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Luxembourg to speed up the standardisation of clinical data

Clinical data.

Real-world clinical data has the potential to transform our understanding of health, disease and treatment. Yet, it is currently dispersed across multiple institutions and countries, stored in different formats and systems, and subject to different rules, challenging policy restrictions and technology considerations. This makes it very difficult to fully exploit its potential to the benefit of European patients.

Generating insights and evidence from real-world clinical data at scale is a major challenge. Yet, it has the optential to support patients, clinicians, payers, regulators, governments, and the industry in understanding wellbeing, disease, treatments, outcomes and new therapeutics and devices.

The Luxembourgish National Cancer Registry (RNC) at the Luxembourg Institute of Health (LIH) joined the consortium of the European Health Data & Evidence Network (EHDEN). The LIH team secured a cross-disciplinary grant for a duration of 12 months to accelerate the standardisation of clinical data.   

Accelerating the harmonised large-scale analysis of health data

The LIH team will set up and implement IT tools and processes, such as those developed by the international Observational Health Data Sciences and Informatics open science collaboration, that will turn the data into the so-called OMOP (Observational Medical Outcomes Partnership) common data model – a model that will allow patient data to be captured in the same way across different institutions.

“Joining the EHDEN consortium is an excellent opportunity for the RNC to proactively demonstrate its commitment to evolving its data structure towards more streamlined and harmonised health data formats, ultimately contributing to facilitating the use of clinical and epidemiological cancer-related data to improve patient outcomes.”

 Dr Claudine Backes, Principal Investigator and coordinator of the project.

EHDEN aims to accelerate the harmonised large-scale analysis of health data in Europe and reduce the time that it takes to provide an answer in real-word health research. Specifically, its goal is to build a federated data network allowing access to the data of over 100 million EU citizens in a harmonised and standardised common data model. This will enable the smarter management and sharing of research methodologies, therefore improving collaboration and expanding education in open science.

EHDEN is a flagship project funded by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2) and is part of the IMI Big Data for Better Outcomes programme. 

Read more about The Luxembourgish National Cancer Registry (RNC) at LIH.

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Luxembourg identifies ‘key’ protein allowing cancer-destroying viruses to enter tumour cells

Novel anticancer strategies.

Researchers from the Luxembourg Institute of Health are working on the development of novel anticancer strategies based on oncolytic viruses, “good” viruses that can specifically infect, replicate in and kill cancer cells. In particular, the Laboratory of Oncolytic-Virus-Immuno-Therapeutics (LOVIT) team elucidated the mechanism through which the H-1PV cancer-destroying virus can attach to and enter cancer cells, thereby causing their lysis and death.

At the heart of this process lie laminins, and specifically laminin γ1, a family of proteins on the surface of a cancer cell to which this virus binds, and which therefore act as the ‘door’ through which the virus enters the cells.

The findings, which were published in the prestigious international journal Nature Communications, carry significant implications for the advancement of virus-based anticancer strategies and for the prediction of a patient’s response to this innovative therapeutic approach. 

Oncolytic viruses to effectively infect and destroy cancer cells

Oncolytic viruses, such as the rat virus H-1PV, have the ability to selectively infect and kill tumour cells, inducing their lysis and stimulating an anticancer immune response, without however harming normal healthy tissues. Despite their notable clinical potential, their use as a standalone treatment does not currently result in complete tumour regression, mainly due to the varying degree of patient sensitivity and responsiveness. It is therefore important to be able to identify patients whose tumours display genetic characteristics that make them vulnerable to the virus and who are thus most likely to benefit from this novel anticancer therapy.

In this context, we sought to elucidate the features of host cancer cells that enable oncolytic viruses to effectively infect and destroy them, focusing specifically on the factors required for cell attachment and entry.”

