Notch inhibitors like gamma-secretase inhibitors (GSIs) are found potential to slow the deterioration of various types of cancer recent studies revealed. Now further study for more accurate information about this application is undergoing, in which different cancer types are involved. A paper published in Cold Spring Harbor Molecular Case Studies presented a patient case about the effect of GSIs on the condition improvement of acute lymphoblastic leukemia.
Notch signaling is the essential element in the development of T-cells. However over activity of notch signaling may bring the risk for cancer, which inspired scientists to make use of notch inhibitor to treat cancer. The patient who participated in the study mentioned above was diagnosed with T-cell precursor leukemia in early stage when he was 53 years old. And no chemotherapy was found effective to suspend the deterioration. Then he was enrolled into the clinic trial for the notch inhibitor BMS-906024 treatment. Improvement was found in the patient soon after he began the trial and he accepted stem cell transplantation after three courses of BMS-906024 treatment. Then, the patient was exempted from the disease for 19 months.
Further study of this patient condition, four mutations were found possible for the cancer progression with the exome sequencing on the leukemic cells of the patient. Hyperactive signaling was traced to one of the four mutations in Notch1 gene. Duplicated version of the mutation was found in the cancer genome, which was the cause of over expression. With the application of gamma-secretase inhibitor, no appearance of Notch 1 mutation was found.
In addition, molecular level reaction to GSIs was inspected by the scientists and they found that Notch1 protein was decreased vastly. Whilst, RNA-seq analysis showed that Notch targeted genes reacted actively to the GSIs treatment.
This case furtherly suggested the effect of Notch inhibitor on the improvement of cancer. And deep study on the mutations showed the mechanism of the novel cancer treatment. At present, a relatively larger scale of clinic trial is performed, and the result will be released once the effect of GSIs on cancer can be ensured.
The study was co-conducted by scientists from the Dana-Farber Cancer Institute, Stanford University, Brigham and Women's Hospital and the paper is initially available in cshlpress.org titled as Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case with the doi number 10.1101/mcs.a000539
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