CRIG 'young investigator proof-of-concept projects’: laureates 19th 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 19th call, following postdocs were awarded, and have started their project in this month.

• Dr. Jonas De Kesel - ‘Characterization of the m6A-driven DNA damage response in acute myeloid leukemia (AML)’ (promotor of the grant: Prof. Panagiotis Ntziachristos) - Acute myeloid leukemia (AML) is today’s deadliest form of leukemia. Through efforts to optimize current AML treatment regimens, the group of Prof. Ntziachristos uncovered that widely-used anthracycline chemotherapeutics strongly synergize with METTL3 inhibitors. METTL3 is responsible for the deposition of m6A methylation marks on RNA. This epitranscriptomic tag regulates practically all aspects of RNA biology, and has gained great interest in the context of hemato-oncology. To understand how the mode-of-actions of anthracyclines and METTL3 inhibitors converge, Jonas plans to do a phenotypic CRISPR screen and subsequent molecular validation studies to help define the m6A-dependent regulatory network that steers the DNA damage response triggered upon anthracycline treatment, and to meet the urgent demand of anthracycline dose reduction in the clinic.
   
• Dr. Marie Deventer - ‘Masked IL-12-T Cell Engagers: Safety Masking for Potent, Tumor-Restricted T cell Killing’ (promotor of the grant: Prof. Bruno De Geest) - The development of immunotherapy marked a true revolution in the search for new cancer treatments. In this approach, the immune system (primarily T cells) is activated to attack tumor cells. A new and promising concept in this context is that of “T cell engagers” (TCEs). These are proteins that bind on one hand to a surface protein of the tumor cell (so-called tumor-associated antigens, or TAAs), and on the other hand to CD3, a protein on the T cell. This therapy literally brings the T cell closer to the cancer cell, allowing it to attack the cancer cell with both high precision and power. However, the environment surrounding the tumor consists of various elements that attempt to inhibit this process, causing the T cells to lose their effectiveness. Through her project, Marie aims to find a way to help these T cells overcome the tumor environment and destroy cancer cells in a highly targeted and therefore safer, yet efficient manner.
   
• Dr. Jon Huyghe - ‘The development and characterization of a selective ATG9A scramblase inhibitor as a potential novel anti-cancer drug’ (promotor of the grant: Prof. Mathieu Bertrand) - Autophagy is a vital cellular recycling process that maintains cell health by breaking down and reusing internal components. Many cancers depend on this mechanism to survive under stress and resist treatment, making autophagy an attractive target for new therapies. However, current approaches typically block autophagy at a late stage, allowing cancer cells to retain some protective benefits. This project investigates a novel strategy to inhibit autophagy at its earliest steps by targeting ATG9A, a key protein in the process. By developing small molecules that block the lipid “scrambling” activity of ATG9A, we aim to shut down autophagy at its source. This approach has the potential to make cancer cells more vulnerable to treatment and improve therapeutic outcomes.
   
• Dr. Nicolas Kint - ‘Evaluating the role of lentiviral insertion and clonal hematopoiesis in CAR-T cell treatment in multiple myeloma’ (promotor of the grant: Prof. Tessa Kerre) - CAR-T cell therapy has become an important new treatment option for patients with multiple myeloma, a type of blood cancer. While some patients experience a deep and lasting response, others develop severe side effects or see the treatment become less effective over time. In this YIPOC project, Nicolas will investigate whether genetic differences in a patient’s own blood and immune cells can help explain these varying outcomes. The study will examine both age-related genetic changes in blood-forming cells and how the CAR gene is inserted into T cells during the production of the therapy. By linking these molecular findings to patient outcomes, this project aims to identify biomarkers that could predict both treatment success and toxicity. In the long term, this research may help make CAR-T therapy safer and more tailored to the individual patient.
   
• Eileen Lambrechts - ‘Co-delivery of antihistamines and IL-12 mRNA to the tumor microenvironment using lipid nanoparticles (LNPs)’ (promotor of the grant: Prof. Koen Raemdonck) - Many tumors, such as triple negative breast cancer (TNBC), are cold tumors, which show resistance against cancer immunotherapy. Delivering antihistamines to the tumor microenvironment (TME) is a promising strategy to make the TME more pro-inflammatory and to enhance immunotherapy efficacy. Antihistamines can shift the tumor-associated macrophages (TAMs) to a more antitumorigenic phenotype and enhance T cell infiltration into the TME. Encapsulation of antihistamines inside lipid nanoparticles enables more targeted delivery of these small molecules to the TAM population as LNPs tend to accumulate in myeloid cells. In her project, Eileen will investigate this technology for the co-delivery of antihistamines together with IL-12 mRNA, a potent immunostimulatory cytokine that enhances cytotoxic T cell activity, in an orthotopic syngeneic mouse TNBC model.
   
