Marikki K. Laiho, M.D., Ph.D.

Application of new cancer therapeutic strategies requires precise understanding of the drug mechanism of action and vulnerability of the cancer to the strategy. Remarkably, cancers have continuous demands for new protein synthesis to supply their growth and proliferation. The first and rate-limiting step in ribosome biosynthesis is RNA polymerase I (Pol I) transcription, and in most cancers this process is highly activated. These findings reveal a therapeutic vulnerability.

Despite the established connections between ribosome biosynthesis and cancer growth, attempts to exploit Pol I as a clinically relevant drug target have been limited. Dr. Laiho and her team have discovered and characterized a family of novel small-molecules that potently and selectively inhibit Pol I transcription. The mechanism of action of the molecules is unique and dependent on the Pol I enzyme. These new molecular entities directly and specifically inhibit Pol I transcription. There are no comparators as other molecules classified as Pol I inhibitors act by targeting cellular topoisomerases. The highly innovative revelations by Dr. Laiho’s team affirm that tumor cells are more dependent on ribosome biogenesis than normal cells and that therapeutic index is attainable. 

The team uses unbiased, broad genomic and cancer cell line vulnerability screens and detailed mechanistic analyses to uncover biomarkers denoting sensitivity. These approaches facilitate the therapeutic use of Pol I inhibitors in the clinic and aid in identifying patients benefiting from this strategy. Their work is built on interdisciplinary expertise in cancer biology, drug discovery, development, and preclinical modeling and aims at clinical translation of these advances.

Dr. Laiho’s lab seeks to understand the regulatory events that prevail in cancer cells, and detect and exploit cancer cell characteristics that could be used as basis of new cancer therapies.

The approaches used in the laboratory are aimed to provide novel information on the regulation of cellular DNA damage and tumorigenesis pathways, to identify new targets for therapy, and to apply this knowledge to therapy efforts. The studies aim at a rapid transfer of findings arising from focused mechanistic studies into translational cancer research.