CRIG 'young investigator proof-of-concept projects’: laureates 18th call

In collaboration with vzw Kinderkankerfonds, CRIG provides research grants for young (postdoctoral and/or senior doctoral) cancer researchers at CRIG to initiate potentially high-risk and innovative cancer research projects. In this 18th call, following postdocs were awarded, and have started their project in this month.
 

This call, there was an additional YIPOC grant available around the rare 'Ewing Sarcoma' (a malignant bone tumour that mainly affects children and adolescents) supported and funded by non-profit organization 'Warre's Hope'. Marthe Boelens was selected as laureate for this grant. Read more in the following article.

• Marthe Boelens - ‘Establishing a physiological in vivo model for Ewing Sarcoma using predictive genome engineering in Xenopus tropicalis’ (promotors of the grant: Prof. Kris Vleminckx & Dr. Thomas Naert) - Ewing Sarcoma is a rare, aggressive pediatric bone and soft tissue cancer driven by the oncogenic fusion EWSR1::FLI1, resulting from a chromosomal translocation that causes extensive transcriptional reprogramming. Current preclinical models fail to capture the tumor’s native enhancer activity and microenvironmental complexity, hampering translational progress. To overcome these limitations, Marthe will leverage Pythia, a deep-learning–based CRISPR design platform predicting microhomology-mediated repair outcomes, to establish the first physiological Ewing Sarcoma model in Xenopus tropicalis.

• Dr. Paul J. Collins - 'Understanding macrophage heterogeneity and changes in the cellular microenvironment in MASLD-HCC' (promotor of the grant: Prof. Charlotte Scott) - Metabolic dysfunction-associated steatotic liver disease (MASLD) has limited treatment options and is a leading cause of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. The healthy liver contains embryonically-derived tissue-resident macrophages called Kupffer cells which act as immune sentinels, initiating protective immune responses to a variety of threats including cancer cells. Yet the role of hepatic macrophages in the progression of MASLD to HCC remains poorly understood. The group of Prof. Scott has shown that as MASLD progresses, Kupffer cells are increasingly replaced by several subsets of bone marrow-derived macrophages. However, the respective roles of these macrophage subsets in initiation of tumorigenesis is unknown. In his project, Paul will analyse spatial gene expression profiles in MASLD-HCC livers using Visium HD to understand more about cellular drivers of tumorigenesis. The long-term goal is to identify therapeutic targets that can be exploited to manipulate macrophages and improve disease outcomes. 

   

• Dr. Stefanie Gijsels - ‘Improved survival of preclinical mouse models with malignant peripheral nerve sheath tumour using a novel combination therapy' (Promotors of the grant:  Prof. Olivier De Wever and Prof. Gwen Sys) -Malignant peripheral nerve sheath tumour (MPNST) is a rare form of cancer, and a subtype of sarcoma. The main treatment consists of surgery, often combined with radio- or chemotherapy. Nowadays, around 40% of patients still succomb to the consequences of the disease. Therefore, there is a clear need for better treatments that decrease the risk of relapse. Prior research in the lab of Prof. De Wever showed that when these tumours are implanted in mice, the tumour behaviour is mimicked. The animals show relapse after surgical resection or administration of standard treatment, similar to many patients. Using these mouse models, novel therapies for this rare type of cancer can be evaluated, and a novel, promising therapy was already identified that completely cured part of the animals. In her project, Stefanie aims to further investigate this treatment, to evaluate the clinical applicability of this treatment. 

   

• Jef Haerinck – ‘Transcriptomic and Spatial Characterization of Dormant Micrometastases Driving Late Breast Cancer Relapse’ (promotor of the grant: Prof. Dr. Geert Berx) - Late metastatic relapse, which can occur more than five years after primary treatment, is a major cause of breast cancer mortality and affects 13-41% of patients. This late recurrence is driven by the awakening of dormant disseminated tumor cells (DTCs) that can remain quiescent for years. The molecular mechanisms that maintain this dormancy and the triggers that cause the switch to proliferative growth are poorly understood. The research team of Prof. Berx has identified a key transcription factor as a regulator that actively maintains this metastatic latency. In his project, Jef will utilize a unique, well-characterized mouse model that recapitulates breast cancer dormancy to investigate what molecular programs and micro-environmental features distinguish dormant lung metastases from actively growing ones. 

• Dr. Zahra Kayani – ‘Targeted delivery of doxorubicin to breast cancer brain metastases using anti-FOLR1 VHH-conjugated gold nanoparticles’ (Promotor of the grant: Prof. Roosmarijn Vandenbroucke) - Brain metastases are among the most severe complications of triple-negative breast cancer (TNBC), for which current treatment options remain highly limited. A key challenge is the restricted drug penetration across the brain barriers, which prevent most anticancer agents from reaching their therapeutic targets within the brain. The research group of Prof. Roosmarijn Vandenbroucke recently discovered single-domain antibodies (VHHs, Nanobodies®) that target the folate receptor alpha (FOLR1) as a new pathway to deliver therapeutics across the brain barrier. Building on this innovative finding, Zahra will develop a VHH-based nanoplatform using anti-FOLR1 VHHs conjugated to polyethylene glycol-coated gold nanoparticles (PEG-AuNPs) for the targeted delivery of the chemotherapeutic drug doxorubicin to TNBC brain metastases, hoping to pave the way toward more effective treatments for patients with metastatic breast cancer and other central nervous system malignancies. 

