-target side effects of therapy. Small molecule inhibitors have shown therapeutic efficacy at targeting oncogenic cell cycle dysregulators, such as polo-like kinase 1 (PLK1). However, their clinical success is limited by a lack of specificity, causing off-target toxicity, and difficulties in delivery to the cancer cells. Herein, we investigated a new treatment strategy whereby a bispecific antibody with dual recognition of methoxy polyethylene glycol (PEG) and a neuroblastoma cell-surface receptor, epidermal growth factor receptor (EGFR), is combined with a PEGylated small interfering RNA (siRNA) nanoparticle, forming BsAb-nanoparticle RNA-interference complexes for targeted PLK1 inhibition against high-risk neuroblastoma. Therapeutic efficacy of this strategy was explored in neuroblastoma cell lines and a xenograft animal model. Using ionizable lipid-based nanoparticles as a low-toxic and clinically safe vector for siRNA delivery, we identified that their complexing with EGFR-PEG BsAb resulted in unprecedented improvements in cell targeting (1.2 to >4.5-fold) and PLK1 silencing (>2-fold) against EGFR+ high-risk neuroblastoma cells, and enhancements correlated with EGFR expression on the cells (r > 0.94). Through formulating nanoparticles with PEG-lipids ranging in diffusivity, we further identified a highly diffusible PEG-lipid which provided the most pronounced neuroblastoma cell binding, PLK1 silencing, and effectively suppressed cancer growth in vitro in high-risk neuroblastoma cell cultures and in vivo in a tumor-xenograft mouse model of the disease. Together, our findings are of major relevance in the advancement of precision medicines for treatment of high-risk neuroblastoma. Research was conducted independently and in collaboration with the University of Queensland (Prof. Kris Thurecht - Centre for Advanced Imaging).

2017 - 2023. Development of targeted nanomedicines for treatment of high-risk paediatric leukaemia.

High-risk childhood leukaemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukaemia cells. This liposome targeting system follows a “mix-and-match” principle where BsAbs were selected on the specific receptors expressed on leukaemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukaemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukaemia. BsAb-assisted improvements in leukaemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukaemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukaemia

Research was conducted independently and in collaboration with other team members and research groups at CCI (Prof. Richard Lock - Leukaemia Biology group; Prof. Michelle Haber – Experimental Therapeutics group), University of Queensland (Prof. Kris Thurecht - Centre for Advanced Imaging), UNSW (Prof. John Pimanda), St Vincent's Centre for Applied Medical Research (Prof. David Ma). In a separate work following a similar approach, I have developed nanomedicines recognizing EGFR for targeted delivery of chemotherapy to non-small cell lung cancer (NSCLC). Outcomes are reported at published in the highly-regarded Science Translational Medicine journal (E. Moles, et al., Sci Trans Med, 15(696), 2023).