Molecular Therapeutics Laboratory
The Molecular Therapeutics Laboratory examines the regulation of cell signalling pathways; to both determine how defects in this contribute to cancer, wound healing, fibrosis, and other conditions, and to develop agents to target these pathways to improve human health. One of the main areas of our work is concerned with the role of the sphingolipid pathway in cancer, as alterations in sphingolipid metabolism can trigger increased cell survival, increased cell proliferation, and new blood vessel formation; three of the classic hallmarks of cancer.
Our research focuses on four main areas:
- Understanding the molecular mechanisms regulating sphingolipid metabolism in disease, and using this knowledge to develop new therapeutics
- Understanding the molecular control of 14-3-3 adaptor protein function in disease
- Developing advanced xenograft models of human cancers to enhance clinical translation of new potential therapies
- Understanding the mechanisms driving chemotherapeutic resistance in cancer
The laboratory comprises several groups, led by senior researchers, which focus on these different areas.
Current research projects
Developing new therapeutic approaches for glioblastoma
The blood-brain barrier is a major impediment to the treatment of brain tumours because it prevents most anti-cancer drugs from entering the brain, and brain tumour, from the bloodstream. We are investigating new approaches to open the blood-brain barrier to allow the use of existing highly potent anti-cancer drugs as brain cancer therapies. This work employs advanced preclinical models, with tumour cells derived from patients. Successful outcomes of this work could lead to substantial improvements in the survival of brain tumour patients.
Understanding the molecular mechanisms of therapeutic resistance and disease relapse in acute myeloid leukaemia
Acute myeloid leukaemia (AML) in one of the most prevalent adult blood cancers, and has poor clinical outcomes with less than 30% of patients surviving 5-years post-diagnosis. We have developed advanced pre-clinical models to define the clonal architecture of this heterogenous disease and to model disease trajectories in patients. From these studies we have identified numerous drug targets which are currently undergoing pre-clinical evaluation with the goal of improving patient outcomes.
Defining the role of novel binding proteins in oncogenic signalling by sphingosine kinase
We have previously established that plasma membrane localisation of sphingosine kinase, a key enzyme in the sphingolipid pathway,is critical for oncogenic signalling by this enzyme. Now we are seeking to understand how this localisation of sphingosine kinase is regulated via characterisation of the roles of a number of proteins that associate with this enzyme. This may identify new targets for anti-cancer therapy, particularly in ovarian cancer.
Characterising novel inhibitors of enzymes involved in sphingolipid metabolism as potential therapeutics
We recently developed novel chemical inhibitors of sphingolipid metabolic enzymes that show exciting potential to overcome chemotherapeutic resistance in acute myeloid leukaemia, multiple myeloma and ovarian cancer. We are now further developing these inhibitors towards the clinic.
Altering lipid metabolism to combat fibrotic diseases
Dysregulated lipid metabolism plays an important role in obesity-related tissue inflammation and subsequent development of fibrotic diseases, which represent a major health burden on society. In collaboration with A/Prof Bernard Flynn of Monash University, and via a $7 million investment by the Medical Research Commercialisation Fund, we have recently established a spin-out biotechnology company, Cincera Therapeutics, which aims to develop new therapeutics targeting fibrotic diseases through correcting defective lipid metabolism.
Understanding the molecular control of 14-3-3 adaptor protein function
The 14-3-3 family of dimeric proteins are sphingosine-regulated adaptor proteins that bind and regulate many important signaling proteins associated with cancer. We have recently defined a number of important structural factors that are critical for the formation and maintenance of 14-3-3 dimers, which are critical for the function of these proteins. Our findings not only reveal fundamental insights into the molecular function of the 14-3-3 proteins, but also identify novel avenues to target these proteins for therapeutic benefit in lung and other solid cancers.
Selected recent publications:
Zhu W, Gliddon BL, Jarman KE, Moretti PAB, Tin T, Parise LV, Woodcock JM, Powell JA, Ruszkiewicz A, Pitman MR and Pitson SM (2017) CIB1 contributes to oncogenic signalling by Ras via modulation of sphingosine kinase 1. Oncogene 36, 2619–2627.
Powell JA, Lewis AC, Zhu W, Toubia J, Pitman MR, Wallington-Beddoe CT, Moretti PAB, Iarossi D, Samaraweera SE, Cummings N, Ramshaw HS, Thomas D, Wei AH, Lopez AF, D'Andrea RJ, Lewis ID and Pitson SM (2017) Targeting sphingosine kinase 1 induces Mcl-1 dependent cell death in acute myeloid leukemia. Blood 129, 771–782.
Wallington-Beddoe CT, Bennett MK, Vandyke K, Davies L, Zebol JR, Moretti PAB, Pitman MR, Hewett DR, Zannettino ACW and Pitson SM (2017) Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress. Oncotarget 8, 43602–43616.
Zhu W, Jarman K, Lokman NA, Neubauer HA, Davies LT, Gliddon BL, Taing H, Moretti PAB, Oehler M, Pitman MR* and Pitson SM* (2017) CIB2 negatively regulates oncogenic signaling in ovarian cancer via sphingosine kinase 1. Cancer Research 77, 4823-4834. * Equal senior authors.
Woodcock LM, Goodwin KL, Sandow J, Coolen C, Perugini MA, Pitson SM*, Lopez AF* and Carver JA* (2018) Role of salt bridges in the dimer interface of 14-3-3ζ control dimer dynamics, N-terminal α-helical order and molecular chaperone activity. Journal of Biological Chemistry 293, 89-99. * Equal senior authors.
Wallington-Beddoe CT, Sobieraj-Teague M, Kuss BJ and Pitson SM (2018) Resistance to proteasome inhibitors and other targeted therapies in myeloma. British Journal of Haematology 182, 11-28.
Neubauer HA, Tea MN, Zebol JR, Gliddon BL, Stefanidis C, Moretti PAB, Pitman MR, Costabile M, Kular J, Stringer BW, Day BW, Samuel MS, Bonder CS, Powell JA and Pitson SM (2019) Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene 38, 1151-1165.
Bennett MK, Wallington-Beddoe CT and Pitson SM (2019) Sphingolipids and the unfolded protein response. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1864, 1483-1494.
Powell JA, Pitman MR, Zebol JR, Moretti PAB, Neubauer HA, Davies LT, Lewis AC, Dagley LF, Webb AI, Costabile M and Pitson SM (2019) Kelch-like protein 5-mediated ubiquitination of lysine 183 promotes proteasomal degradation of sphingosine kinase 1. Biochemical Journal 476, 3211-3226.
Tea MN, Poonnoose SI and Pitson SM (2020) Targeting the sphingolipid system as a therapeutic direction for glioblastoma. Cancers 12, 111.
Pitman MR, Oehler MK and Pitson SM (2021) Sphingolipids as multifaceted mediators in ovarian cancer. Cellular Signalling 81, 109949.