   

• Deyna Keppens - ‘Expanding the therapeutic scope of menin inhibitors: preclinical evaluation of KMT2A and NPM1 fusions as candidate therapy response biomarkers in Ewing sarcoma’ (promotors of the grant: Prof. dr. Bram De Wilde and Prof. dr. Kaat Durinck) – Therapies for pediatric sarcomas have remained largely unchanged over the past thirty years. Because these tumors vary greatly from patient to patient, it is crucial to be able to tailor treatments to the individual. Prof. Durinck's research group is developing so-called ‘patient avatars’ for this purpose: cancer cells from a young patient are introduced into zebrafish and mice, allowing researchers to test different drugs and predict which therapy will be most effective for that specific child. Our research team recently discovered that menin inhibitors, originally developed for the treatment of leukemia, also show potential for the treatment of pediatric sarcomas. In her project, Deyna will  evaluate the effectiveness of new combination therapies with menin inhibitors in the context of Ewing sarcoma, a common bone tumor in children. 

   

• Thibault Lootens - 'Patient-derived glioblastoma fragments as an ex vivo screening platform for personalized drug testing' (Promotors of the grant: Prof. Robrecht Raedt and Prof. Olivier De Wever) - Glioblastoma is characterized by a high degree of inter- and intra-tumoral heterogeneity, resulting in variable drug responses and poor patient outcomes, emphasizing the need for a personalized medicine approach. Evaluating these responses at a patient-specific level using primary tumor samples, while maintaining the 3D-architecture and a functional tumor-microenvironment (TME), represents a promising strategy. Therefore, the lab of Prof. Raedt and Prof. De Wever designed a platform to establish ex vivo patient-derived fragments from glioblastoma tissue samples. In this project, Thibault will optimize this platform by performing an in depth characterization of these fragments to look at changes in tumor and TME cell populations over time. Furthermore, he will assess the potential of this platform as a personalized medicine approach by comparing ex vivo responses to standard of care, consisting of chemo- and radiotherapy, to responses observed in the clinic. Doing so, he hopes to establish a platform which may predict the most suitable therapy for each individual patient.  
   
• Eleni Staessens - 'Interactome studies to better understand nuclear receptor crosstalk in multiple myeloma' (promotors of the grant: Prof. Karolien De Bosscher and Dr. Dorien Clarisse) - Glucocorticoids (GC) are crucial drugs for the treatment of multiple myeloma, an incurable plasma cell cancer. Unfortunately, the clinical use of GC therapy is hampered by drug resistance and severe side effects that limit patient quality of life. Nonetheless, their low cost and high efficacy to kill myeloma cells through activation of the glucocorticoid receptor (GR) render them indispensable for myeloma treatment, thus emphasizing the need for improved GC-based therapies. Prior research in the lab of Prof. De Bosscher has demonstrated that, in myeloma cells, GC-activated GR can interact or crosstalk with the mineralocorticoid receptor (MR), and that dual targeting of both receptors can enhance the GC-induced myeloma cell killing. However, little is known about how the interaction partners of GR and MR, which may include coregulators and/or other transcription factors, may steer GR-MR crosstalk mechanisms. Therefore, Eleni will study the GR-MR interactome to identify and validate GR-MR interaction partners that contribute to the GC-induced myeloma cell killing. This way, she can establish if these interactors hold promise as novel therapeutic targets in multiple myeloma to further fine-tune GC therapy.  

• Dr. Jonas Steenbrugge - 'Combining JAK inhibition and immune checkpoint blockade in triple-negative breast cancer' (promotor of the grant: Prof. Evelyne Meyer) - Triple-negative breast cancer (TNBC) remains one of the deadliest cancers in women worldwide. Immunotherapies, such as anti–programmed death ligand 1 (anti-PDL1), offer a promising approach to treat this aggressive breast cancer type. Unfortunately, many TNBC patients do not achieve a durable response to anti-PDL1 therapy, which may be due to persistent production of interferon-gamma (IFNγ) induced by the treatment. While initial IFNγ production helps eliminate cancer cells, prolonged exposure can lead to T-cell exhaustion. Previous research in the group of Prof. Meyer suggests that this exhaustion may result from overactive JAK signaling. In his project, Jonas will investigate whether combining anti-PDL1 therapy with subsequent JAK inhibition can sustain T-cell–mediated tumor killing, potentially improving survival for patients with TNBC. 

   

• Annagiada Toniolo – ‘Keratinocyte death as a driver of squamous carcinogenesis’ (promotors of the grant: Prof. Esther Hoste & Prof. Geert van Loo) - Squamous cell carcinoma (SCC) is a common epithelial malignancy with rising global incidence. The oral subtype (oSCC) remains particularly concerning, with a 5-year survival rate below 50% due to therapy resistance and high recurrence. While many anti-cancer treatments aim to induce cell death, there is limited understanding of the specific cell death pathways involved and their effects on the tumour (niche). Previous research in the team of Prof. Hoste showed that excessive keratinocyte death can drive skin carcinogenesis and that apoptosis plays a major role in oSCC formation and progression. In this project, Annagiada will explore how apoptosis influences clonal expansion during early carcinogenesis, and whether inhibiting this pathway could represent a promising therapeutic strategy for these aggressive tumours. 

An overview of all the ‘young investigator proof-of-concept’ projects that were awarded by CRIG since 2017 can be found on this page.