Dr. Markus Muschen – Translational Science Research Grant

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Over the past two years, Dr. Markus Muschen and his team have developed a fundamentally new concept to treat childhood B-cell leukemia based on what they call the “Goldilocks-drugs”. This is based on the idea that the cells that give rise to leukemia are special in that they originate from the immune system, specifically the cells that make antibodies (B-cells). To function properly, the immune system has evolved a set of rules that B cells need to follow to pass quality control of the antibodies that they make. Thereby, B-cells have to test their antibodies based on feedback signals from the outside (either bacteria, viruses or “self”). The feedback signals cannot be too weak, they cannot be too strong, either. Hence, the Goldilocks concept. Signals that are too strong typically mean that the antibodies react with our own cells (self), this is a problem in many autoimmune diseases, such as diabetes Type 1, rheumatoid arthritis, lupus and others. The vast majority of all B cells eventually fail QC of the immune system and die. Only the very few cells that have it “just right” can survive and pass QC so their antibodies become part of our immune systems’ arsenal. Earlier this year, the Müschen laboratory discovered that B-cell leukemia in children is bound by the exact same rules as normal antibody-producing B-cells. Even though the leukemia cells are very aggressive, they still remember their origin and hence follow the same QC rules. The Goldilocks therapy concept is based on new drugs that are designed to will throw off balance the feedback signals that leukemia and lymphoma B cells receive when they test their antibodies. As a result, all these cancerous B cell leukemia cells will fail antibody-QC of the immune system and die. Cancerous leukemia and lymphoma cells are easy to throw off balance because their feedback signals are much stronger than in normal cells and already at the maximum limit. Normal cells are more balanced and less likely to exceed the limit to make them fail antibody-QC. This is a major development in the lab with direct implication for therapy, because some “Goldilocks” drugs are already in the clinic, albeit for different reasons.Designate a gift for Dr. Muschen's research


About the research lab

Over the past 10 years, the Müschen laboratory has developed a multi-disciplinary research program to study oncogenic signaling and clonal evolution in acute lymphoblastic leukemia (ALL), the most frequent type of cancer in children and young adults. Despite increasing survival rates over the past decades, still ~70% of children who relapse die from their disease. With current algorithms of risk stratification, relapsing patients are undistinguishable from patients who will respond well to standard chemotherapy. Many of the ~110,000 survivors in the US who would benefit from milder forms of chemotherapy are nonetheless treated with aggressive regimen and suffer late effects from unnecessary toxicity. For these reasons, Markus Müschen’s group has developed a comprehensive research program to predict relapse of ALL. Applying forward genetic screens in PDX models, his drug-discovery program will leverage newly discovered vulnerabilities to broaden treatment options and validate a diagnostic test. Markus Müschen’s research is guided through close collaboration with clinician-scientists in the Children’s Oncology Group (COG). As PI of the NCI CTEP ‘Pre-clinical drug-testing’ program, he developed a testing platform with clinical, phenotypic and genetic annotation.