Origins of Cancer
Tumours require a constant supply of nutrients to maintain their growth advantage. Increased understanding of the nutrients required for tumours to grow and how they are brought into the cancer cells, may lead to new avenues to stop cancer growth.
Recent Research
The importance of lifestyle and environmental factors on development of disease has long been a focus of biomedical research and media attention. Diet in particular is implicated in many different diseases however measuring the effects of nutrition on disease is difficult. There is growing literature that obesity can be linked with diabetes, cardiovascular disease and cancer, however the mechanisms still remain unclear. It is known that the expression of specific amino acid (nutrient) transporters is increased in many primary cancers and we are examining whether this can explain some of the links between diet and disease.
Over the last decade, drugs designed to block blood vessel formation have provided an entirely new string to the cancer treatment bow. Blocking the blood supply restricts the amount of nutrients available to cancer cells. Since there are over 350 different nutrient transporters which can bring a variety of substrates such as amino acids into the cell, we propose that blocking specific transporters in cancer may offer new opportunities for therapeutic intervention.
Major projects
The role of amino acid transport in prostate cancer
One of the essential nutrients required by growing cells is leucine, an amino acid found at high levels in red meat and dairy. Leucine is supplied to cells by specialised transporters (pumps). Jeff and his colleagues have discovered that cancer cells have more transporters, which can then supply the cell with more growth promoting nutrients.
They have also discovered that they can disrupt the uptake of leucine by reducing the expression of the transporters or by introducing a drug that competes with leucine. This disruption slows cancer growth, in essence “starving” the cancer cells.
Jeff’s recent research into prostate cancer has been published in the prestigious journal, Cancer Research. His work offers several potential targets for new drug development – with the aim of slowing growth of the prostate cancer so that it may not require surgical removal. His laboratory is also examining these transporters in breast cancer and melano ma.
Meet Project Leader: Dr Jeff Holst
In between his golfing obsession and growing a Mo to raise money for Movember Jeff heads up the Origins of Cancer group at the Centenary Institute.
Jeff completed his PhD in 2003 at St Vincent’s Hospital Centre for Immunology in Sydney, before undertaking postdoctoral studies at St Jude Children’s ResearchHospital in the USA. He returned to Australia in 2006, switching his focus from immunology to cancer research and received a fellowship from the Cancer Institute NSW. He has received funding from the NHMRC, Cancer Council NSW and the Prostate Cancer Foundation of Australia, the very charity he fundraises for during Movember.
His most significant research contributions (outlined below) have been published in Nature Biotechnology, Nature Immunology, Nature Methods, Nature Protocols and most recently Cancer Research. He also received the Research Australia Discovery Award in 2008.
Publications (selected)
1. WangQ, Bailey CG, Ng C, TiffenJ, ThoengA, MinhasV, Lehman ML, HendySC, Buchanan G, Nelson CC, RaskoJEJand Holst J. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport in prostate cancer progression. Cancer Research, Accepted, 11 October 2011.
2. Holst J, Watson S, Lord M, Eamegdool S, Bax D, Nivison–Smith L, Kondyurin A, Ma L, Oberhauser A, Weiss A and Rasko JEJ. Substrate elasticity provides mechanical signals for expansion of hemopoietic stem and progenitor cells. Nature Biotechnology 28(10):1123-8, 2010.
3. TiffenJC, Bailey CG, Ng C, RaskoJEJ and Holst, J. Luciferase expression does not affect tumor cell growth in vitro or in vivo. Molecular Cancer 9:299, 2010.
4. Holst J, Wang H, Durick Eder K, Workman CJ, Boyd KL, Baquet Z, Singh H, Forbes K, Chruscinski A, Smeyne R, van Oers NSC, Utz PJ & Vignali DAA.Scalable signaling mediated by T cell antigen receptor–CD3 ITAM ensures effective negative selection and prevents autoimmunity. Nature Immunology 9, 658-666, 2008.
5. HolstJ, VignaliK, BurtonAR, VignaliDAAV. Rapid analysis of T cell selection in vivo using T cell receptor retrogenic mice. Nature Methods 3(3), 191-197, 2006.
View Dr Jeff Holst's complete publications here. You can also view his profile at The University of Sydney, search the available listings on PubMed or contact Dr Holst.
