MARCH5 is a master regulator of BCL2 proteins and a potential anti-cancer drug target
Background
Blood cancers are severe and often life-threatening diseases that impact people of all ages, genders, and ethnic backgrounds. In Australia, around 6,000 people are expected to die from blood cancer this year alone.
Blood cancers frequently re-wire the normal process of cell death (apoptosis) in order live longer and resist currently available treatments, leading to treatment failure, progressive disease and often death.
Venetoclax – a cancer treatment arising from landmark research at WEHI – inhibits a critical survival protein and re-awakens cell death in many blood cancer cells.
The cancer drug is now used to treat certain types of blood cancers worldwide, replacing chemotherapy in the treatment of the most common leukaemia in adults, chronic lymphocytic leukaemia (CLL), and one of the most severe blood cancers, acute myeloid leukaemia (AML). Due to its novel mechanism of action, many patients whose diseases would have not been effectively treated by conventional chemotherapy have a better chance at enjoying improved outcomes.
However, despite the effectiveness of venetoclax, not all blood cancers respond to this drug and patients often report lengthy remissions as enduring cancer cells can resist treatment and cause the disease to return.
About the Project
Dr van Delft and Dr Lew co-lead a team with Dr White that aims to enhance the effectiveness of venetoclax, rendering resistant cancer cells sensitive to treatment. This will broaden the spectrum of patients who can benefit and lead to longer lasting treatment responses, and potentially cures.
By studying all genes in the human body, the team have pinpointed a gene called MARCH5 that controls how blood cancer cells respond to venetoclax. Removing this gene profoundly enhances the ability of venetoclax to kill blood cancer cells, irrespective of how sensitive they are to begin with.
The team’s data suggests that inhibiting MARCH5 can dramatically boost the effectiveness of venetoclax to eliminate blood cancer cells.
Dr van Delft, Dr Lew, and their team plan to develop a drug capable of inhibiting MARCH5 and translate this exciting finding into clinical trials.
Impact
The team expects that a MARCH5 inhibitor will make venetoclax effective for a wider range of cancers and enhance current therapies to achieve deeper remissions and potentially cures.
If successful, these treatments could replace traditional chemotherapy protocols, which can often be toxic, with significant benefit to prolong and improve the quality of life for patients with cancer.