Periodic Reporting for period 1 - TRENDO (Translational Research on Endometriosis)
Periodo di rendicontazione: 2021-08-01 al 2023-07-31
Endometriosis is a severe disease affecting 10% of reproductive age women, characterized by the presence of endometrial-like tissue outside of uterus. Due to the associated pain, inertility and a small, but increased risk for developing ovarian cancer, its socioeconomic impacts have a profound effect on women’s mental and physical health. Endometriosis is characterized by a diagnostic delay of a decade, as its diagnosis is surgery-based, and all attempts to identify the non-invasive biomarkers have not been progressed beyond the discovery. Moreover, current treatments include only surgery or hormonal medications with significant side effects. In view of the above, the endometriosis care is challenging, and is hampered by the considerable heterogeneity of clinical manifestations. TRENDO consortium addresses the main problems in endometriosis diagnosis and therapy in a multidisciplinary and trans-sectoral effort, bringing together the clinical and translational science experts, and industry partners from six European and South American countries. We develop non-invasive biomarkers and testing, shortening diagnostic delay, and reducing unequal access to expensive healthcare. These biomarkers are tested for the suitability as drug targets, to monitor treatment response, and to predict personalized clinical recommendations. Our combined expertise will provide novel tools addressing the most urgent priorities in endometriosis and to successfully translate our findings into novel therapeutic approaches. This challenging scientific task provides an ideal career-enhancing setting for young scientists, providing them with transdisciplinary and trans-domain training, and with essential transferable skills. The training program provides a new generation of researchers with a strong competitive advantage on the job market and increase European academic and industry competence in one of the under-investigated clinical domains.
TRENDO has 4 scientific workpackages (WPs). The aim of WP1 is a multi-omics biomarker-based non-invasive test prototype for endometriosis. We assembled endometriosis sample collectives for the TRENDO biobank, which have been used to perform experiments towards the non-invasive test. TRENDO identified novel biomarkers at the genetic, transcriptomic and glycosylation level. Particularly noteworthy is TRENDOs contribiution to a study published in Nature Genetics that revealed 42 areas across the genome with variants that increase the risk of endometriosis. These variants could be linked to the profiles of molecules in the endometrium and blood and were able to identify a number of genes that were differently expressed in these tissues, therefore possibly playing a role in disease development. Some genetic variants were found to have a closer link to ovarian cystic endometriosis than superficial disease spread throughout the pelvis. The research also showed that these genes affect pain perception and maintenance. In fact, the team found significant genetic correlations between endometriosis and 11 pain types, such as migraine, back pain and multi-site chronic pain, and between endometriosis and inflammatory conditions such as asthma and osteoarthritis.
The aim of WP2 is the functional characterisation of biomarkers for preclinical testing of drugs by modelling of endometriosis. TRENDO developed a novel 3D model of endometriosis comprising epithelial and stroma cells that reflects separate extracellular matrix constituents of stroma and epithelium. The impact of cytokines dysregulated in endometriosis on the window of implantation as a fertility-associated readout of endometriosis was studied using trophoblastoid cell lines, guided by our transcriptomic data. The impact of endometriotic organoids on neurons as a readout of pain-related parameters of endometriosis,was demonstrated using carnosic acid treatment, demonstrating its possible suitability for reducing pain associated neuronal growth in vitro.
The aim of WP3 is the development of novel theranostic solutions for imaging and treatment of endometriosis. We explored the application of homing peptides for precision delivery of diagnostic and therapeutic compounds to endometriotic lesions. Silver nanoparticles functionalized with synthetic PL1 peptide showed specific internalization endometriotic cells. PL1-nanoparticles loaded with antimitotic monomethyl auristatin E decreased the viability of endometriotic cells and specifically bound to the cryosections of clinical peritoneal endometriotic lesions in the areas positive for TNC-C and Fn-EDB.
