The Hannan Group - Cancer Therapeutics

As head of the Cancer Therapeutics Group, Professor Ross Hannan's work focuses on the molecular analysis of major pro-malignant transcription factor networks that operate in cancer cells using an integrated approach that combines cell biology, genomics, proteomics, biochemistry, genetics, bioinformatics and strong interactions with oncologists in the clinic. Through this molecular understanding, he hopes to identify key therapeutic nodes to impede the progression of aggressive cancers. The availability of ribosomes is a fundamental rate-limiting step for tumour cell proliferation. He is examining the genetic and epigenetic processes by which ribosomal RNA gene transcription, is regulated by RNA Polymerase I, and how this process is dysregulated during cancer.

Professor Hannan and his group have progressed this fundamental research a step closer to treating patients and changing clinical practice. His group developed the world’s first selective inhibitors of Pol I transcription (Bywater et al. Cancer Cell 2012; Bywater et al., Nature Reviews Cancer 2013), which are a new class of therapeutic. This inhibitor is currently in Phase I clinical trials at Peter Mac for the treatment of haematological malignancies. His lab is also involved in the development of second-generation drugs and evaluating their effectiveness in other cancers such as ovarian and prostate.

The second area of research focus for Professor Hannan is ribosomopathies, a group of inherited diseases including Diamond Blackfan Anaemia (DBA) and myelodysplastic (5q-) syndrome. Such patients are also predisposed to developing haematological malignancies such as acute myeloid leukaemia (AML). Ribosomopathies are caused by dysregulated ribosome biogenesis. Thus understanding the mechanisms mediating these diseases may identify novel approaches for their treatment, which at this time is palliative only.

Professor Hannan’s group has utilized genome-wide and chemical screening to identify potential candidates, which underlie the genetic and/or functional cause of various ribosomopathies. Expanding from this understanding the mechanisms underlying the increased predisposition for patients with ribosomopathies to develop cancers such as AML is also being evaluated.

Professor Hannan is a Group Leader at the Peter MacCallum Cancer Centre in Melbourne in The Oncogenic Signalling And Growth Control Program.

Enquiries are welcome from potential Honours or PhD students. A variety of projects are available within all of the areas of research undertaken by this Group.

 

Professor Hannan presenting at Life Science Across the Globe (LSAG):

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A novel role for the pol I transcription factor UBF in the regulation of expression of histone gene clusters and cellular DNA damage responses Current
Application of Bayesian modelling of high-throughput genomic data to obtain robust and interpretable estimates of model parameters Current
Click chemistry enables evaluation of the molecular mechanism of the 2nd generation RNA polymerase I inhibitor, PMR-116 Current
Establish a robust and reproducible high-throughput data analysis workflow using snakemake Current
Identifying the genetic signatures of acquired resistance to Pol I transcription inhibitors in cancer Current
Investigating how pertubations in ribosome biogenesis and the nucleolar surveillance response modulate cellular growth Current
Regulation of chromatin remodeling of the rRNA genes in mouse embryonic stem cells Current
RNA polymerase I inhibitors as therapeutics for cancer: analysis of p53 -dependent and – independent cell cycle checkpoints Current
RNA polymerase I inhibitors as therapeutics for cancer: Testing combination therapies for haematologic malignancies Current
Simulation of “in-silico” genomic high-throughput sequencing data to assess and benchmark results from different computational tools, and to guide parameter optimisation Current

Devlin, JR, Hannan, KM, Hein, N, Cullinane, C, Kusnadi, E, Ng, PY, George, AJ, Shortt, J, Bywater, MJ, Poortinga, G, Sanij, E, Kang, J, Drygin, D, O'Brien, S, Johnstone, RW, McArthur, GA, Hannan RD and Pearson, RB (2016) Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discovery 6(1):59-70

Guo L, Zaysteva O, Nie Z, Mitchell NC, Er J, Lee A, Ware T, Parsons L, Luwor R, Poortinga G, Hannan RD, Levens DL and Quinn LM (2016) Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the Mediator Complex to modulate MYC transcription and tissue growth. Nucleic Acid Research 44(16):7646-58

Kang J, Kusnardi EP, Ogden A, Hicks RJ, Bammert L, Kutay U, Hung S, Sanij E, Hannan RD, Hannan KM and Pearson RB (2016) Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription Oncotarget 7(31):48887-48904

Quin J, Chan KT, Devlin JR, Cameron DP, Diesch J, Cullinane C, Ahern J, Khot A, Hein N, George AJ, Hannan KM, Poortinga G, Sheppard KE, Khanna KK, Johnstone RW, Drygin D, McArthur GA, Pearson RB, Sanij E and Hannan RD (2016) Inhibition of RNA Polymerase transcription initiation activates non-canonical ATM/ATR signaling. Oncotarget 7(31): 49800-49818

Chan KT, Paavolainen L, Hannan KM, George AJ, Hannan RD,  Simpson KJ,  Horvath P and Pearson RB (2016) Whole-Genome RNAi screening and phenotypic classification analysis to identify regulators of oncogene-Induced senescence. Assay and Drug Development Technologies 14(7): 416-428

Rebello RJ, Kusnadi E, Cameron D, Pearson H, Lesmana A, Devlin J, Drygin D, Clark AK, Porter L, Pedersen J, Sandhu S, Risbridger GP, Pearson RB, Hannan RD and Furic L (2016) The dual inhibition of RNA Pol I transcription and PIM kinase as a new therapeutic approach to treat advanced prostate cancer. Clinical Cancer Research 22(22):5539-5552

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