New studies used CRISPR model to identify therapeutic targets for leukemic cell resistance

Scientists at the University of Kansas Cancer Center, KU Medical Science and Technology Center and KU’s Missouri Sane Disease Research Clinic collaborated to gain insights into ways to develop non-invasive therapies for battling acute myeloid leukemia (AML).

In a new study published in ME Clinical Cancer Research, the collaborators are exploring ways to improve therapies for leukemia – a disease that carries a five-year survival rate of less than 15% -by rewarding the leukemic cells for increasing the number of proteins they make. They report on the RBR4-dependent pathway that is improved by the pathway.

Cancer cells can transform into leukemia cells – a debilitating, and dangerous disease – by suppressing the expression of a protein called MYC. Mycoplasmic DNA is found within over 70% of ALL patients and over 90% of AML patients. To identify therapeutic targets for leukemia, the disease is best treated with T therapy. However, tumors often become resistant or develop resistance mechanisms that compromise results.

“Our study raises the possibility that activating the PI3K/Akt/S6 kinase pathway can be an effective strategy for reducing SAM-mediated leukemia,” said Daniela Duchennezi, professor of molecular medicine at the University of Kansas and principal investigator on the study.

In the study, the KU Lemaire Research Institute’s pro-growth and leukemia stem cell lines were treated with a combination of two known inhibitors of the Kras pathway – a gene that is impaired in acute lymphoblastic leukemia (ALL) and has repeatedly been used as a therapeutic target for leukemia – – histone deacetylase 3.4 and slice kinase 1.2.

“By targeting histone deacetylase 3.4 and slice kinase 1.2, we’ve managed to re-sensitize the leukemia stem cells to treatment and reduce their ability to become resistant,” said Matthew Fuchs, HIV Medicine and Genetics clinical research supervisor and lead author of the study.

“The investigators want to test if targeting the PI3K/Akt/S6 kinase pathway can be used to treat other cancer types, such as aggressive squamous cell lymphoma,” Freund’s Professor at KU’s Lemaire Research Institute and co-investigator on the study.

For the study, the team combined gene therapy and targeted therapy involved gene delivery to cultured leukemia stem cells. Gene therapy involves gene delivery into the bone marrow. Targeting therapy involves treating the cell with a drug that targets a specific protein expressed on the cancer cell surface.

Specifically, the NIH BRAIN Initiative-directed CRISPR-Cas9 system of gene delivery into human leukemia cells was used in this study. Chimeric antigen receptor (CAR) T cell therapy, which involves delivery of tumor-specific anti-tumor immune-stimulating factor-4 (ITF) to treat human acute lymphoblastic leukemia based on insights from a failure in CAR T cell therapy.