CD98-New Target for Breaking the Supportive Microenvironment of Leukemia Cancer Cells

Acute myeloid leukemia (AML) is a type of highly invasive cancer. Due to abnormalities in the process of producing blood cells from the bone marrow, relapses and drug resistance often occur. Researchers at the University of California, San Diego (UCSD) have discovered that CD98, a cell surface protein expressed by AML cancer cells, promotes canceration, while CD98 antibody IGN523 can inhibit the growth of AML cancer cells in vitro and in mice. This result was published in the recent Cell sub-issue "Cancer Cell".

"To improve the treatment of this disease, we need to focus not only on the cancer cells themselves, but also their interactions with other surrounding tissues, cells, molecules and blood vessels," said Professor Tannishtha Reya, the corresponding author of the article. In this study, we revealed the key role of CD98 in promoting the growth of AML cancer cells, and found that blocking CD98 can effectively prevent cancer cells from acquiring nutrients from the surrounding environment, which is expected to inhibit its proliferation and improve patient survival. . "

Researchers point out that CD98 itself is related to the proliferation and regeneration of hematopoietic stem cells in the bone marrow. In the case of AML, CD98 seems to be the "accomplice" of cancer. Experiments have shown that CD98 is necessary for the survival of AML cancer cells. When it was knocked out, the expression of Bcl2L1 and Akt1 genes that suppress apoptosis in cancer cells suddenly decreased, while the expression of genes such as Casp1 that promoted apoptosis was up-regulated. Consistent with this, CD98 expression in mouse and human leukemia stem cells (LSCs) is significantly higher than normal hematopoietic stem cells.

In mouse experiments, the role of CD98 in AML has become more prominent. When CD98 was knocked out, the survival rate of AML model mice could be increased to nearly 50% at once, and the "cancer suppression" effect of CD98 knockout was still very obvious even after AML had occurred. Further analysis showed that the levels of leukemia stem cells in the above-mentioned CD98 knockout mice showed a significant decrease.

What molecular mechanism does CD98 have in AML? It turned out that AML cancer cells rely on integrin proteins on their surface to interact with their surrounding microenvironment, such as adhesion to the surface of blood vessel endothelium. When CD98 is knocked out, the above-mentioned effects of integrin no longer exist, so that the growth of AML cancer cells that are separated from the surrounding environment is inhibited, and even apoptosis occurs.

Thus, CD98 is a potential target for AML treatment. In fact, due to the over-expression of CD98 in a variety of cancer cells, the anti-cancer target potential of CD98 has been recognized by the medical community, but its specific molecular mechanism is unknown. Currently, Igenica Biotherapeutics is conducting a phase 1 clinical trial of the anti-CD98 humanized antibody IGN523, with indications for relapsed or refractory leukemia. Existing results show that IGN523 shows good security and preliminary effects. In addition, preclinical studies have also shown that when IGN523 is used in combination with the chemotherapeutic drug cytarabine, its anti-cancer effect can be significantly amplified, and it has also shown efficacy in mouse models of non-small cell lung cancer and colorectal cancer.

The anti-cancer effect of IGN523 was also supported in this study. IGN523 was found to significantly inhibit the proliferation of human AML cancer cells in vitro and the interaction with endothelial cells, and reduce its carcinogenicity in immunodeficient mice.

On the other hand, Professor Tannishtha Reya's team paid particular attention to the potential of IGN523 in the treatment of childhood leukemia. "Many of the AML mouse models we use are based on mutations that occur in children with leukemia," she said. "Although many pediatric cancers are currently being treated, pediatric leukemia still has a high recurrence rate and Mortality. We plan to work with pediatric cancer experts to test whether CD98 blockers can treat childhood leukemia, including the emergence of resistance, or to improve the anti-cancer effects of existing therapies. "