Apeiron team will attend AACR 2023 in Orlando, FL on April 18th 2023.
Dr. James D. Joseph, Executive Director of biology will present our latest research on targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers. Dr. Fred Aswad, SVP of biology and Dr. Minghua Wang, Director of AIDD will be available to meet with you there as well.
Stay tuned for Apeiron poster:
Abstract Title: Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers
Session category: Experimental and Molecular Therapeutics
Session title: Novel Targets and Pathways
Published abstract number: 4965
Session date & time: April 18, 2023, 1:30 PM – 5:00 PM
Chromosome instability (CIN), characterized by frequent and ongoing loss or gain of chromosome number, is commonly observed in tumor cells. Although long recognized as a vulnerability of cancer cells, potential CIN-selective therapeutic targets have only recently been discovered. Genetic studies from multiple groups have identified the mitotic kinesin, KIF18A, as selectively essential for the proliferation of CIN and aneuploid cells. By targeting KIF18A genetically and with novel small molecule inhibitors here we present data supporting KIF18A as therapeutic target in CIN tumors.
– Methods and Materials:
To explore the therapeutic potential of KIF18A, we evaluated the effects of KIF18A genetic depletion and small molecule inhibition in both CIN-positive and CIN-negative cell lines. Biochemical, cell proliferation and phenotypic assays were used to characterize the potency and cellular activity of reference and novel KIF18A small molecule inhibitors. Anti-tumor activity of KIF18A inhibitors was assessed in CIN-positive cell line xenograft models.。
In triple negative breast and colorectal CIN positive cancer cell lines siRNA mediated KIF18A knockdown and small molecule inhibition of the KIF18A ATPase activity both lead to a reduction in proliferation associated with an increase in mitotic index and multi-polar spindles. Consistent with KIF18A knockdown, KIF18A inhibition results in increased spindle length and chromosome alignment defects. Importantly, these effects are not observed with KIF18A knockdown or KIF18A inhibition in non-transformed, near diploid cells. In vivo, treatment of CIN-positive xenograft tumors with potent, novel KIF18A inhibitors results in robust anti-tumor activity with minimal impact on body weight.
Collectively our data support KIF18A as a therapeutic target and provide rationale for the continued development of potent selective small molecule KIF18A inhibitors for the treatment of CIN positive cancers.
The AACR Annual Meeting 2023 (American Association for Cancer Research) being held in Orlando, Florida from April 14-19, 2023, is the focal point of the cancer research community.
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