Lecture will be held in English

Hosted by

Jan Škoda

About the lecture

Exploiting the Polyamine Dependency of MYC-driven Tumors

Neuroblastoma is a commonly lethal childhood cancer. Therapy is intensive and toxic, yet we cure only half of these children. Neuroblastomas are driven by activated MYC genes, and despite 40 years of effort, no direct Myc inhibitor has been developed. We studied the building blocks created by MYC and identified essential cellular cations called polyamines as pivotal. MYC genes regulate each step of polyamine synthesis, and the chance of a child dying of neuroblastoma is directly proportional to how strongly their polyamine system is upregulated. DFMO is an oral drug that inhibits the ODC enzyme that converts ornithine into polyamines. The drug slows neuroblastoma growth in mouse models, and the FDA approved DFMO for neuroblastoma therapy in 2023. Notably, this approval is for low-dose DFMO while we only see anti-tumor activity with high-dose DFMO. Even at high-dose the effect size is modest, and polyamines are reduced only 30-50%. We reasoned that depleting polyamines further would enhance the treatment effect. We used metabolic tracing to identify the substrate for tumor polyamines and then used high-dose DFMO while also depleting this substrate. We found it to be exceptionally effective with durable complete responses in ~1/3rd of mice and tumor polyamines reduced to <10% of normal. Such profound polyamine depletion also unmasked a novel role for these metabolites in support of translation, necessary for decoding select codons. The inability to do so leads to translation level reprogramming that abolishes cell cyle programs and enhances differentiation programs. We are working to bring this novel therapeutic approach to the clinic.

Registration for lunch with the speaker /for Ph.D. students/

The sponsored lunch usually takes place in the Campus River restaurant. Please meet the speaker and other students at 12:45 at the reception desk at the main entrance (building B22, see the map below).