Art style

Cutting-edge protein analyzes reveal new treatment target for bone marrow cancer

Multiple myeloma is a cancer that affects ‘plasmocytes’, a type of immune cell found in the bone marrow. This cancer can weaken the immune system, cause kidney damage and weaken bones, which can lead to broken bones. Average survival rates have improved dramatically with new treatment options. These include lenalidomide and pomalidomide, drugs that are often successful in forcing cancer into remission. In almost all cases, however, the cancer will become less and less sensitive to these drugs, which means it will develop drug resistance. When cancer growth eventually resumes despite treatment, the patient’s prognosis is poor.

Using the latest improvements in a method known as proteomics, an interdisciplinary team of researchers in Berlin has been able to decode a previously unknown mechanism that can cause this type of relapse. “We were able to show that the production of CDK6, a cell cycle regulator promoting cell division, is particularly high once the cancer has become resistant to treatment”, explains one of the two co-leaders of the study, Professor Jan Krönke of the Department of Hematology, Oncology and Cancer Immunology at the Benjamin Franklin Campus. “Based on our data, we believe that CDK6 inhibition could represent a novel therapeutic approach in relapsed multiple myeloma.”

Despite extensive DNA sequencing studies, treatment resistance in multiple myeloma has only rarely been linked to changes at the genetic level, such as gene mutations or deletions. “This suggests that the changes occurring within the cancer cell that would explain this relapse must be taking place at a different level,” says study co-lead Dr Philipp Mertins, an MDC researcher who leads the proteomics platform at both MDC and BIH. He continues: “The growth potential of cancer cells can also be subject to different means of control at the protein level. Here, we observed this type of effect in relation to the protein CDK6.” The researchers used state-of-the-art mass spectrometry technology to determine whether protein-level changes are responsible for cancer’s resistance to treatment. Using both pre- and post-relapse samples from patients with multiple myeloma, the researchers were able to quantify over 6,000 different proteins.

By comparing cancer cells collected before and after relapse, the researchers found that a range of proteins were present in higher or lower concentrations after relapse. Using statistical and bioinformatics analyses, the researchers were able to trace the majority of these effects to a single protein: cyclin-dependent kinase 6, or CDK6, an enzyme that controls the cell’s entry into the phase of cell cycle cell division.

First, the researchers used cell cultures to demonstrate that CDK6 plays a key role in the development of treatment resistance in multiple myeloma. “When we artificially increased the amount of CDK6 present in cultured myeloma cells, they lost their sensitivity to the drugs lenalidomide and pomalidomide,” says study first author Dora Ng, a researcher in the Department of Hematology, oncology and cancer immunology on campus. Benjamin Franklin. She adds: “However, when we also added a CDK6 inhibitor, the drugs became effective again and the cancer cells died. myeloma.”

The researchers were then able to confirm this effect in an animal model, where the combination of pomalidomide with a CDK6 inhibitor significantly improved the chances of survival. “These data suggest that patients with treatment-resistant multiple myeloma may also benefit from the addition of CDK6 inhibitors,” says Professor Krönke, a researcher at the German Cancer Consortium (DKTK) Translational Research Center in Berlin, who is funded through DFG’s Noether Emmy Program. “Further studies will be needed to test this hypothesis. One advantage is that some CDK6 inhibitors have already been approved for use in the treatment of breast cancer.”

The study’s second first author, Dr. Evelyn Ramberger, was responsible for carrying out the project’s protein analyses. Post-doctoral researcher at Charité and at the MDC/BIH proteomics platform, she is convinced that the technology has enormous advantages for the field of cancer research: “We want to continue to pursue this new approach of using modern, comprehensive protein assays to study cancerous tissue — both in multiple myeloma and other cancers. We hope this will uncover additional treatment targets and biomarkers for use in personalized cancer medicine.” she says.

Source of the story:

Material provided by Charity – Universitätsmedizin Berlin. Note: Content may be edited for style and length.