Researchers in the Pearson laboratory investigate the molecular basis of the regulation of signalling pathways and their control of cell growth
We aim to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease, by:
- Understanding the signal transduction pathways underpinning cell growth control.
- Conducting biochemical and cell biology analysis of the role of deregulated cell growth in cancer.
- Analysing novel therapies targeting cell growth to treat cancer in pre-clinical models of lymphoma, ovarian and prostate cancers.
- Pharmacogenomic analysis of the pathogenesis of ovarian cancer and predictors of response to emerging targeted therapies.
- Defining the therapy-induced senescence response in ovarian cancer and identifying strategies to harness it to treat cancer.
Targeting the ribosome to treat oncogene-driven blood cancer
The majority of human tumours are characterized by deregulated signalling through the PI3K/RAS/MYC oncogenic network, leading to an increased rate of ribosome synthesis, mRNA translation and hence protein synthesis. We proposed that direct targeting of elevated ribosome biogenesis would provide a new treatment option for oncogene-driven cancers and developed the “first-in-class” selective inhibitor of ribosome biogenesis, CX-5461. Targeting ribosome biogenesis has shown remarkable potency in mouse models of solid and blood cancers that are characterized by deregulated MYC activity, including lymphoma, multiple myeloma and acute myeloid leukaemia (AML). We demonstrated that the nucleolar stress response induced by CX-5461 is driven by multiple pathways including the p53-dependent “impaired ribosome biogenesis checkpoint” and a p53-independent DNA damage-like response. Activation of this checkpoint is independent of global DNA damage, providing low genotoxic stress and potentially greatly reducing toxicity compared to DNA-damaging cytotoxic drugs. Critically, our first-in-human trial of CX-5461 demonstrated single-agent efficacy in treating patients with refractory lymphoma and multiple myeloma (MM). Our goal is to optimize the efficacy of this new treatment paradigm by defining combination therapies based on the intensive mechanistic understanding of the response of models of lymphoma, AML and multiple myeloma.
We are taking four complementary approaches to achieve this goal:
- Initiating a comprehensive program composed of transcription and translation profiling, proteomics, genome sequencing and high-throughput genomic screens for unbiased identification of mechanisms of resistance to inhibition of ribosome synthesis and function.
- Targeting the signalling network that controls ribosome synthesis and function at multiple steps to improve potency of inhibition and prevent on-target acquired resistance or harnessing nucleolar DNA damage response in combination with standard-of-care cancer therapies to improve efficacy and reduce toxicity in clinic.
- Investigating the potential of exploiting the immune response to improve the efficacy of CX-5461.
- Analysing samples from the CX-5461 blood cancer trials by an array of techniques including genomic sequencing of either bulk tissue or single cell sequencing, multiplex immunohistochemistry and in situ hybridisation to identify predictors of response to CX-5461.
Our Specific Aims are to:
- Identify and characterize the novel targets that mediate resistance to ribosome-targeting therapy.
- Evaluate new combination therapies that improve the efficacy of targeting the ribosome in vitro and in vivo.
- Determine the role of anti-tumour immunity in the response and resistance to ribosome-targeting therapy.
- Identify the predictive biomarkers of sensitivity to CX-5461 to facilitate patient selection.
Using single-cell and spatial technologies to improve current therapies in prostate cancer
While prostate cancer is considered a highly manageable disease, a subset of patients develops metastatic disease unresponsive to treatment. Novel theranostic therapies are emerging for treatment, but unfortunately tumours acquire a diversity of genetic and transcriptional changes during their evolution which may promote treatment resistance. Beyond these tumour-intrinsic factors, the surrounding microenvironment may also promote or inhibit distinct tumour populations, driving tumour evolution and resistance. This project aims to understand the role of genetics, transcriptional programs and the microenvironment in driving tumour heterogeneity and treatment resistance using a combination of genomics, single-cell and spatial technologies with the aim of identifying novel biomarkers and treatments.
Developing computational methods for spatial analysis of the tumour microenvironment
The tumour microenvironment is composed of a myriad of cell types, including immune cells, fibroblasts and endothelial cells. Rather than a homogeneous mixture of cells, cells are organized in biologically meaningful ways, referred to as ‘spatial patterns’. Unfortunately, methods to quantitatively characterize these spatial patterns are at their infancy. This project aims to develop novel bioinformatics methods to analyse spatial patterns of ecosystems of cancer cells and cells of the microenvironment and investigate their use as novel biomarkers.
