黑料吃瓜资源

黑料吃瓜资源 scientists, with chemists and cancer biologists from Dana-Farber Cancer Institute (DFCI), have developed a new therapy that extended the survival of mice with acute myeloid leukemia.

The scientists are the first to demonstrate the anti-cancer effect of blocking the Salt-Inducible Kinase 3 (SIK3) pathway in leukemia using YKL-05-099, a drug developed within the lab of Nathanael Gray at DFCI. SIK3 is a kinase that controls cell division and survival of leukemia cells. Blocking SIK3 prevents leukemia cells from growing.

鈥淥ur experiments validate that pharmacological blockade of SIK3 is well-tolerated and extends the survival of leukemic mice,鈥� said CSHL Professor Christopher Vakoc, who co-led the study with Kimberley Stegmaier at DFCI. Yusuke Tarumoto, a former postdoctoral researcher in Vakoc鈥檚 lab, and Shan Lu of Stegmaier鈥檚 lab are the co-first authors of the paper. Dr. Tarumoto is now a professor at Kyoto University. The team鈥檚 findings are published in the journal .

Vakoc refers to this type of leukemia treatment as epigenetic therapy, which can change gene activity within the cancer cell. 鈥淏ecause epigenetics is a cellular system that is malleable and dynamic, it’s something that we can modulate with drugs,鈥� he said. 鈥淒eveloping epigenetic cancer therapies is the core mission of my lab, with SIK3 inhibition in leukemia being our most recently developed strategy.鈥�

In 2018, the Vakoc lab used CRISPR genetic screening to identify the SIK3 kinase as a non-obvious leukemia drug target.

鈥淚t’s an under-studied signaling molecule in the pathogenesis of cancer because it鈥檚 not mutated in cancer,鈥� Vakoc said.

The subtype of leukemia the researchers focused on, MLL, is an aggressive form of cancer that occurs in infants and can be caused by an abnormal rearrangement of chromosomes, which is known as an MLL translocation. 鈥淲e discovered SIK3 has a very important role in the MLL translocation positive subtype of leukemia,鈥� Vakoc said.

The most important finding in this study is in revealing a drug development strategy for treating MLL leukemia.

The new compound created by the team to target SIK3 reprograms a transcription factor, which is a protein that can help turn specific genes on or off by binding to DNA. Vakoc鈥檚 lab has been at the forefront of trying to reprogram transcription factors in cancer therapy.

鈥淚t’s widely considered that this is impossible to do,鈥� he said. 鈥淥ur lab wants to challenge that idea.鈥�

The study also helped researchers gauge the side effects of the drug. After using YKL-05-099 to suppress SIK3 in mice for a month, the researchers observed the drug to be well-tolerated, not causing any weight loss or significant changes to the animal鈥檚 normal blood production.

鈥淲e took a basic science idea that we published in a paper last year and now we’ve shown that it may have some usefulness in the clinic,鈥� said Vakoc. 鈥淭his new study advances our fundamental science towards clinical application, and it鈥檚 a very important milestone in that process.鈥�

Written by: Charlotte Hu, Content Developer/Communicator | [email protected] | 516-367-8455

Funding

This research was funded by the CSHL NCI Cancer Center, the Forbeck Foundation, Pershing Square Sohn Cancer Research Alliance, National Institutes of Health, the Leukemia & Lymphoma Society, and the Lauri Strauss Leukemia Foundation.

Citation

Tarumoto et. al, 鈥淪alt-Inducible Kinase inhibition suppresses acute myeloid leukemia progression in vivo鈥� appeared in Blood on November 1, 2019.