Targeting Macromolecule Biosynthesis in Cancer by In Vivo Flux Measurement for rational Drug Development

Cancer is primarily a disorder of cell growth which ultimately kills the patient. Historically, the study of cancer growth
pathways have focused on a rare non-representative cell lines and the results have not translated into effective clinical
therapy.

Worldwide, very few comprehensive metabolism studies have been performed with primary cancer samples
from patients. South Australia stands poised to be a world leader in this new and vital area of research for 3 critical
reasons:- (i) We have some of the best clinically annotated tissue banks in Australia and an outstanding track record in
clinical trials for targeted therapies, beginning with blood cancers; (ii) world class investment in mass spectrometry
expertise and, (iii) cancer researchers in South Australia have engineered sophisticated in vivo models of cancer using
primary cells, including humanized ossicles, multiple myeloma metastasis models, colon organoids and in situ brain
cancer models. We are thus well-positioned to begin to measure primary cancer cell growth in pre-clinical models and
clinical trial patients receiving targeted therapy.

Recently, we and others have used new non-radioactive isotope technology to label and track nutrients inside cancer cells. This has revolutionized the study of cancer growth. We have the opportunity to lease cutting edge equipment, software, standards and isotopes to track how cancer cells metabolise any nutrient or any small molecule from a world class company that has developed dedicated components and analytical methods. The package includes training and financial support of future PhD students and a dedicated operator to work leading cancer researchers in SA. Our exciting results published in leading journals have shown that primary human cancer cells metabolise nutrients in many different ways and struggle to adapt to sudden changes in metabolism, unlike healthy normal cells. We have developed new small molecules that can block cancer cell metabolism at key branch points in the cell. Blocking cell growth pathways represent a unique opportunity to target cancer without chemotherapy or radiotherapy.

The equipment and skills arising from this infrastructure grant will establish our centre in Adelaide as a world leader in primary cell tissue banking and metabolic flux analysis. Marten Snel is a world leader in applied mass spectrometry and lipidomic imaging, leads an outstanding core facility at SAHMRI and will assist in training PhD and post-doctoral researchers together with leading cancer investigators.