Scientists take new approach to tackle chemo-evading blood cancer

Professor David Curtis works on acute
leukaemia

Series about National Health and Medical Research Council (NHMRC) Project Grant recipients in Central Clinical School (CCS) starting in 2019

by Anne Crawford

Acute leukaemia is an unusually lethal cancer. Despite achieving complete remission after intensive chemotherapy, 80% of patients will be dead within five years of diagnosis.

Professor David Curtis, clinical haematologist and head of blood cancer research at the Australian Centre for Blood Diseases (ACBD) at Monash University's Central Clinical School, is investigating the mechanisms behind the cancer’s ability to resist chemotherapy.


“One of the hardest things is that you can say to a patient ‘your chemotherapy has worked’ but usually these resistant cells start growing again and cause a recurrence within 12 months,” Prof. Curtis said.

The low survival rate for acute leukaemia, which kills more than 1000 Australians a year,
is only exceeded among cancers by pancreatic and high grade glioma, a type of brain cancer.

A groundbreaking paper by Professor Curtis and colleagues in Nature Communications recently tracked the cells in one form of acute leukaemia, T-cell acute lymphoblastic leukemia (T-ALL), and demonstrated that recurrence arises from long-lived, chemo-resistant leukaemia cells that ‘hibernate’ in the body.

“It’s counter-intuitive but the cells that cause recurrence after chemotherapy are the ones that are not growing,” Prof Curtis said.

The idea isn’t new. However, the mechanisms of chemo-resistance in acute leukaemia remain poorly defined, he said.

Prof Curtis has been funded in the latest NHMRC grants to progress this research. He will take a new approach to tackling the problem of the surviving cells using a transgenic mouse model and repurposing drugs currently in clinical use for other conditions.

This will potentially overcome the problems involved with previous approaches, he said. Clinical trials in the 1990s used growth factors on the leukaemia cells to try to stimulate them so they could be killed during chemotherapy.

“But the trouble was that it keeps them alive too,” Prof Curtis said. “Our work provides a new way of attacking the problem. We have found better ways of stimulating cells to start growing without keeping them alive,” he said.

“We’ve shown that this method makes them more sensitive to chemotherapy.”

The researchers will also investigate whether the problem of hibernating cells is true for all types of leukaemia and identify candidate targets to overcome chemo-resistance. They already have sufficient pre-clinical data to allow them to quickly initiate Phase I trials to test Galunisertib, Bortezomib or Pioglitazone in combination with chemotherapy in acute lymphoblastic leukaemia.

The new methods being developed in the study may also apply to a broad range of cancers, Prof Curtis said.

The ACBD researchers are Australian leaders in early phase clinical trials for blood cancers.

Dr Cedric Tremblay is Chief Investigator - B.

To read more about Prof Curtis;

https://ccsmonash.blogspot.com/2018/11/congratulations-to-professor-david.html
www.monash.edu/medicine/ccs/blood-disease/research/stem-cell