Multiple myeloma is the second most common blood cancer in the US. It usually comes back and is salvageable (recyclable and does not respond to treatments). Despite novel treatments, treating poisons remains a challenge for patients and clinicians.
In multiple myeloma, bone marrow-derived proinflammatory cytokines and antiviral interferons play a key role in disease progression, including interleukin 6 (IL-6) activation by signaling a down-response interferon-response (IRF) response. .
IRF4 has been shown to be an essential multiple myeloma cell survival factor with unstable activity during pathogenesis and progression of the disease. In multiple myeloma, high IRF4 sensitivity is also associated with lower overall survival rates.
IRF4 is known to regulate expressions of gas cell reprogramming genes such as the oncogenes MYC and KLF4. However, the role of IRF activity in the maintenance of malignant promoters in multiple myeloma has not been studied. Therefore, the researchers thought that IRF4 regulates multiple myeloma progenitor reproduction to promote disease progression.
Because transcription factors (such as IRF4) are difficult to target with traditional small-molecule strategies, researchers from the University of California (UC) San Diego School of Medicine and Ionis Pharmaceuticals used an oligonucleotide-based antisense barrier platform to stabilize Reduce IRF4. transcripts for disturbing cancer metabolism.
Preclinical evaluation of antisense oligonucleotides
The researchers tested a panel of human-specific antisense oligonucleotide agents targeting IRF4 in vitro and described their effect on the functional viability of multiple myeloma cells and IRF4 expression to determine a candidate that inhibits optional on human IRF4. The antisense oligonucleotides significantly reduced myeloma multicellular survival and decreased human IRF4 messenger RNA (mRNA) and protein expression, as well as reduced expression of the IRF4 MYC target gene.
To confirm their results, the team performed ex vivo treatments using xenograft-derived human myeloma multiple cells. Cells were sensitive to treatment with significant reductions in cell functional capacity and IRF4 mRNA expression.
The left image represents a microscopic view of the bone marrow of a mouse with myeloma controlled by the control, and the right image represents the same for a mouse with myeloma treated with the oligonucleotide antisense ION251. The red dots represent IRF4 proteins within human myeloma cells, which are much more sparser after ION251 treatment. Image courtesy of UC San Diego Health Sciences.
In xenograft mouse models, they were well treated in mice carrying myeloma tumors and significantly reduced tumor growth and IRF4 mRNA expression in tumor tumors in a dose-dependent manner after two to six weeks of treatments. The authors noted that 70% -100% of treated mice survived, compared with none in the control group of untreated mice.
“The results of these preclinical studies were so remarkable that half of the microscopy images we took to compare bone marrow samples between treated and untreated mice were reversed blank – in the mice treated. treatment, we could not leave any myeloma cells for our study, “co – author Leslie Crews, PhD, assistant professor in the Department of Regenerative Medicine at UC San Diego School of Medicine, said in a statement.” It makes science harder, but it gives me hope for patients. “
The researchers noted a strong effect on the agent’s target in reducing IRF4 transcripts and reducing protein production in myeloma-related cigarettes. Importantly, they found that treatment reduced expressions of IRF4 target genes, as well as other regulatory transcripts that are responsive to microenvironment and cell cycle but protect normal hematopoietic cells.
The researchers noted that one advantage of antisense oligonucleotides is that they can be delivered into cells by free renewal by natural endocytic mechanisms, which enable rapid gene expression compared to other gene delivery strategies. In addition, the treatment improved myeloma tumor cell sensitivity to standard-care cancer therapeutic therapy such as lenalidomide therapy.
“These confirmatory-principle studies allow rapid clinical development of oligonucleotide-mediated antisense IRF4 inhibition to prevent drug-induced myeloma recurrence by cancer-resistant cancer cells,” said co-author Dr. . Catriona Jamieson, PhD, and director of the California Institute for Regenerative Medicine (CIRM) Alpha Stem Cell Clinic at UC San Diego Health.
The team concluded that comprehensive preclinical studies showed that inhibition of human IRF4 by selective antisense oligonucleotide agents strongly inhibits the survival and regeneration of myeloma stem gas while developing. normal stem cell proliferation and immune cell development.
The studies also led to the identification of a major antisense oligonucleotide candidate for clinical improvement (ION251) leading the way for clinical evaluation in human trials targeting IRF4. The phase I clinical trial for ION251 safety, supported by Ionis Pharmaceuticals, is now recruiting participants at the Moores Cancer Center at UC San Diego Health and elsewhere.
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