Next-generation CAR T cells for pediatric rhabomyosarcoma
Group Bernasconi, Rössler We aim to improve existing therapies for pediatric solid tumors and to devise more effective and less toxic therapies, with a particular focus on rhabdomyosarcoma.
Pediatric sarcomas account for about 15% of pediatric cancers. The relapse rate is generally high with extremely poor prognosis. CAR T cells are engineered T cells expressing chimeric antigen receptors (CARs). CAR T cells therapy is one of the most promising approaches against relapsed or otherwise untreatable cancers.
Since 2018, our laboratory focuses on this personalized immunotherapy, in order to enhance the normal capacity of the patient's immune system to recognize and attack the tumor. We have investigated rhabdomyosarcoma surfaceome by proteomics and we have identified several targets for CAR T cells. We are now conducting in vitro and in vivo experiments to improve CAR T cells activity against rhabdomyosarcoma.
Oncogenic signaling via receptor tyrosine kinases in crosstalk with DNA damage repair
Group Medova Tyrosine kinase receptors activate a wide range of different cellular signaling pathways. Physiologically, intact signaling via the MET receptor is indispensable in embryonic development and tissue homeostasis. At the same time, MET dysregulation promotes features clearly associated with tumor growth and progression such as uncontrolled proliferation, angiogenesis, local invasion, and systemic dissemination. Accumulating data suggest that MET signaling may also protect tumor cells from DNA damage, hence relating its aberrant activity to resistance to DNA-damaging agents routinely used in cancer treatment. We have identified a previously unreported phosphorylation site on MET, which can be recognized by DNA damage master kinases and is involved not only in cellular responses towards DNA damage, but also in metastatic processes, cancer cell migration, and anchorage-independent growth. This project aims at dissecting the nature, function, and regulation of this phosphorylation site in oncogenic signaling of the receptor.
Myeloid Malignancies
Group Meyer Myeloproliferative neoplasms (MPN) are chronic leukemias characterized by constitutive activation of JAK2 tyrosine kinase signaling. Clinical JAK2 inhibitors bring benefits for patients, but have limited disease-modifying activity. Allogeneic hematopoietic cell transplantation is the only curative treatment to date.
The Meyer lab has a specific interest in the oncogenic signaling driving MPN. We have demonstrated that activation of the MAPK pathway with MEK1/2 and ERK1/2 kinases, which is involved in several cancers, limits JAK2 inhibitor therapy and needs to be adressed to enhance efficacy (Stivala, JCI 2019; Brkic, Leukemia 2021). These findings have translated to a clinical study (Adore, NCT04097821).
Our lab is investigating mechanisms of resistance, which mediate loss of response to clinical JAK2 inhibitors, and approaches to overcome resistance. Notably, we are involved in the characterization of novel types of JAK2 inhibitors incl. type II JAK2 inhibitors currently in development towards clinical studies (Meyer, Cancer Cell 2015; Codilupi, CCR 2024).
Unravelling therapy resistance mechanisms for precision medicine in lung cancer and mesothelioma
Group Peng Lung cancer and malignant pleural mesothelioma (MPM) are major thoracic tumors characterized by high morbidity and mortality, as well as high heterogeneity and resistance to therapy. There is an unmet need for a better understanding of the resistance mechanisms, the identification of novel targets and strategies to prevent or overcome therapeutic resistance, and the rational development of precision medicine approaches for personalized disease management to improve clinical outcomes for patients with thoracic tumors.