Pioneering research into the chronic inflammation often seen in certain blood cancers has identified a promising treatment approach for myelofibrosis, a life-threatening bone marrow cancer.
New research from UVA Cancer Center identifies a major factor contributing to the unrelenting inflammation associated with a group of blood cancers called myeloproliferative neoplasms. These cancers cause the bone marrow to make too many blood cells. This leads to symptoms such as headache, fever, fatigue, weakness, bone pain, bleeding, and an enlarged spleen.
Research by Golam Mohi, PhD, and colleagues at UVA provides new insight into how bone marrow cancer cells promote the development of myelofibrosis. They have identified a cytokine, called interleukin-1, that contributes to the progression of myelofibrosis. Targeting this cytokine could prevent the progression of myelofibrosis, the scientists report. This could spare the bone marrow the damaging scarring that is the hallmark of the disease.
The JAK2 inhibitors ruxolitinib and fedratinib are currently approved therapies for myelofibrosis, but they do not significantly reduce bone marrow fibrosis. Therefore, we believe that other factors, in addition to JAK2 activation, could be involved in the development of myelofibrosis. Our research provides new insight into how interleukin-1-mediated inflammatory signaling contributes to the development of bone marrow fibrosis and could lead to a new therapeutic approach for this deadly bone marrow cancer.”
Golam Mohi, of the UVA Cancer Center and the University of Virginia School of Medicine
A bone marrow transplant, to physically replace diseased bone marrow, is the only potential cure now available for myelofibrosis. But that procedure is very taxing on the body and associated with many complications, making it risky for older patients (the group most likely to develop cancer). Because not all patients are eligible for bone marrow transplants, new treatment options are urgently needed.
The new UVA discovery could not only provide a new treatment approach, but also shed light on the fundamental mechanisms of progression of myeloproliferative neoplasms. Mohi and his team found that interleukin-1 (commonly called IL-1) is crucial to the development of myelofibrosis. Increasing it in lab mice sped up bone marrow healing and fueled excessive blood cell production. Reducing it, on the other hand, had the opposite effect.
The researchers also looked at interleukin-1 levels in human patients. They found that these patients exhibited elevated levels of two forms of IL-1, strengthening the case for IL-1 or the IL-1 receptor as a promising treatment target.
Researchers believe that IL-1 sends signals that amplify inflammation in the body and promote damaging changes in the bone marrow. They were able to block that process in lab mice using an antibody, dramatically reducing bone marrow scarring. Scientists may be able to adapt this approach or use other means to block IL-1 and stimulate similar benefits in human patients, although much more research and testing will be needed.
“Based on the findings of this study, we suggest that combination therapies targeting both JAK2 and IL-1 might be useful for the treatment of myelofibrosis,” said Mohi, of UVA’s Department of Biochemistry and Molecular Genetics. “We hope that our exciting laboratory finding will translate into clinical trials and significantly improve the treatment of patients with myelofibrosis.”
Finding new and better ways to treat even the most challenging cancers is a key mission of the UVA Cancer Center. Earlier this year, UVA became one of 53 cancer centers in the country to be designated a Comprehensive Cancer Center by the National Cancer Institute. The designation recognizes elite cancer centers with the nation’s leading cancer programs. Comprehensive Cancer Centers must meet rigorous standards for innovative research and cutting-edge clinical trials.
UVA’s many efforts to improve care for rare blood cancers were bolstered this summer with a generous anonymous donation of $5.75 million, enabling the Cancer Center to accelerate research and provide more patients with access to cutting-edge clinical trials.
Mohi and his collaborators have published their findings in the scientific journal nature communications. (The article is open access, which means it is free to read.) The research team consisted of Mohammed Ferdous-Ur Rahman, Yue Yang, Bao T. Le, Avik Dutta, Julia Posyniak, Patrick Faughnan, Mohammad A. Sayem, Nadine S Aguilera, and Mohi.
The research was supported by grants R01 HL095685 and R01 HL149893 from the National Institutes of Health. In addition, Mohi revealed that she received unrelated research funding from the oncology company Erasca Inc.