Project description:Pediatric blood cancers are among the most common malignancies that afflict children. Intensive chemotherapy is not curative in many cases, and novel therapies are urgently needed. NK cells hold promise for use as immunotherapeutic effectors due to their favorable safety profile, intrinsic cytotoxic properties, and potential for genetic modification that can enhance specificity and killing potential. NK cells can be engineered to express CARs targeting tumor-specific antigens, to downregulate inhibitory and regulatory signals, to secrete cytokine, and to optimize interaction with small molecule engagers. Understanding NK cell biology is key to designing immunotherapy for clinical translation.
Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells Gene expression profiling using sorted B cells, Natural killer cells and Natural killer B cells from WT mouse spleen. Total RNA extracted from WT cells were quantified by the NanoDrop ND-1000 and RNA integrity was assessed by standard denaturing agarose gel electrophoresis. The sample preparation and microarray hybridization were performed based on the NimbleGenâs standard protocols.
Project description:Development of novel PI3Ks inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We studied the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines by RNA-Seq, mass spectrometry, biochemical pull-down assays, and CRISPR/Cas9 gene knock-out. We demonstrated that the PI3Kgamma isoform was identified as a direct target of Brusatol, and inhibition was lost on PI3Kgamma deficient cells. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. They also had minimal toxicity to normal human cells. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.