Press Release

05.03.2021

New IDC Paper in Embo Molecular Medicine

A new paper by Götz Hartleben, Stephan Herzig, Mauricio Berriel Diaz et. al. has been published in Embo Molecular Medicine: "Combination Therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism."

Figure by Luke Harrison (IDC)

https://www.embopress.org/doi/full/10.15252/emmm.202012461

Repurposing of approved drugs for new combination therapies targeting cancer metabolism

Götz Hartleben et. al. have conducted a combinatorial screen using clinically approved drugs to identify molecules that synergistically induce cancer cell death in combination with niclosamide ethanolamine (NEN), a so-called mitochondrial uncoupler that causes metabolic stress. The identified novel drug combinations uncovered distinct metabolic vulnerabilities of cancer cells and sensitized pancreatic tumor-derived organoids to chemotherapy, enabling further developments towards clinical translation.

Cancer cells are characterized by having high nutrient demands in order to sustain bioenergetics and biosynthesis for cell proliferation, driving tumor growth. Nutrient deprivation results in an adaptive rewiring of their metabolism, which however leaves the cells more sensitive to further alterations. Dr. Götz Hartleben and Dr. Mauricio Berriel Diaz from the Institute for Diabetes and Cancer (IDC) hypothesized “A state of pharmacologically-induced cellular starvation could provoke secondary metabolic vulnerabilities that can be targeted with a second drug.” Following this concept, they teamed up with colleagues from the Assay Development and Screening Platform (ADSP) at the HMGU and screened for drugs that, in combination with NEN, causing the primary metabolic stress, would induce cell death. By employing a drug-repurposing approach, they identified several antidepressant drugs (including imipramine) and a dopamine receptor antagonist (domperidone) to synergize with NEN treatment in killing cancer cells from different tumor entities. Integration of transcriptomic and metabolomic analyses elucidated underlying mechanisms including the persistent activation of distinct cellular stress responses contributing to cell death by altering the regulation of pyrimidine metabolism, the latter representing molecular components of DNA synthesis. Importantly, the identified drug combinations sensitized patient-derived pancreatic cancer organoids to chemotherapy, which might facilitate translation into clinical testing by implementation into standard therapies in the future.

 

By utilizing drug efficacy and impeding treatment resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of cancer. Intriguingly, the observed sensitization to classical chemotherapy may enable implementation into established treatment regimens, which would be further facilitated by the advantages of drug repurposing. Further preclinical and clinical validation is currently ongoing at the IDC, which will prove key for translation into clinical application.