Researchers make breakthrough in overcoming drug resistance in a rare, devastating blood cancer

South Australian scientists have made a significant breakthrough in overcoming drug resistance in acute myeloid leukemia (AML), a rare and devastating blood cancer that kills most patients within a few years.

In a new study published in the world-leading hematology journal Blood, researchers from the University of South Australia and SA Pathology's Centre for Cancer Biology describe how they have discovered a way to suppress a specific protein that promotes resistance to drugs commonly used to treat AML patients.

Professor Stuart Pitson, one of the lead authors of the study, says the finding could revolutionize the treatment of AML, a disease that has claimed the lives of Australian football great Russell Ebert, professional golfer Jarrod Lyle, high-profile American journalist Nora Ephron and filmmaker Lynn Shelton.

This year, it is estimated that 20,000 people in the United States and 900 people in Australia will be diagnosed with acute myeloid leukemia, a cancer of the blood and bone marrow characterized by an overproduction of cancerous white blood cells called leukemic blasts.

Prof Pitson says these cells crowd out normal white blood cells, which then can't do their usual infection-fighting work, thereby increasing the risk of infections, low oxygen levels and bleeding.

SA Pathology hematologist Associate Professor David Ross says many AML patients initially respond to Venetoclax, a new therapy for AML recently listed on the PBS, but over time AML cells become resistant to it.

Using a large biobank of patient-donated AML biopsies and world-leading advanced pre-clinical models, the CCB researchers demonstrated that by modulating lipid metabolism in the body, a protein called Mcl-1 is inhibited in AML cells – the protein that facilitates drug resistance.

This process makes AML cells exquisitely sensitive to Venetoclax, while leaving the normal white blood cells unaffected."

Associate Professor Jason Powell, SA Pathology researcher and co-lead author

The CCB team is now working hard to optimize drugs targeting this pathway to take into clinical trials for AML patients.

"For most people with AML, the chances of long-term survival are no better now than they were last century," Assoc Prof Ross says.

"Now, we have a chance to remedy that. New treatments that prevent Venetoclax resistance have the potential to prolong survival, or even increase the chances of a cure in a disease for which improved outcomes are desperately needed."

Source:
Journal reference:

Lewis, A.C., et al. (2022) Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia. Blood. doi.org/10.1182/blood.2021013277.

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