multiple myeloma
Micrograph showing
Tofacitinib, a pan-JAK inhibitor approved to treat rheumatoid arthritis, may advance as a potential treatment for multiple myeloma (MM) based on results from preclinical studies.
In these studies, tofacitinib was able to reverse proliferative effects in stromal-responsive human MM cell lines and reduce tumor growth in mouse models of MM.
Christine Lam, of University of California, San Francisco, and her colleagues conducted this research and reported the results in haematologica.
The researchers showed that, in co-cultures of MM cell lines and bone marrow stromal cells (BMSCs), tofacitinib inhibited the growth of MM cells in a dose-dependent manner.
RNA sequencing and phosphoproteonomics revealed an upregulation of 67 transcripts in MM cell lines co-cultured with BMSCs—most related to JAK-STAT and interleukin signaling.
Additional cell culture experiments showed that tofacitinib inhibited the downstream signaling molecule STAT3, which is responsible for proliferation through the JAK/STAT pathway.
The JAK1/2 inhibitor ruxolitinib did not replicate results seen with tofacitinib.
Further experiments showed that carfilzomib did not have synergistic effects with tofacitinib.
Venetoclax did demonstrate synergy with tofacitinib but only in MM cells cocultured with BMSCs, not in MM cells alone.
The researchers also tested tofacitinib in vivo. They injected mice with an MM cell line, and, after 2 weeks, mice were treated with tofacitinib for 4 weeks.
Mice treated with tofacitinib had lower tumor burden and a significant improvement in survival compared to untreated control mice.
Finally, the researchers tested tofacitinib in bone marrow mononuclear cells from patients. After stimulation with IL-6, the cells were exposed to tofacitinib.
The researchers observed “modest” viability against malignant plasma cells. They noted that because ex vivo MM plasma cells are minimally proliferative even with added cytokines or stromal stimulations, “these results may not fully reflect the potential therapeutic efficacy of tofacitinib in MM patients, where plasma cells are constantly proliferating within the [bone marrow].”
The researchers concluded that “tofacitinib is a promising agent to reverse the tumor-proliferative effects of the [bone marrow] microenvironment that can be rapidly repurposed to benefit MM patients.”