Dr Antonio Marchini, leader of LOVIT and corresponding author of the publication

Laminins play a crucial role in mediating cell attachment and penetration

Using a technique known as RNA interference, the research team progressively ‘switched off’ close to 7,000 genes of cervical carcinoma cells to detect those that negatively or positively modulate the infectious capacity of H-1PV. They thus identified 151 genes and their resulting proteins as activators and 89 as repressors of the ability of H-1PV to infect and destroy cancer cells.

The team specifically looked at those genes that coded for proteins localised on the cell surface, in order to characterise their role in determining virus docking and entry. They found that a family of proteins called laminins, and particularly laminin γ1, play a crucial role in mediating cell attachment and penetration. Indeed, deactivating the corresponding LAMC1 gene in glioma, cervical, pancreatic, colorectal and lung carcinoma cells resulted in a significant reduction in virus cell binding and uptake, and in increased cancer cell resistance to virus-induced death. A similar effect was observed when switching off the LAMB1 gene encoding the laminin β1 protein. 

“Essentially, laminins at the surface of the cancer cell are the ‘door’ that allows the virus to recognise its target, attach itself and penetrate into it, subsequently leading to its destruction. In particular, the virus interacts with a specific portion of the laminin, a sugar called sialic acid, which is essential for this binding and entry process and for infection.

Dr Amit Kulkarni, first author of the publication

The team went a step further and sought to assess the clinical implications of their findings for cancer patients. They found that laminins γ1 and β1 are differentially expressed across different tumours, being for instance overexpressed in pancreatic carcinoma and glioblastoma (GBM) cells compared to healthy tissues. Moreover, in brain tumours, their expression increases with tumour grade, with late-stage GBM displaying higher laminin levels than lower grade gliomas. Similarly, based on the analysis of 110 biopsies from both primary and recurrent GBM, the researchers reported significantly higher levels of laminins in recurrent GBM compared to primary tumours.

These observations indicate that elevated laminin expression is associated with poor patient prognosis and survival in a variety of tumours, including gliomas and glioblastoma. The encouraging fact, however, is that cancers displaying high laminin levels are more susceptible to being infected and destroyed by the H-1PV virus and that patients with these tumours are therefore more likely to be responsive to this therapy.”

Dr Antonio Marchini, leader of LOVIT and corresponding author of the publication

These findings could lead to the classification of cancer patients according to their individual laminin expression levels, thereby acting as a biomarker that predicts their sensitivity and responsiveness to H-1PV-based anticancer therapies. This will in turn allow the design of more efficient clinical trials with reduced costs and approval times and, ultimately, the development of enhanced combinatorial treatments to tangibly improve patient outcomes.

The study was published in June 2021 in the renowned journal Nature Communications, with the full title “Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry”.

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In conversation with our young researchers: Dr Sunday Ojochegbe Okutachi

K-Ras protein and cancer.

For over 40 years since its discovery, researchers around the world have been working to develop drugs against the K-Ras protein with very little success. This protein is involved in about 15% of all cancer cases worldwide.

In 2020, cancer was the second leading cause of death in the world. We expect the global cancer burden to continue to rise as a result of lifestyle changes, increased life expectancy and a growing ageing population. Dr Sunday Ojochegbe Okutachi, a newly graduated doctor in cancer biology of the department of Life Sciences and Medicine at the University of Luxembourg, is developing new compounds that act against major chaperones of K-Ras in the cell.

Mutations in the KRAS gene associated with 15% of all human cancers

Ras proteins were among the earliest identified oncogenes. Being implicated in approximately 19% of all human solid tumors, those proteins are the most frequently mutated oncogenes in cancer.

Major breakthroughs have recently led to the clinical development of the first direct and covalent inhibitors of the K-RasG12C mutant. Yet, the majority of K-Ras driven cancers are not G12C mutated.

To effectively treat K-Ras mutated and/or K-Ras driven cancers, the need to pursue multiple direct and indirect therapeutic strategies including the targeting of K-Ras trafficking chaperones as well as the synergistic targeting of different nodes in K-Ras mediated signaling pathways will be crucial. Hence, Sunday Ojochegbe Okutachi focuses on identifying novel isoform specific inhibitors of Ras protein signalling.

