Current treatments for acute lymphoblastic leukemia (ALL) eliminate cancer cells initially, but in many cases, the disease eventually recurs. Most chemotherapeutics do not distinguish between cancer cells and other frequently dividing cells, causing inadvertent damage to the existing immune system and bone marrow, epithelial cells, and GI tract. Thus, patients become immunosuppressed and vulnerable to infection and other malignancies, in addition to the side effects in their epidermis and GI system. An ideal treatment would selectively eliminate ALL cells without affecting the immune system. A small molecule inhibitor against the Artemis nuclease would specifically target ALL and early lymphoid cells without affecting the existing pool of mature lymphocytes. Early lymphocytes undergo V (D) J recombination, producing a diverse array of antibodies and T-cell receptors. Artemis is essential to opening the DNA hairpins created by RAG proteins in the chromosome. Inhibiting Artemis prevents the resolution of double-strand breaks (DSBs) during V (D) J recombination, resulting in chromosomal breaks. Slower proliferation and cell death has been observed in Artemis-deficient ALL cells. An Artemis inhibitor would selectively generate DSBs in RAG-expressing cells such as ALL and pre-B and pre-T cells. Mature lymphocytes and other cell types do not express RAG and will not be affected; humans born without Artemis are fine as long as they receive a replacement immune system via bone marrow transplantation, and as long as they do not receive chemotherapy or radiation, illustrating that a complete Artemis inhibitor would have minimal or no side effects for the patient. Hence, cancer cells will be specifically targeted without damaging the established immune system. Artemis is also important in resolving DSBs generated by radiation and etoposide, both of which are commonly used to treat cancer. An Artemis inhibitor would likely increase the sensitivity of lymphoid and non-lymphoid cancer cells to radiation therapy and etoposide treatment. A library of more than 433,000 compounds was screened for potential Artemis inhibitors. Candidate compounds are being evaluated using a gel-based biochemical assay. Counter-screen assays using other nucleases will select for Artemis-specific inhibition. These compounds will also be tested in cellular assays for their ability to kill primary ALL cells and inhibit V (D) J recombination. The overall goal is to developa small molecule inhibitor for Artemis to potentially target ALL cells without affecting the immune system. This inhibitor is also projected to work synergistically with radiation therapy and etoposide treatment to improve treatment efficiency in a wide range of epithelial, mesenchymal, and hematopoietic malignancies in addition to ALL.

Public Health Relevance

Statement Artemis is essential in generating antibody diversity in the immune system and in repairing double- stranded DNA breaks caused by radiation and type II topoisomerase inhibitors, both of which are commonly used to treat cancer. Our goal is to develop a chemical inhibitor for Artemis to selectively cause permanent chromosomal breaks in acute lymphoblastic leukemia (ALL) cells while causing little or no harm to normal cells throughout the body. An Artemis inhibitor would also increase the sensitivity of other cancer cell types to radiation and topoisomerase inhibitor treatments, and thus such an inhibitor would be of value not only for ALL patients but for patients with many other neoplasms as well.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Brown, Patrick
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University of Southern California
Schools of Medicine
Los Angeles
United States
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