Location: Campus Drie Eiken, D.S.037

Registration requested

Time: 13u - 16u

Speakers:

1. Toon Suls - Laboratorium voor Experimentele Hematologie (LEH)
"Targeting the NF-KB pathway with targeted protein degradation for the treatment of hematological malignancies"
Hematologic malignancies primarily affect the blood, bone marrow and lymph nodes. Among the different subtypes, Acute Myeloid Leukemia (AML) is one of the indications with the worst prognosis. Constitutive activation of the Nuclear Factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway is found in about 40% of AML patients and has been shown to play a role in AML cell survival and chemoresistance. Interleukin-1 receptor associated kinases (IRAKs) represent promising therapeutic targets as they are part of a key signalling complex within the NF-κB pathway. Kinase inhibitors targeting IRAK1 and/or IRAK4 have been extensively studied in different hematological malignancies, ultimately showing limited efficacy in the clinic. Common limitations associated to conventional small molecule inhibitors (SMI) include resistance mutations, lack of response due to scaffolding functions or undruggability of the target. To tackle these limitations, this project is aimed at exploring the therapeutic potential of selective target degradation through PROteolysis-TArgeting Chimera (PROTAC). PROTAC represents an innovative approach able to induce protein degradation through the selective ubiquitination and proteasomal degradation of a target of interest. This project aims at better understanding the therapeutic potential of PROTACs specific for IRAK1 and IRAK4 in comparison to their SMI counterparts. To this end, we will investigate the molecular and functional consequences of target degradation or inhibition in relevant cellular models or primary patient samples of AML. The results obtained in this project will deepen our understanding of the potential use and limitations of PROTAC based approaches as therapies for AML.

2. dr. Roberto Fernández Acosta - Vanden Berghe Lab, Department of Biomedical Sciences
"Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells"
Ferroptosis is an iron-dependent cell death driven by excessive lipid peroxidation of cell membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.

3. Adrien Arrigo - Antwerp Research in Radiation Oncology (AReRO), Centre for Oncological Research (CORE)
"FLASH radiotherapy for breast cancer, an in vivo investigation"
Every year in Belgium 10 000 women are diagnosed with breast cancer, and more than 75% of them are treated with radiotherapy (RT). Thoracic radiotherapy can induce side effects to surrounding healthy organs (lung, heart, skin, healthy breast) potentially leading to debilitating side effects that can limit the dose necessary to treat aggressive tumours, but also decrease the QoL of long-term survivors. Ultra-high dose rate “FLASH-RT” has been described as a technique able to limit normal tissue toxicities while keeping a similar antitumor effect as conventional dose rate radiotherapy (CONV-RT). The exact mechanisms behind this so called “FLASH effect” are still under investigation. This work aims to investigate the in vivo response of triple negative breast cancer (TNBC) to FLASH-RT along with the protection of the surrounding normal tissues, and further understand the mechanisms of the FLASH effect.
All CONV (0.24Gy/s) and FLASH-RT (2000Gy/s) irradiations were performed using the ElectronFLASH (SIT, Sordina) linear accelerator, with defined beam parameters. To assess the healthy lung toxicity, a single dose of 17.5 Gy was delivered to the whole thorax of female C57BL/6 mice. Lungs were harvested at 5-13 days and 14 weeks to quantify lung fibrosis, senescence and macrophage phenotypes by histology and flow cytometry. To assess the antitumor efficacy, 5x105 4T1 cells were injected in the flank of female balb/c mice, locally irradiated with a 20 Gy single dose of FLASH or CONV-RT. Tumour follow-up was performed, and tumours were harvested at 24h, 5-14 days and endpoint. Proliferation, vasculature morphology and tumour stemness were assessed by histology.
14 weeks post-CONV-RT, subpleural fibrosis was observed, along with an increased number of senescent macrophages compared to FLASH-RT and unirradiated mice. Flow cytometry analysis at all timepoints showed a progressive increase in macrophage infiltration after FLASH-RT, but significantly higher after CONV-RT. Additionally, M1 and M2 macrophage populations were increased 14 weeks post-CONV-RT compared to FLASH-RT and unirradiated. On an aggressive 4T1 murine model of TNBC, both RT treatments elicit an identical 6-day TGD after 20 Gy compared to controls. At late time point post-RT, Ki67 score, stemness (ALDH1) and vasculature morphology were found similar after both RT modalities. GADD45B expression, a p53 effector previously showed as response marker to FLASH-RT, showed clustering at low scores for some tumours and higher spread scores in others.
These first results confirm the iso-efficacy of FLASH-RT on an aggressive model of TNBC, associated with a relative preservation of the surrounding healthy lung. Further investigation will be performed to assess the implication of senescent macrophages and their polarization after FLASH-RT. Tumour phenotypes will be characterized at earlier time points post-RT and the heterogenous expression of GADD45 will be further investigated and potentially linked to response to RT.