The overarching aim of my research is to identify novel small molecules that can interfere with K-Ras membrane localisation through the inhibition of K-Ras trafficking chaperones by both covalent and non-covalent binding. To this end, we designed and developed relevant assays for the in vitro and in cellulo characterisation of small molecules against the trafficking chaperone proteins CaM and PDE6D.”

— Sunday Ojochegbe Okutach

Research as a vocation

The cancer biologist grew up in a relatively rural city in Nigeria. His experience with the direct consequences of poor healthcare instilled in him a strong interest to pursue a career that attempts to proffer solutions to the issue. Hence, he naturally took interest in the life sciences and graduated valedictorian in Biochemistry in his bachelors programme. Then, he secured a scholarship to study Translational Oncology in the UK where he also graduated with distinction.

The exposure to the interface between basic research and clinical oncology practice informed his subsequent decision to go deeper into the cancer drug discovery and development process. To this end, he joined the cancer cell biology and drug discovery group of Professor Daniel Abankwa at University of Luxembourg to pursue his PhD in 2018.

“I am deeply committed to helping fight disease both at the scientific and on a private level. My long-term desire is to help bring useful healthcare solutions to people. As such, I will be working at the interface between basic research and translational outcomes in the molecular diagnostics industry. Also, I recently founded a cancer nonprofit that helps in increasing cancer awareness and organise fundraising to support cancer preventive and diagnostic activities in my home country of Nigeria.”

Sunday Ojochegbe Okutachi

Why Luxembourg as a research destination?

To Sunday Ojochegbe Okutachi, “Luxembourg is at the forefront of many research fields. Researchers from here regularly publish in high impact and open access journals. Research is well funded and innovation is greatly encouraged. If you are looking for a highly dynamic, international and globally competent scientific environment, Luxembourg is the place for you.”

As Prof. Abankwa is a leading expert in Ras biology, It was a great opportunity to work in his lab in Luxembourg. Also, Luxembourg has one of the most innovative, agile and competent research programs out there. Through various initiatives, Luxembourg continuously attract some of the best academics across the globe, as a result, the research environment is filled with highly competent, international and diverse professionals. All these factors informed my decision to execute my PhD in the only Grand duchy in the world.”

— Sunday Ojochegbe Okutachi

A robust research environment fostering collaboration

Working in the laboratory of Prof. Daniel Abankwa, Sunday Ojochegbe Okutachi executed his research project at the University of Luxembourg in collaboration with scientist from Finland and the NCI-Ras initiative in the USA.

“Luxembourg has a very robust research environment that supports innovation and collaborative research. “

“The country invests heavily in obtaining state-of-the-art equipment in biomedical research. Consequently, researchers are able to carry out their work with minimal hassle. Indeed, the commitment of the relevant authorities to make the country a leading scientific hub is highly commendable.”

Sunday Ojochegbe Okutachi

About living in Luxembourg

The researcher sees the country as very safe, family oriented, welcoming and socially generous. These very positive experiences largely instructed his decision to stay in the country beyond his PhD.

“Luxembourg has one of the highest standards of living in the world, its extremely charming medieval castles, beautiful and safe streets are solid reasons to live here. In addition to these, what I love most about the country is that it is a great place to have and raise a family.”

Sunday Ojochegbe Okutachi

Sunday Ojochegbe Okutachi recently completed his PhD, entitled Characterization of novel covalent and non-covalent drugs against K-Ras surrogate targets.

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‘Suffocating’ cancer: a new headway in melanoma immunotherapy

Melanoma immunotherapy.

Disrupting cancer cell ability to adapt to low oxygen conditions shows promise in melanoma.

