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.
Targeting Metabolic Supercomplexes in Therapy-Resistant Prostate Cancer
Pandey group Prof. Dr. phil. Amit V. Pandey
Castration-resistant prostate cancer (CRPC) represents a lethal stage of the disease, primarily driven by the tumor's ability to overcome therapy through the synthesis of its own androgens.
Our research has advanced beyond studying single enzymes to investigate their higher-order organization into what we term "metabolic supercomplexes" or "metabolons."
Our central hypothesis is that key enzymes in androgen production, such as CYP17A1, AKR1C3, and STS, do not function in isolation. Instead, they form organized, multi-protein complexes at the interface of cellular compartments, like the endoplasmic reticulum and the cytosol. These supercomplexes act as hyper-efficient production lines, utilizing a mechanism called "substrate channeling" to rapidly convert precursors into potent androgens that fuel cancer growth.
This model provides a powerful new explanation for the robust resistance observed against drugs like abiraterone. Our current work focuses on characterizing the structure and function of these supercomplexes. The ultimate goal is to develop innovative therapeutic strategies that not only inhibit key enzymes but also disrupt the crucial protein-protein interactions that hold these metabolic machines together, potentially using novel small molecules or advanced nanoparticle-based delivery systems.
Towards understanding the role of the minor spliceosome in cancer
Group Rubin Genes are composed of coding units (exons), interspersed with non-coding regions called introns. The process of protein production involves splicing together exons while removing introns from the mRNA molecule. Evolution has given rise to a cellular apparatus called the spliceosome, responsible for carrying out this splicing process. Alternative splicing enables the generation of diverse protein isoforms from a single gene. Splicing is tightly regulated under normal physiological conditions. Our recent findings indicate that cancer cells use a specialized spliceosome, the so-called minor spliceosome, to increase cancer relevant mRNAs. As such cancer hijacks the minor intron-splicing machinery to enhance the expression of transcripts containing minor introns. Proteins encoded by those genes have been shown to activate critical cell survival pathways such as cell cycle regulation and DNA repair. Exploiting the reliance of cancer cells on minor intron-containing genes presents a novel therapeutic opportunity for targeting cancer. By inhibiting the minor spliceosome, we can selectively induce cell death in cancer cells while sparing healthy neighboring cells.