Kang, J., Brajanovski, N., Chan, K. T., Xuan, J., Pearson, R. B., & Sanij, E. (2021). Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduction and Targeted Therapy, 6(1), 323. https://doi.org/10.1038/s41392-021-00728-8
Yan, S., Xuan, J., Brajanovski, N., Tancock, M. R. C., Madhamshettiwar, P. B., Simpson, K. J., Ellis, S., Kang, J., Cullinane, C., Sheppard, K. E., Hannan, K. M., Hannan, R. D., Sanij, E., Pearson, R. B., & Chan, K. T. (2021, 2021/02/01). The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer. British Journal of Cancer, 124(3), 616-627. https://doi.org/10.1038/s41416-020-01158-z
Chan, K. T., Blake, S., Zhu, H., Kang, J., Trigos, A. S., Madhamshettiwar, P. B., Diesch, J., Paavolainen, L., Horvath, P., Hannan, R. D., George, A. J., Sanij, E., Hannan, K. M., Simpson, K. J., & Pearson, R. B. (2020, Feb). A functional genetic screen defines the AKT-induced senescence signaling network. Cell Death Differ, 27(2), 725-741. https://doi.org/10.1038/s41418-019-0384-8
Kusnadi, E. P., Trigos, A. S., Cullinane, C., Goode, D. L., Larsson, O., Devlin, J. R., Chan, K. T., De Souza, D. P., McConville, M. J., McArthur, G. A., Thomas, G., Sanij, E., Poortinga, G., Hannan, R. D., Hannan, K. M., Kang, J., & Pearson, R. B. (2020). Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis. The EMBO Journal, 39(21), e105111. https://doi.org/https://doi.org/10.15252/embj.2020105111
Sanij, E., Hannan, K. M., Xuan, J., Yan, S., Ahern, J. E., Trigos, A. S., Brajanovski, N., Son, J., Chan, K. T., Kondrashova, O., Lieschke, E., Wakefield, M. J., Frank, D., Ellis, S., Cullinane, C., Kang, J., Poortinga, G., Nag, P., Deans, A. J., Khanna, K. K., Mileshkin, L., McArthur, G. A., Soong, J., Berns, E., Hannan, R. D., Scott, C. L., Sheppard, K. E., & Pearson, R. B. (2020, May 26). CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. Nat Commun, 11(1), 2641. https://doi.org/10.1038/s41467-020-16393-4
Khot, A., Brajanovski, N., Cameron, D. P., Hein, N., Maclachlan, K. H., Sanij, E., Lim, J., Soong, J., Link, E., Blombery, P., Thompson, E. R., Fellowes, A., Sheppard, K. E., McArthur, G. A., Pearson, R. B., Hannan, R. D., Poortinga, G., & Harrison, S. J. (2019, Aug). First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discov, 9(8), 1036-1049. https://doi.org/10.1158/2159-8290.CD-18-1455
Trigos, A. S., Pearson, R. B., Papenfuss, A. T., & Goode, D. L. (2019, Feb 26). Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer. Elife, 8. https://doi.org/10.7554/eLife.40947
Hein, N., Cameron, D. P., Hannan, K. M., Nguyen, N. N., Fong, C. Y., Sornkom, J., Wall, M., Pavy, M., Cullinane, C., Diesch, J., Devlin, J. R., George, A. J., Sanij, E., Quin, J., Poortinga, G., Verbrugge, I., Baker, A., Drygin, D., Harrison, S. J., Rozario, J. D., Powell, J. A., Pitson, S. M., Zuber, J., Johnstone, R. W., Dawson, M. A., Guthridge, M. A., Wei, A., McArthur, G. A., Pearson, R. B., & Hannan, R. D. (2017, May 25). Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood, 129(21), 2882-2895. https://doi.org/10.1182/blood-2016-05-718171
Trigos, A. S., Pearson, R. B., Papenfuss, A. T., & Goode, D. L. (2017, Jun 13). Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proc Natl Acad Sci U S A, 114(24), 6406-6411. https://doi.org/10.1073/pnas.1617743114
Devlin, J. R., Hannan, K. M., Hein, N., Cullinane, C., Kusnadi, E., Ng, P. Y., George, A. J., Shortt, J., Bywater, M. J., Poortinga, G., Sanij, E., Kang, J., Drygin, D., O'Brien, S., Johnstone, R. W., McArthur, G. A., Hannan, R. D., & Pearson, R. B. (2016, Jan). Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discov, 6(1), 59-70. https://doi.org/10.1158/2159-8290.CD-14-0673
Kang, J., Kusnadi, E. P., Ogden, A. J., Hicks, R. J., Bammert, L., Kutay, U., Hung, S., Sanij, E., Hannan, R. D., Hannan, K. M., & Pearson, R. B. (2016, Aug 2). Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription. Oncotarget, 7(31), 48887-48904. https://doi.org/10.18632/oncotarget.10346
Rebello, R. J., Kusnadi, E., Cameron, D. P., Pearson, H. B., Lesmana, A., Devlin, J. R., Drygin, D., Clark, A. K., Porter, L., Pedersen, J., Sandhu, S., Risbridger, G. P., Pearson, R. B., Hannan, R. D., & Furic, L. (2016, Nov 15). The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer. Clin Cancer Res, 22(22), 5539-5552. https://doi.org/10.1158/1078-0432.CCR-16-0124