CRIG 'young investigator proof-of-concept projects’: laureates 15th 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 15th call, following postdocs were awarded, and have started their project in this month.
Dr. Dorien Clarisse – ‘Why and how do nuclear receptors (cross)talk in multiple myeloma cells?’ (promotors of the grant: Prof. Karolien De Bosscher & Prof. Fritz Offner) - Despite advances in myeloma treatment, synthetic glucocorticoids remain an important pillar in all myeloma treatment stages. Unfortunately, long-term glucocorticoid treatment is severely hampered by therapy resistance and deleterious side effects, underscoring the need for alternative treatment strategies. Recently, the group of Prof. De Bosscher published that functional crosstalk between the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) improves myeloma cell killing, which likely arises from a modulated endogenous interaction between GR and MR. To evaluate whether specific targeting of these so-called GR-MR heterodimers further improves the therapeutic index, the group assembled an interdisciplinary team that has developed novel bivalent ligands which combine a GR agonist with an MR antagonist in one molecule. Encouragingly, several of these bivalent ligands displayed enhanced anti-myeloma potency compared to the single ligands (combined). In her project, Dorien wants to unravel the molecular mechanisms that underlie the enhanced anti-myeloma potency of bivalent ligands, as such allowing to establish the therapeutic potential of the novel ligands versus classic glucocorticoids.
Dr. Loren Deblock – ‘Dual-modality nanocrystals for the detection of sentinel lymph nodes: a new pre-and intraoperative workflow’ (promotors of the grant: Prof. Christian Vanhove & Prof. Wim Ceelen) - Despite advances in breast cancer treatment, surgery is still one of the most important treatment options for breast cancer patients, independent of their cancer subtype. During surgery, the standard practice is to remove the primary tumour as well as the so-called sentinel lymph nodes (SLNs), the lymph nodes that have the highest probability of being invaded by cancer cells. The current clinical standard to detect these SLNs (based on 99m Technetium-labelled nanocolloids visualized by SPECT/CT & intraoperative injection of a blue dye) has several downsides, including a.o. radioactive exposure, long-lasting breast staining & low spatial resolution. Recently, dr. Loren Deblock proposed an improved method to detect SLNs using contrast-enhanced CT and NIR-fluorescence based on dual-modality nanocrystals, a study which was a collaborative effort between the research groups of Prof. Christian Vanhove and Prof. Klaartje De Buysser. In his project, Loren joins forces with the Experimental Surgery Research group of prof. Wim Ceelen and aims to perform the first-ever large animal study (in vivo porcine model) of these dual-modality nanocrystals to further validate their potential for SLN detection in breast cancer patients.
Dr. Stijn De Munter – ‘Generation of a non-viral CRISPR-Cas9-mediated gene transfer method’ (promotor of the grant: Prof. Bart Vandekerckhove) - Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented response rates in hematological malignancies. Most CAR T cell products are generated using lentiviral transductions of autologous T cells. The production costs of and technical necessities for lentiviral vectors are high. In addition, there is also a safety risk due to the random insertion of the CAR transgene. CRISPR/Cas9-mediated homology directed repair (HDR) with ‘naked’ synthetic dsDNA could solve these drawbacks, hence Stijn will investigate this alternative approach in his project.
Dr. Thomas Naert – ‘Investigating the Impact of EZH2 Inhibition on the Desmoid Tumor Microenvironment’ (promotor of the grant: Prof. Kris Vleminckx) - Desmoid tumors, driven by Wnt signaling network hyperactivation cause significant clinical morbidity and mortality. In previous research, the lab of Prof. Vleminckx identified EZH2 as key in desmoid tumor development in a Xenopus model. Preclinical studies using FDA-approved Tazemetostat showed significant tumor shrinkage in this frog model, however, in human desmoid primary cell lines EZH2 inhibitors significantly reduced Wnt signaling transcriptional responses but had no effect on cell proliferation or cell death. This suggests that the tumor microenvironment (TME) plays a crucial role in the tumor regression observed upon Tazemetostat treatment in vivo, a phenomenon that remains insufficiently understood. In his project, Thomas will perform experiments to enhance our understanding of the impact of EZH2 inhibition (EZH2i) on the microenvironment of desmoid tumors, with a particular focus on Wnt signaling, collagen structure, and immune cell dynamics.
Dr. Kathleen Schoofs – ‘Uncovering the origin of tumoral nucleic acids in blood using molecularly barcoded mouse models' (promotor of the grant: Prof. Katleen De Preter) - Like healthy cells, tumor cells release nucleic acids into the blood, but the mechanisms behind this tumor-related nucleic acid release remain to be elucidated. Eventually, the group of Prof. De Preter wants to investigate the spatial location of the subclones releasing nucleic acids in blood in neuroblastoma mouse models and determine how the nucleic acid composition changes upon therapy resistance. To do so, they will use mouse models with molecularly barcoded tumours to trace DNA and RNA coming from different genetic tumour clones. In her project, Kathleen aims to develop an optimized sequencing protocol and data analysis pipeline for identifying the genetic barcodes in cell-free DNA and cell-free RNA.
Dr. Annelies Van Hemelryk – ‘Spatial profiling of macrophage heterogeneity in neuroblastoma' (promotors of the grant: Prof. David Creytens & Prof. Charlotte Scott) - Despite recent advances with anti-GD2 immunotherapy, effectively treating high-risk neuroblastoma (NB) remains a significant challenge, as this type of immunotherapy often yields only transient effects. Tumor-associated macrophages (TAMs) have been identified as potential contributors to the transient nature of anti-GD2 effectiveness. To gain a more in-depth understanding of TAMs in NB, the groups of Prof. De Preter and Prof. Scott have recently generated an integrated single-cell transcriptomic atlas, covering 68 NB patient samples and found considerable heterogeneity among TAMs, with the identification of different macrophage subsets. To understand the functional relevance of these different TAMs, Annelies will try to localize these TAM subsets within the tumors and/or in the TME. Moreover, by investigating their colocalization with other key actors in the TME she wants to gain additional insights into potential crosstalk between these cell populations.
This call, there was an additional YIPOC grant available around 'leukemia (and immunotherapy or information provision around leukemia),' supported and funded by non-profit organization SuperNils. Dr. Lisa Demoen was selected as laureate for this grant.
Dr. Lisa Demoen – ‘In vivo CRISPR-Cas9 mediated KO of dependency factors in patient derived xenograft (PDX) models of T-cell acute lymphoblastic leukemia (T-ALL)' (promotors of the grant: Prof. Steven Goossens & Dr. Tim Pieters) - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although intensified therapeutic protocols have improved the outcome of T-ALL patients, they coincide with severe short- and long-term side effects. Furthermore, primary therapy-resistant or relapsed patients still have a dismal outcome. Therefore, the lab of Prof. Goossens focuses on the identification of new targets in T-ALL which allows the development of less toxic targeted therapies. A recurrent issue in the validation of their newly identified potential targets is the lack of specific inhibitors. Therefore, in her project, Lisa wants to establish the therapeutic relevance of these targets by optimizing and validating an in vivo CRISPR-Cas9 mediated KO of dependency factors approach in patient derived xenograft (PDX) models of T-cell acute lymphoblastic leukemia (T-ALL).
