Universit� degli studi di Modena e Reggio Emilia

A new potential therapeutic strategy for patients with blood cancers

Myelofibrosis is a cancer that affects blood stem cells and, to date, no fully effective cure exists. The disease is characterised by the development of fibrous tissue in the bone marrow, leading to a progressive impairment in blood cell production and a worsening of patients’ clinical conditions.

A new potential therapy to inhibit the early fibrotic transformation of the bone marrow has emerged from researchers at Unimore’s Interdepartmental Centre for Stem Cells and Regenerative Medicine (CIDSTEM), thanks to the support of the AIRC Foundation for Cancer Research. The findings were obtained within the “5 per mille” programme entitled MYeloid NEoplasms Research Venture AIRC (MYNERVA), coordinated by Professor Alessandro Vannucchi, onco-haematologist at the University of Florence.

Data collected by Professor Rossella Manfredini’s group and colleagues show that specifically targeting the protein osteopontin can interfere with the progression of bone marrow fibrosis. The results have been published in Blood Cancer Journal, an important international haematology journal belonging to the Nature group.

“Even the most advanced therapies for patients with myelofibrosis are unable to significantly interfere with the development of marrow fibrosis, which leads to a substantial worsening of clinical conditions and a reduction in patient survival,” explains Professor Manfredini, head of the Genomics and Transcriptomics programme at the Stefano Ferrari Centre for Regenerative Medicine. “The identification of new anti-fibrotic therapies therefore remains an unmet clinical need, as well as a priority for treating the disease. For this study, we tested in laboratory mice with myelofibrosis a drug already used in clinical practice in patients with melanoma and other types of cancer. The aim was also to accelerate the transition of results from the laboratory bench to the patient’s bedside.”

“In a previous study,” adds Dr Lara Tavernari, research collaborator, “we discovered that osteopontin — a molecule that promotes fibrosis — is significantly increased in the plasma of patients with myelofibrosis. Patients with higher levels of this protein also show a greater degree of bone marrow fibrosis associated with a poorer prognosis. Based on these data, we therefore focused on identifying new therapeutic approaches aimed at inhibiting osteopontin activity. After testing several osteopontin inhibitors on patient-derived cultured cells, we selected the drug cobimetinib and administered it to laboratory mice with myelofibrosis. The drug produced a marked reduction in both plasma osteopontin levels and bone marrow fibrosis.”

“The most significant result,” concludes Professor Manfredini, “is that combining cobimetinib with ruxolitinib, the most widely used targeted therapy for myelofibrosis, shows a synergistic effect in inhibiting both bone marrow fibrosis and spleen enlargement. This suggests the use of this drug combination as a first-line curative therapy to inhibit the progression of the disease to a more severe form. Thus, cobimetinib, a drug already approved by regulatory bodies and used clinically against melanoma and other cancers, could be repurposed for myelofibrosis in combination with ruxolitinib, should clinical trials in patients with myelofibrosis confirm the preclinical data.”

“My warmest congratulations to my colleague Professor Manfredini for this outstanding result, which opens — indeed demands — the initiation of clinical trials of this new combined therapeutic proposal in patients with myelofibrosis. This result also demonstrates the great potential of basic research conducted within the Department of Biomedical, Metabolic and Neural Sciences, and its direct applicability to clinical trials in humans, within the context of the close integration between laboratory research and clinical practice,” comments Professor Marco Vinceti, Director of the Department. “This integration has long characterised our Department, and its value is once again recognised by highly prestigious international scientific journals.”

Rossella Manfredini

Graduated in 1988 in Biological Sciences from the University of Modena with top honours (110/110 summa cum laude), she obtained her PhD in Experimental Haematology in 1994 and her Specialisation in Biochemistry and Clinical Chemistry in 1996. A recipient of AIRC and Italian League Against Cancer research fellowships, she carried out postdoctoral work in the United States at Temple University in Philadelphia, Pennsylvania, obtaining in 1998 a US patent for the “Use of AS c-fes oligonucleotides and ATRA in M3-type leukaemias”. Since 2013, she has been Full Professor of Applied Biology in the Department of Life Sciences at the University of Modena and Reggio Emilia. She is the author of 119 scientific publications in high-impact international journals. For more than thirty years she has studied the biology of normal and pathological stem cells, with particular reference to the molecular mechanisms underlying self-renewal, proliferation and differentiation processes. Her main research topics include: the molecular and functional characterisation of normal and leukaemic haematopoietic stem cells; the study of clonal heterogeneity of the stem cell compartment in chronic myeloproliferative diseases; and the study of functional exhaustion of cytotoxic T lymphocytes in myeloproliferative neoplasms.

Categorie: International - english, Notizie_eng