Selective cytotoxic effects of CDK12 inhibition on metastatic osteosarcoma cells
Project Goal: To investigate the activity of the cyclin-dependent kinase 12 (CDK12) protein in order to develop a safer, targeted therapy for metastatic osteosarcoma.
Institution: Dana-Farber Cancer Institute, Harvard Medical School
Researchers: Matthew Harlow, PhD
Year Awarded: 2020
Type of Childhood Cancer: Metastatic Osteosarcoma (OS)
Patients diagnosed with metastatic osteosarcoma (OS), the most frequent bone tumor of childhood and adolescence, most commonly succumb to disease following its spread to the lung. Since the development of chemotherapy in the 1970’s, survival rates for children with metastatic OS have not improved but have remained at approximately 20-30%. The main reason for this stagnation is due to the lack of recurrently druggable targets found in OS patients. However, groups have recently shown that cellular processes, such as ribosomal RNA transcription and ribosome synthesis, are affected by the activity of the cyclin-dependent kinase 12 (CDK12) protein. Moreover, these processes are critically important for cells to thrive in the lung microenvironment suggesting that drugs targeting CDK12 activity may be useful in treating cancers which disseminate to the lung, including OS. Importantly, our lab has demonstrated that disrupting the activity of CDK12 leads to the death of OS cells growing in the lung microenvironment with little effect on the normal cells that constitute the lung. In this grant proposal, I will demonstrate that the inhibition of CDK12 activity disrupts the surveillance of aberrant transcription in the ribosomal DNA loci, which ultimately results in perturbed OS cell homeostasis.