Targeting transcription elongation to modulate the tumour immune microenvironment in prostate cancer
Primary Supervisor: Dr Pedro Durao/Prof. Ian Mills
Project Overview:
Prostate cancer (PC) is the most common male cancer in the United Kingdom and more effective treatments are needed to control the late-stage disease. In the lethal disease, termed castration-resistant PC (CRPC), cancer cells sustain the pro-proliferative gene expression program despite of the presence of anti-androgens. This gene expression program is dependent on cyclin-dependent kinase 9 (CDK9), and CDK9 inhibitors are currently in clinical trials for solid tumours. All cells depend on CDK9 to sustain gene expression, and it has not been comprehensively established why cancer cells are sensitive against the CDK9 targeting drugs. Our preliminary data in human cell lines show that CDK9 inhibition activates innate immune response through viral mimicry. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows transcription and translation of the pro-inflammatory cytokines, such as CXCL10, TNF-alpha and CXCL8. In this project, we aim to further characterise the role of two CDK9 inhibitors currently on clinical trials: AT7519 and AZD4573. We will study how these drugs affect the transcriptome of prostate cancer cells. Furthermore, we will analyse the cytokine storm unleashed in cancer cells upon CDK9 inhibition using mouse cell lines. Additionally, we aim to investigate whether the CDK9-dependent cytokine secretion by cancer cells affects macrophage polarisation from a pro-tumour (M2) to an anti-tumour phenotype. For this we will use qPCR, Luminex as well as perform cell confluence and spheroid assays. This data will then be validated using in vivo models of prostate cancer where we will not only analyse how CDK9 inhibition affects tumour growth but also studying the tumour immune microenvironment using spectral flow cytometry. Our ultimate goal is to turn a well-known immunosuppressed tumour (prostate cancer tumours) into an immune responsive tumour amenable to immunotherapies.
References:
"Yalala, S., Gondane, A., Poulose, N., Liang, J., Mills, I.G. and Itkonen, H.M., 2024. CDK9 inhibition activates innate immune response through viral mimicry. The FASEB Journal, 38(8), p.e23628.
Itkonen, H.M., Poulose, N., Steele, R.E., Martin, S.E., Levine, Z.G., Duveau, D.Y., Carelli, R., Singh, R., Urbanucci, A., Loda, M. and Thomas, C.J., 2020. Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9. Molecular Cancer Research, 18(10), pp.1512-1521.
Cidado, J., Boiko, S., Proia, T., Ferguson, D., Criscione, S.W., San Martin, M., Pop-Damkov, P., Su, N., Roamio Franklin, V.N., Sekhar Reddy Chilamakuri, C. and D'Santos, C.S., 2020. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clinical cancer research, 26(4), pp.922-934."