New Drug Combination Shows Promise in Acute Lymphoblastic Leukemia

Highlights:

• The anti-malarial drug dihydroartemisinin increases the sensitivity of lymphoblastic leukemia cells to the BH3-mimetic ABT-263
• The combination improves survival in mice with the cancer
• The combination could possibly improve outcomes in patients with Philadelphia-chromosome positive acute lymphoblastic leukemia

Scientists have found that a drug used for the treatment of malaria called dihydroartemisinin sensitizes the cancer cells of Philadelphia-chromosome positive acute lymphoblastic leukemia to an investigational molecule called ABT-263. Further research in the direction could result in the development of a combination of medications that could improve the outcomes of the potentially fatal cancer. The study was published in the Clinical Cancer Research. New treatment options are being evaluated for the treatment of acute lymphoblastic leukemia (ALL), a type of blood cancer, with the hope of improving outcomes in afflicted patients. Among these are the BH3-mimetics which include navitoclax (ABT-263) and venetoclax (ABT-199). These drugs target molecules on the cancer cells called anti-apoptotic molecules. Navitoclax targets BCL-2, BCL-XL and BCL-W, while venetoclax targets BCL-2. Anti-apoptotic molecules prevent the cell death and increase the survival of the cancer cells. ABT-263 has the disadvantage that it reduces platelet counts. These drugs are still under development.

Another molecule on cancer cells called MCL-1 increases the resistance of the cancer cells to the treatment with BH3-mimetics. Therefore, drugs that block this molecule could increase the sensitivity of the cancer cells to the treatment. Exclusive MCL-1 inhibitors are still under development.

Scientists studied the effect of dihydroartemisinin an anti-malarial drug in combination with the BH3-mimetic ABT-263 on mouse and human BCR-ABLþ lymphoblastic leukemia cells, as well in a mouse model with the cancer. This type of leukemia, also called Philadelphia-chromosome positive leukemia, has poor outcomes.

The scientists found that:

• Dihydroartemisinin reduced the expression of the MCL-1 molecule, thereby increasing the sensitivity of the leukemic cells to death induced by ABT-263. It induces a protein called CHOP and triggers a cellular stress response that blocks protein synthesis. Resistance to treatment with ABT-263 was not noted in the cells treated with the combination
• The combination increased the survival duration of the mice with the cancer

The combination of DHA with ABT-263 thus appears to be effective in the treatment of ALL associated with poor outcomes.

It must be remembered that other normal cell types are also dependent on MCL-1 for their survival. Therefore, the treatment could have adverse consequences on the normal cells. The scientists selected dihydroartemisinin to reduce the MCL-1 expression since it is already approved for the treatment of malaria, and is therefore likely to be associated with acceptable side effects.

Further developments in this direction could result in better outcomes for ALL patients that are positive for the Philadelphia chromosome.

About Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia, also called acute lymphocytic leukemia, is a type of blood cancer that affects a type of white blood cells called lymphocytes. The immature lymphocytes multiply in an uncontrolled manner and if the patient is not treated early, the cancer can progress quickly. The cancer affects children as well as adults. The symptoms include weight loss, fever, bruising, painless lumps, bone pain and extreme fatigue.

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The presence of the Philadelphia-chromosome increases the risk of developing ALL. The chromosome is formed due to the exchange of small parts of chromosomes between chromosome 22 and chromosome 9; the resultant chromosome 22 is the Philadelphia chromosome. The Philadelphia chromosome has the BCR-ABL gene at the point of attachment of the piece of chromosome 22 to chromosome 9.

The treatment options for ALL includes chemotherapy, radiotherapy chemotherapy with stem cell therapy, or targeted therapy.

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Reference:

1. Budhraja A et al. Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia. Clin Cancer Res (2017); 23(24); 1–11.

Source-Medindia