Designer DNA therapeutic wipes out cancer stem cells, treats multiple myeloma in mice

 

Main Ideas and Background:

Multiple myeloma is a blood cancer that has devastated many people, on account of its resistance to cancer treatments. However, a recent discovery by researchers at the University of California San Diego School of Medicine and Ionis Pharmaceuticals sheds light on the possibility of a new treatment that could target myeloma stem cells, stopping their growth, proliferation, and regeneration. The researchers found that an IRF4 antisense oligonucleotide could impair the cell cycle of the myeloma cell, as well as reduce the expression of the IRF4 gene, a gene associated with the survival of the myeloma cell. They also found that this treatment, known as ION251, was successful in killing off the myeloma cells while sparing healthy blood cells. Finally, this treatment increased sensitivity of the myeloma cells to previously used clinical drugs, showing that it is useful not only on its own, but as an addition to improve current treatments being used.

Methods:

One of the experiments was done on mice who had human myeloma cells transplanted into them, as myeloma cells are not able to grow well in laboratory dishes. These mice lacked an immune system, therefore did not reject the human myeloma cells. The mice received one week of daily doses of ION251, followed by three doses of the treatment per week. The IRF4 antisense oligonucleotide binded to the mRNA transcript of IRF4, causing it to degrade. The degradation of IRF4 mRNA disrupted the myeloma cell cycle, rendering it unable to differentiate and form tumours.

Another experiment was performed, where human cells taken from individuals with myeloma and healthy individuals were treated with doses of ION251. This experiment was performed in order to identify whether the ION251 treatment would have any effects on healthy blood cells.

Results:

The mice treated with ION251 showed a reduction in myeloma cells after 2-6 weeks of treatment. When observing microscopic images of the mice’ bone marrow, the researchers were astounded to find almost no traces of myeloma cells. As well, these mice had a survival rate of 70-100%, while none of the mice in the control group (no ION251 treatment) survived.

The second experiment was successful in demonstrating the ION251 treatment’s effectiveness in eliminating myeloma cells while keeping the healthy blood cells untouched.

Thinking Outside the Box:

The results of this treatment allowed researchers to understand how myeloma forms and how IRF4 inhibition would affect its progression. The treatment not only proved effective in eradicating myeloma stem cells, but also improved tumor cell sensitivity to other standard-of-care cancer treatments. Co-senior author Dr. Catriona Jamieson mentions, “[we can expect] rapid clinical development of anti-sense oligonucleotide-mediated IRF4 inhibition to prevent myeloma relapse driven by drug-resistant cancer stem cells".

Fun Facts:

  • Building mouse models and using mouse avatars for clinical trials is actually very common in cancer research 
  • Multiple myeloma is a rare blood cancer, with nearly three thousand new cases diagnosed annually in Canada

Keywords and Supplementary Figures:

  • Antisense Oligonucleotide: a single stranded deoxyribonucleotide that binds to the target mRNA, downregulating it and ultimately inhibiting translation

MYC gene: A protein coding gene, the suppression of which leads to tumor regression.

References

Designer dna therapeutic wipes out cancer stem cells, treats multiple  myeloma in mice. (2021, January 20). Retrieved March 14, 2021, from https://medicalxpress.com/news/2021-01-dna-therapeutic-cancer-stem-cells.html

(Figure) Mondala, P. K., Vora, A. A., Zhou, T., MacLeod, R., Jamieson, C. H., & Crews, L. A. (2021, January 20). Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Retrieved March 14, 2021, from https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30601-9#secsectitle0010 

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