Iron links offer hope of a new treatment for incurable blood cancer

The important discovery linking iron regulation to rare blood cancers has led to clinical trials of potential new treatments for patients with incurable diseases.

The study focused on polycythemia vera (PV), a blood disorder that causes an excess of red blood cells, and found that limiting access of iron to the bone marrow can reduce red blood cell production in this disease.

Research led by WEHI in collaboration with the University of Melbourne, the Peter MacCallum Cancer Center (Australia) and the University of Cambridge and Silence Therapeutics (UK), has resulted in new clinical trials of a drug that has the potential to control iron. regulation in patients with PV.

Glance

• Researchers discovered a new way to potentially treat polycythemia vera (PV), a rare form of blood cancer characterized by too many red blood cells.
• Studies find increasing hepcidin, a hormone that regulates how your body uses iron, reduces red blood cell production and disease complications in pre-clinical models.
• Recruitment for clinical trials based on this important study has begun, investigating the potential effects of drugs on iron regulation in patients with PV.

An estimated 250 Australians are diagnosed with polycythemia vera (PV) each year. PV is a chronic disease and there is currently no cure.

Without treatment, PV can be life-threatening because the overproduction of red blood cells causes the blood to become thicker, increasing a patient’s risk of developing blood clots and cardiovascular conditions such as heart attack and stroke.

Cancers are currently treated with venesection, in which about 500mL of blood is drawn from the patient several times a month, to rapidly reduce the red blood cell count and blood viscosity.

The new study, published in Bloodprovides a promising new avenue of treatment that could replace painful and annoying frequent blood draws with simple injections every few months.

First author, Dr Cavan Bennett, said finding that limiting iron access to the bone marrow could reduce the severity of PV disease was a gamechanger.

“Through our pre-clinical study, we found that the hormone hepcidin, which is a key regulator of iron availability, is critical for controlling red blood cell production in this disease model,” said Dr Bennett.

“The more hepcidin you have in your body, the more you limit the access of iron to the bone marrow.

“Iron restriction is critical for preventing overproduction of blood cells and is what is important for alleviating disease severity in PV patients.”

Patients with PV often experience iron deficiency while being treated with venesection, but they are also advised not to take iron supplements as this will speed up the production of red blood cells in their body.

Dr Bennett said targeting hepcidin could also help combat the iron deficiency symptoms faced by PV patients.

“This approach limits iron access only to the bone marrow, without depleting iron from other organs, such as the liver,” he says.

The power of silence

This research is being translated into Phase 1/2 clinical trials ongoing in Australia, Malaysia and the United States.

The trial will use SLN124, a new drug being developed by London-based Silence Therapeutics, with the hope of controlling hepcidin expression in PV patients for the first time.

Senior author and Head of WEHI’s Population Health and Immunity Division, Professor Sant-Rayn Pasricha, said the trial involved PV patients receiving injections every few weeks, in hopes of replacing their need for regular venesections.

“Treatment options like this will simplify long-term therapy for this disease for patients and healthcare systems,” said Professor Pasricha.

SLN124 is a gene silencing therapy that works by inhibiting the gene responsible for hepcidin regulation in the liver. Clinical trials will investigate the effects of temporarily ‘silence’ this gene to increase hepcidin production by the liver, which is expected to reduce the severity of the disease.

“We recognized the opportunity to adapt new clinical therapies originally designed for other hematological diseases such as b-thalassemia and apply them to polycythemia vera.

“To go from concept to clinical trials in less than four years is quite astonishing.

“Our work has laid important foundations that can hopefully change patient care options for people with PV and provide unique insights that can lead to a better understanding of the disease.”

Recruitment for clinical trials has begun.

Famous genome studies

The study also uncovered a genetic link between disorders leading to excess iron accumulation (hemochromatosis) and PV, which was made possible through WEHI’s analysis of a broad population genetic database including the UK Biobank.

The research team was able to use this data to conduct a genome-wide association study that analyzed data from 440 PV patients to further examine the role of iron in blood cancer.

Professor Melanie Bahlo, head of laboratory in WEHI’s Division of Population Health and Immunity, said having access to the UK’s Biobank was key to this discovery.

Analysis of a second dataset, Finland’s FinnGen Biobank, confirmed the findings – highlighting the power of this database to help formulate and test new biological hypotheses.

“We were the first research team to use the UK Biobank to focus solely on PV samples, which led us to powerful and new insights into iron and PV status,” he said.

“This allowed us to further discover that the genetic mutation that causes hemochromatosis is one of the strongest risk factors for the diagnosis of PV – insight that will help research fields better understand this rare disease.”

Dr Victoria Jackson, a postdoc in Professor Bahlo’s lab, conducted the genetic analysis using a method called genome-wide association studies.

The study, “Iron homeostasis regulates erythroid phenotype in Polycythemia Vera”, was published in Blood (DOI:10.1182/blood.2022016779).

Research conducted at WEHI is funded by the National Health and Medical Research Council (NHMRC).

WEHI Writers: Cavan Bennett, Victoria Jackson, Anne Pettikiriarachchi, Thomas Hayman, Gemma Moir-Meyer, Katherine Fielding, Ricardo Ataide, Danielle Clucas, Andrew Baldi, Alexandra Garnham, Connie Li-Wai-Suen, Warren Alexander, Melanie Bahlo, Ashley Ng and Sant-Rayn Pasricha.