The aim of WP4 is the evaluation of Innovative therapeutics and novel treatments. We have adapted an sCD44 assay to endometriotic samples and performed a pilot study to measure levels of specific set of 16 estrogen metabolites in 209 patients with endometriosis and 115 control patients, revealing higher levels of 2-hydroxy 3-methoxy estrone (2OH, 3MeO-E1) in serum samples of endometriosis patients compared to controls. Higher metabolite levels were linked to an increased endometriosis risk, representing 2OH, 3MeO-E1 as potential adverse markers. The study showed that 2OH pathway is associated with ovarian endometriotic lesions and unfavorable pain outcomes.
The aim of WP2 is the functional characterisation of biomarkers for preclinical testing of drugs by modelling of endometriosis. TRENDO developed a novel 3D model of endometriosis comprising epithelial and stroma cells that reflects separate extracellular matrix constituents of stroma and epithelium. The impact of cytokines dysregulated in endometriosis on the window of implantation as a fertility-associated readout of endometriosis was studied using trophoblastoid cell lines, guided by our transcriptomic data. The impact of endometriotic organoids on neurons as a readout of pain-related parameters of endometriosis,was demonstrated using carnosic acid treatment, demonstrating its possible suitability for reducing pain associated neuronal growth in vitro.
The aim of WP3 is the development of novel theranostic solutions for imaging and treatment of endometriosis. We explored the application of homing peptides for precision delivery of diagnostic and therapeutic compounds to endometriotic lesions. Silver nanoparticles functionalized with synthetic PL1 peptide showed specific internalization endometriotic cells. PL1-nanoparticles loaded with antimitotic monomethyl auristatin E decreased the viability of endometriotic cells and specifically bound to the cryosections of clinical peritoneal endometriotic lesions in the areas positive for TNC-C and Fn-EDB.
The aim of WP4 is the evaluation of Innovative therapeutics and novel treatments. We have adapted an sCD44 assay to endometriotic samples and performed a pilot study to measure levels of specific set of 16 estrogen metabolites in 209 patients with endometriosis and 115 control patients, revealing higher levels of 2-hydroxy 3-methoxy estrone (2OH, 3MeO-E1) in serum samples of endometriosis patients compared to controls. Higher metabolite levels were linked to an increased endometriosis risk, representing 2OH, 3MeO-E1 as potential adverse markers. The study showed that 2OH pathway is associated with ovarian endometriotic lesions and unfavorable pain outcomes.
We expect the impact on society to be very high, as endometriosis constitutes a substantial, yet under-investigated health problem of women in the European (and World) population, as the associated pain and fertility problems are a frequent cause of productivity loss at work, besides affecting well-being and personal relationships in affected women. Therefore, TRENDO has a considerable socioeconomic perspective. Moreover, we expect a high impact through the development of novel, innovative based drugs, by strengthening innovative and technically advanced areas of therapeutics development. Notably, currently no noninvasive test / biomarker for endometriosis exists, and diagnosis via the invasive procedure of laparoscopy is still the gold standard. There are several Pharma companies which include women's health programs that would be interested in commercial exploitation of non-invasive biomarkers and novel therapeutics. However clinical validation and development of assays suitable for commercialization is prerequisite – TRENDO will provide the groundwork for future exploitation at this level. One important aspect is the development of algorithms and the use of AI to identify the most suitable marker. We will explore biomarkers that were not explored earlier, and the combination of multiple omics has also not been previously explored. Biomarker discovery in combination with the phenotypic characterisation is also novel, ensuring an impact in the scientific community. We expect to have a high impact by providing excellent multidisciplinary and trans-sectoral training for young European scientists, with a considerable perspective of providing a competitive advantage at the job market. Finally, the involved research groups will increase their international competitiveness through the extensive knowledge transfer provided by TRENDO. Our communication strategy to clinicians and industry will facilitate commercialisation and clinical application of TRENDO results, whereas our communication with politicians and the public will pave the way for sustainable support of our translational research offers, e.g. through generation of new funding programs.