Professor Yifat Merbl and a Winning Partnership in the Fight Against Cancer

June is Cancer Immunotherapy Awareness month, a time to highlight the cancer-fighting potential of therapies that harness the body’s immune system. Cancer cells succeed in overrunning the body’s defenses in part by tricking the systems within cells responsible for the destruction of proteins, which is required in order to keep the cells healthy. Proteasomes are like cellular garbage cans, important for getting rid of unwanted or damaged proteins and helping the immune system recognize harmful invaders and cancer cells. Research on proteasomes shows promise in determining how some cancers resist drugs meant to target them.

ICRF is proud to partner with the Cancer Research Institute (CRI), which focuses on the discovery and development of immunotherapies for all types of cancer, to fund the work of Israeli scientist Professor Yifat Merbl, who was recently awarded the 2024 Rappaport Prize for Excellence in Biomedical Research. Merbl’s lab at the Weizmann Institute of Science in Rehovot is at the cutting edge of research into the role of proteasomes in different types of cancers. This partnership between ICRF and CRI will maximize the potential of Prof. Merbl’s research and bring us closer to our shared goal of ending the suffering caused by cancer.

Prof. Merbl’s lab studies proteostasis control mechanisms, the interconnected chemical pathways that ensure the health of the cell by maintaining a proper balance between the creation of new proteins and the destruction of proteins that have become damaged or are no longer needed. These control systems are extensive and complex, involving over 1,000 proteins. The Merbl Lab focuses on epiProteome regulation, a term they introduced to reflect the control mechanisms of proteins after they have been made, which includes both protein modifications and degradation. This concentrates on protein post-translational modifications, meaning changes made to proteins by adding or subtracting bonds between atoms on specific parts of protein molecules to alter protein function, and on the health and disease progression effects of processes associated with the degradation of proteins.

Prof. Merbl and her team recently received the $200,000 CRI-ICRF Technology Impact Award, for which work begins in July 2024. Thanks to the current $200,000 CRI-ICRF Clinic and Laboratory Integration Program (CLIP) grant, which will soon conclude, Prof. Merbl and her colleagues are digging deeper into an approach they call proteasome profiling, seeking to understand detailed processes of the cell by examining the molecular waste produced when proteasome protein degradation systems disintegrate proteins marked for destruction. Merbl and her team have mapped this so-called degradation landscape in both tumor cells and adjacent healthy cells in lung cancer. Now, they hope to use the same technology to study the degradation landscapes of melanoma cells, one way of learning more about which proteins cells mark for disintegration and which are left in. Proteasomes are critically important in tumor immunogenicity. They regulate inflammatory signaling, activate immune cells, and play a crucial role in antigen processing and presentation.

Prof. Merbl’s work shows promise for greater understanding of how cancer cells evade the immune system, by modulating the ubiquitin-proteasome system that is required for generating the peptides, little pieces of proteins, that are presented to the immune system on the surface of tumor cells. The approaches the Merbl lab developed address a gap that is currently limiting our knowledge regarding cancer-driven alteration of the tumoral degradation landscape in cancer. The hope is that their research will ultimately lead to improved treatments for melanoma by developing new systems to specifically target proteasome degradation. Immunotherapy is a crucial and growing area of cancer treatment. ICRF and CRI believe the Merbl Lab is an essential part of creating a future of more effective treatments for melanoma and other cancers.