Starving CML stem cells to overcome therapy resistance
Chronic myeloid leukemia (CML) occurs when parts of two chromosomes switch places to produce the “Philadelphia chromosome” and the cancer-causing BCR-ABL gene. Current therapies, known as tyrosine kinase inhibitors (TKIs), include imatinib (Gleevec®) and subsequent, more potent agents. These are highly effective in chronic phase CML patients and the five-year survival rate is more than 90 percent. However, the treatments are not curative and if discontinued, the disease generally recurs due to a small number of CML stem cells that resist therapy.
Dr. Xiaoyan Jiang, senior scientist at the British Columbia Cancer Agency, is using a new approach to target blood cancer stem cells that survive after treatment. Funded by Leukemia & Lymphoma Society of Canada, Dr. Jiang is investigating autophagy (au-TAH-fa-jee), a process that enables cells to recycle proteins and release nutrients to counteract cell death. Although autophagy is a well-studied process, its role in regulating the formation of blood cell components and developing leukemia has yet to be fully explored.
Dr. Jiang hypothesizes that CML stem/progenitor cells harbour a unique autophagy gene known as ATG4B that could predict patient response to TKI therapy and serve as a new therapeutic target. Using a technique known as knockdown, ATG4B expression can be reduced by genetic modification and thus block the fuel needed by the stem cells to survive.
Dr. Jiang and her colleagues have identified several ATG4B inhibitors and are testing whether the combination of TKIs and ATG4B inhibitors will inhibit the growth of BCR-ABL stem cells and block leukemia development. If successful, this can present a new approach to overcome TKI resistance in CML.