Hypoxia, or the inadequate oxygenation of a tissue, is a condition occurring frequently in all solid tumours such as melanoma skin cancer. Melanoma cells are not only able to survive oxygen deprivation, but also to use it to their own advantage by hijacking the anti-tumour immune response and developing resistance mechanisms to conventional anti-cancer therapies. A key gene responsible for cancer cell adaptation to hypoxia is HIF-1α (Hypoxia Inducible Factor-1 alpha).

Led by Dr Bassam Janji, head of the Tumor Immunotherapy and Microenvironment (TIME) research group at the Luxembourg Institute of Health (LIH) and in collaboration with Gustave Roussy Cancer Center in France and the Thumbay Research Institute of Precision Medicine at Gulf
Medical University in the United Arab Emirates, the team used gene editing technologies to show how targeting HIF-1α could not only inhibit tumour growth, but also drive cytotoxic (toxic to cells) immune cells to the cancer tissue.

This discovery provided a valuable new target to make resistant melanomas more vulnerable to available anti-cancer treatments.

Certain solid tumour survive by activating HIF-1α

Melanoma is a type of skin cancer that develops from melanocytes, cells that are responsible for the production of pigments. Melanomas become harder to treat if not detected early, with emerging treatment resistance being an important barrier to their effective management. Due to their rapid growth rate and low blood supply, solid tumours including melanoma often exhibit areas of hypoxia. Hypoxia, or the decrease of oxygen in the tumour microenvironment, would normally cause tumour cell death.

“Certain solid tumours have evolved to survive this hostile microenvironment by activating HIF-1α, a gene reported to be a major factor mediating the adaptive response to changes in tissue oxygen level.”

Dr Janji. William G. Kaelin Jr, Sir Peter J. Ratcliffe
and Gregg L. Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019 for their discovery of HIF-1α and how cells use it to sense hypoxia.

Hypoxia has also been reported to be responsible for the failure of tumour response to conventional anti-cancer therapies and can prevent the infiltration of immune cells into the tumour. It is therefore crucial to understand the mechanisms by which cancer cells overcome this hypoxic environment to improve the effectiveness of available anti-cancer therapies.

Blocking the activity of HIF-1α significantly inhibit melanoma growth

The team led by Dr Janji sought to inactivate the functionality of the HIF 1α gene using CRISPR gene editing technology and investigate the impact of such inactivation on tumour growth, immune cell infiltration and response to immunotherapy in a preclinical melanoma mouse model.


“Our study revealed that blocking the activity of HIF-1α significantly inhibited melanoma growth and amplified the infiltration of immune cells into the tumour microenvironment by increasing the release of CCL5, a well-defined mediator involved in driving cytotoxic immune cells to the tumour battlefield”

Dr Audrey Lequeux, first author of the publication

Importantly, the study also showed that combining a drug devised to stop hypoxia significantly improves melanoma immunotherapy. When the results were validated retrospectively in a cohort of 473 melanoma patients, the hypoxic signature of tumours was correlated to worsened outcomes and the lack of immune cell infiltration into tumours, which is considered as a major characteristic of tumour resistance to immunotherapies.


“Together, our data strongly argue that therapeutic strategies disrupting HIF-1α would be able to modulate the tumour microenvironment to permit the infiltration of immune cells. Such strategies could be used to improve vaccine-based and immune checkpoint blockade-based cancer immunotherapies in non-responder melanoma patients.”

Dr Chouaib, Gulf Medical University and Dr Janji, Luxembourg Institute of Health


Entitled “Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy” was published in June in the Oncogene journal, part of the prestigious Nature publishing group.

The article was listed under the category of ‘brief communication’, a category reserved for articles of exceptional interest due to their significance and timely contribution to cancer biology.

This study was supported by grants from FNRS Televie, the Luxembourg National Research Fund, the Fondation Cancer, the Kriibskrank Kanner Foundation, Luxembourg, Janssen Cilag Pharma, Roche Pharma, Action LIONS Vaincre le Cancer Luxembourg and Sheik Hamdan Bin Rashid Al Maktoum Foundation.

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