• Dr. Ana Lores Padín - ‘Quantitative cell-type-resolved cisplatin partitioning in tumour microenvironment models’ (promotor of the grant: Prof. Frank Vanhaecke) - Platinum-based drugs are a cornerstone treatment for solid tumours, including ovarian cancer, yet their effectiveness is often limited by uneven drug distribution. Increasing evidence suggests that the tumour microenvironment plays a key role in this process. Cancer-associated fibroblasts (CAFs) may sequester platinum-based drugs and reduce their availability to cancer cells. In this project, Ana will apply cutting-edge elemental mass spectrometry to simultaneously identify cell types and quantify platinum uptake at the single-cell level. By combining antibody-based phenotyping with ICP-TOF-MS, she will analyse both controlled models and patient-derived tumour samples (ovarian cancer), including single-cell suspensions and tissue sections. This integrated approach enables cell-type–resolved mapping of drug distribution across tumour cells, CAFs, immune populations, and even extracellular matrix, allowing the identification of cellular “drug sinks”. The results will provide new insights into chemotherapy resistance and support the development of more effective treatment strategies.
   
• Tom Luijts - ‘Reconstruction of metastatic spreading trajectories using genomic profiling of tumor tissues derived from zinc-embalmed whole-body donors’ (promotor of the grant: Prof. Jimmy Van den Eynden) - Multi-site metastasis is rarely surgically removed as the procedure is considered too invasive. As a result, there is limited access to tissue samples needed to study how metastases spread throughout the body. One approach to address this limitation is the use of body donors: individuals who donate their bodies to science after death. This enables the collection of multiple metastatic lesions from a single patient, providing an opportunity to study patterns of metastatic dissemination from DNA mutations. However, prior to sampling, the bodies are embalmed using a zinc chloride–based solution. The impact of this preservation method on DNA quality remains poorly characterized. In this project, Tom will assess the effect of zinc chloride embalming on DNA integrity and suitability for downstream analyses. In addition, he will perform DNA sequencing to reconstruct the evolutionary relationships between metastases and infer their routes of dissemination within the body. Together, this work aims to provide new insights into the biology of metastatic spread and the final, often fatal stage of cancer progression.
   
• Faye Naessens - ‘Immunogenic near-infrared photodynamic therapy against colon cancer via EGFR-targeted bacteriophage nanocarriers’ (promotor of the grant: Dr. Elena Catanzaro) - Photodynamic therapy (PDT) is a minimally invasive cancer treatment that uses light-activated molecules, known as photosensitizers (PSs), to induce tumor cell death. However, most clinically used PSs are activated by visible light, which restricts treatment to superficial tumors due to its poor tissue penetration depth. In contrast, near-infrared (NIR) light penetrates more deeply into tissue, making it suitable for deep-seated malignancies such as colorectal cancer (CRC). CRC remains a leading cause of cancer-related mortality, yet it is a particularly promising target for PDT because of the technique’s minimal invasiveness, compatibility with localized light delivery via colonoscopy, and the ability to stimulate systemic antitumor immunity through the induction of immunogenic cell death (ICD). In collaboration with Agfa-Gevaert, Faye has developed a novel NIR-activated PS for PDT targeting CRC. In her project, she will investigate the immunogenic effects of PDT using this PS in both in vitro and in vivo models. In addition, she will explore engineered bacteriophages, which are viruses that naturally infect bacteria but are modified to target EGFR in CRC, as nanocarriers for targeted delivery of the PS.
   
• Lasse Vleminckx - ‘Validation of a novel dbh-MYCN; P53KO GEMM as a model for metastatic and therapy-resistant neuroblastoma’ (promotor of the grant: Prof. Kaat Durinck) - Neuroblastoma is the most common extracranial solid tumor in children and accounts for 10% of pediatric cancer deaths. This high mortality is mainly caused by metastasis and relapse, as approximately 70% of patients present with metastatic disease at time of initial diagnosis. Despite this, existing transgenic mouse models still only model primary, local neuroblastoma, and fail to recapitulate the genetic and molecular features of relapsed and highly metastatic disease. To address this research gap, we developed a novel mouse model (dbh-MYCN/Tp53KO) driven by MYCN overexpression and Tp53 knock-out in dopamine-beta hydroxylase expressing cells. This combination was selected since MYCN is the most commonly amplified oncogene in neuroblastoma and Tp53 loss-of-function mutations are specifically enriched in relapsed patients. We showed that this model is highly penetrant, genomically unstable, and is able to metastasize to secondary sites. In this project we will investigate the occurrence of secondary driver mutations in metastatic loci contributing to therapy resistance and metastasis. Additionally we will decipher the phylogenetic evolution of multiple tumors occurring in single mice. Finally, we will also examine transcriptional and epigenetic programs driving metastasis using a novel, state-of-the-art technique called SPLONGGET.

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