New combined therapy for late stage multiple myeloma patients
New combined therapy for late stage multiple myeloma patients - Research at Peter Mac
|Pictured: Myeloma is a cancer of plasma cells which reside in the bone marrow.|
|A team of scientists and clinician researchers from Peter MacCallum Cancer Centre is developing ways of overcoming drug resistance in blood cancer cells, making them once again vulnerable to existing treatments.|
|For years, the steroid drug dexamethasone has proved a powerful weapon against multiple myeloma. Today, it is used in combination with newer agents such as thalidomide, lenalidomide (Revlimid) and bortezomib (Velcade), however, when used over time, myeloma cells build up resistance to these drugs by deploying self-preserving housecleaning processes.|
The results from a clinical trial designed by Peter Mac clinical researchers, Dr Simon Harrison and Professor Miles Prince, have shown that by blocking the cleansing activities within a myeloma cell, the cell fills with an unmanageable amount of protein, forcing the cancerous cell to die. A combination of bortezomib and Romidepsin, a drug normally used to treat rare forms of skin lymphoma, blocks the myeloma cell’s housecleaning operations and resensitises the cell to attack from other drugs such as dexamethasone.
The results of the trial, performed through Peter Mac’s Clinical Trials Unit, were published last week in Blood, the leading peer-reviewed haematology medical journal.
‘What we’re doing is combining therapies to rescue relapsed patients by rendering their disease sensitive again,’ says Dr Simon Harrison, lead author and Peter Mac haematologist.
‘The results from this study are some of the first to show that epigenetic drugs such as HDAC inhibitors have an exciting role in improving treatment outcomes for patients with myeloma.’
Myeloma is a blood cancer caused by the accumulation of malfunctioning plasma cells. Cancerous myeloma cells overproduce protein, which is hastily assembled, resulting in what is referred to as ‘misfolded’ protein that threatens the viability of the entire cell. Two cellular mechanisms go to the cancer’s rescue, allowing the cell to thrive, and the myeloma to spread throughout the body.
The two mechanisms at work are proteosomes and aggresomes. Proteosomes ‘degrade’ the misfolded protein, cutting it up and breaking it down into smaller, manageable pieces. Aggresomes reduce misfolded protein levels by hiding, storing and disposing them without the cell’s recognition.
Professor Ricky Johnstone, Head of the Gene Regulation Laboratory and the Cancer Therapeutics Program at Peter Mac, says that by using Romidepsin, a HDAC inhibitor, the Peter Mac team aims to revert the gene activities of a cancer cell to a more normal state.
‘Drugs like Romidepsin restore the activity of cell pathways that remind a cell how to die.
‘HDAC inhibitors are proving to be very effective as single agent therapies for the treatment of certain cancers, however, in work such as this we can see potential benefits to a more extensive use of HDAC inhibitors in combination with other anti-cancer drugs.’
Dr Paul Neeson, Co-Head of the Haematology Immunology Translational Research Laboratory, says that this clinical trial is an example of the importance of the immune system to the future of cancer treatment.
‘There is a tremendous global focus on immunogenetic cell death at the moment, the death of a tumour cell induced by drugs. With HDAC inhibitors, we can help out the body’s defensive immune cells that have become exhausted by fighting on their own.’
Highlighting Peter Mac’s uniqueness as Australia’s largest cancer research group wholly embedded in a dedicated public cancer hospital, this trial involved clinicians and scientists from across the organisation’s clinical and translational research programs, as well as the trial design expertise of the Centre for Biostatistics and Clinical Trials. This trial has been an important example of what can be achieved with these drugs and is the first study to be produced by researchers affiliated with the Victorian Epigenetics Group, which includes clinician researchers from Peter Mac, The Alfred, The Royal Children’s and The Royal Melbourne hospitals.
Heartened by these results, Peter Mac researchers will conduct ongoing research and follow-up trials into epigenetic drugs. One study that is soon to commence — investigating the combination of Romidepsin with another powerful drug that is used to treat myeloma, Revlimid (lenalidomide) — has been designed by Dr Harrison and Dr Michael Dickinson at Peter Mac in collaboration with Professor Francine Foss from Yale University in the United States.