Ninib Baryawno

Neuroblastoma is the most common and most devastating solid tumor in children. Despite intensive multimodal therapy, long-term survival in high-risk disease is only 50% and chances of survival after a relapse are dismal. Neuroblastoma is a radio-sensitive tumor, making targeted radiopharmaceutical therapy attractive, by delivering radiation to the cancer cells, wherever they reside in the body. We are leading a European multicenter trial where the efficacy of radiopharmaceutical therapy with 177-Lutetium, is being assessed in high-risk neuroblastoma in children (LuDO-N trial). One of the greatest challenges is that patients who experience a relapse are severely weakened by the cancer and by previous therapy, and optimally this type of treatment should be given at an earlier time point. For this purpose, we aim to develop radio-pharmaceutical therapy based on 225-actinium or 211-astathine, that emits a significantly higher radiation energy within a very congined space, to deplete single, or small clusters of metastatic cells and thus prevent metastatic relapses. The overriding aim is to generate data to support a future clinical trial that utilises targeted α-particle therapy early in the course of the disease. By controlling the systemic disease early, we believe that the cure rates in high-risk neuroblastoma could be significantly improved. We aim to translate our results into a clinical trial in humans, within a time period of 5-10 years.

Neuroblastoma is one of the most aggressive forms of childhood cancer. Despite intensive treatment, survival in high-risk patients is less than half today. The reason for this is that after a long period of treatment, these tumors have developed resistance to chemotherapy, which leads to the cancer becoming very difficult to treat. There is therefore a great need to identify the critical biological mechanisms underlying treatment resistance and thus relapse. By increasing the biological understanding of neuroblastoma, we can thus develop new treatments that lead to better survival for these patients. Preliminary data from our research group, where we used single cell analysis on human neuroblastoma, indicate the discovery of the cell of origin in neuroblastoma. This cell is believed to be a stem cell in which the disease develops during the fetal stage. This immature cell is few in number in the tumor and rarely divides, which means that it is not sensitive to chemotherapy drugs used in treatment. Thus, we believe that it is this cell that is primarily involved in the onset of relapse. In this research program we will map the cellular, genetic and functional nature of the cell of origin and find new treatments that aim to kill this cell. Using our data from single cell analysis, we have already identified targeted therapies that will be tested using preclinical models. We will develop new treatments that either kill this original cell or cause it to mature into cancer cells that are more sensitive to chemotherapy. This can thus lead to us counteracting resistance to cancer treatment. Our strategy aims to increase the biological understanding of neuroblastoma where we with new targeted treatments that specifically target mechanisms that drive resistance to chemotherapy. With this strategy, we hope to cure patients with neuroblastoma in the long term.

The knowledge of normal embryonic development of a cell lineage is key to understand the heterogeneity and progression of cancer arising from this particular lineage. Cancer cells replay gene expression modules active during developmental dynamics in specific microenvironments. Indeed, the interactions between the tumor and its microenvironment are often critical to uncovering the mechanisms of tumor survival. Our preliminary data has identified malignant Schwann Precursor cells (tSCPs) as the putative neuroblastoma stem cell. We believe that tSCPs produce malignant adrenergic and mesenchymal cell-states and facilitate the survival of the tumor. Building on our expertise with preclinical modeling, we will generate in vitro and in vivo models that recapitulate tSCPs, that will be further used to characterize the function and preclinical targeting of these cells. Moreover, we have already used our single-cell profiling data on human neuroblastoma and normal fetal sympatho-adrenal tissue to identify the sources and nature of microenvironment signals that channel sympatho-adrenal differentiation during normal development. By contrasting interactions in normal fetal and neuroblastoma tissue, we aim to target factors, pathways, or signals that would push tSCP towards terminally differentiated tumor cell fates with the long-term goal to cure childhood neuroblastoma.

Neuroblastoma is one of the most aggressive forms of childhood cancer. Despite intensive treatment, the survival of high-risk patients is less than half. The reason for this is because many of these tumors after a while developed resistance to cytotoxic drugs and therefore started to grow again, which makes the cancer very difficult to treat. There is therefore a great need to identify critical biological mechanisms that lead to treatment resistance and thus to relapse. By increasing the biological understanding of neuroblastoma, we can thus develop new treatments that provide better survival for high-risk patients with neuroblastoma. In order to discover which cells and genes drive resistance to cancer treatment, we will in this study use single cell analysis. Using single-cell analysis, we will map in detail the cellular and genetic composition of human neuroblastoma that has undergone treatment. This analysis will allow us to create a cell map of neuroblastoma and, using functional cell culture experiments and animal models, identify which cells and genes are resistant to neuroblastoma treatment. Through single-cell analysis of human neuroblastoma, we hope to identify the different cell types in cancer that drive resistance to cancer treatment. With this increased biological understanding, we hope to find new new targeted therapies that specifically target mechanisms that drive resilience to treatment and, in the long run, improve the survival of migraine patients with neuroblastoma.