VANCOUVER, BRITISH COLUMBIA – March 31, 2021 – SignalChem Lifesciences Corporation (“SLC”) is pleased to announce that a paper entitled “Targeting AXL Kinase Uniquely Sensitizes Therapy-Insensitive Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia” has been published as First Edition by the journal “Blood” today. The research work described in this paper is the collaboration between University of British Columbia and SLC and it was supported by MITACS Accelerate program.
In this study, we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in stem/progenitor cells. We developed a potent, selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.
“This new study has uncovered that AXL, one of key cancer drivers, is abnormally activated in blood cancer cells from AML patients, a difficult disease to treat. In this study we found that both genetic inhibition of AXL and the use of a highly selective AXL inhibitor SLC-391, in combination with a BCL-2 inhibitor (venetoclax) preferentially eliminate AML blast cells from drug-insensitive patients both in vitro and in preclinical PDX models, while not being toxic to healthy bone marrow cells. This new combination treatment approach may lead to more effective disease eradication, especially in patients at high risk of drug resistance and disease progression. Encouragingly, SLC-391 is currently being evaluated in a Phase I clinical trial in solid tumors, which opens a promising avenue for combination cancer therapies,” commented by Professor Xiaoyan Jiang in the Department of Medical Genetics of the University of British Columbia and Distinguished Scientist at BC Cancer, the senior author and the principal investigator of this paper. “We are very pleased with the recognition of this discovery by Professor Jiang’s lab in collaboration with SLC. We are going to pursue the clinical research in combination therapy of SLC-391 with a putative BCL-2 inhibitor in this AML patient population and hope that it will provide another valuable therapy to fight against this terrible disease,” said Mr. Jun Yan, President of SLC, “We have been working very hard to develop new anti-tumour therapies which provide superior advantages over the existing treatments.”
SLC-391 is clinical stage small molecule AXL inhibitor with good potency and selectivity with desirable pharmaceutical properties. It has good selectivity against other tyrosine kinases. The pharmacokinetic studies in rodents and dogs indicated that SLC-391 has high bioavailability with a simple suspension formulation (>50%). The in vivo studies demonstrated efficacy in different animal models including NSCLC, CML and AML models. Moreover, it has exhibited a strong synergistic effect in tumour growth inhibition in combination with erlotinib and paclitaxel in NSCLC xenograft models and demonstrated a strong synergistic effect in decreasing leukemia burden and enhancing survival of leukemic animals in a novel combination approach with BCL-2 inhibitor venetoclax in aggressive xenotransplant AML leukemic models and PDX models. In a CT-26 colon cancer syngeneic model, SLC-391 played a role in modulating both the innate and adaptive immune responses and demonstrated a synergistic effect in tumour growth inhibition and overall survival in combination with an anti-PD-1 antibody. In addition, SLC-391 promotes anti-tumour immunity through modulation of tumour-associated macrophage polarization. Currently, SLC-391 is under phase I safety clinical evaluations in multi-cancer centres in Canada and the dose expansion phase is anticipated to be complete by Q3/2021.
SignalChem Lifesciences Corporation (“SLC”) is a multi-platform, clinical-stage, drug discovery and development company focusing on development of next generation of novel, small molecule kinase inhibitors as targeted therapy for the treatment of cancer. SLC has a strong small-molecule drug development pipeline. SLC is seeking strategic partners to aid in bringing our clinical-stage drug pipeline to the market.
SignalChem Biotech Inc. (https://www.signalchem.com), a separate division from SignalChem Lifesciences, is a biotech company focused on the research, development and production of innovative and high-quality human recombinant cell signaling products. Throughout the years, SignalChem has capitalized on its core expertise in cellular signaling, molecular biology and protein biochemistry to generate more than 3,000 functional protein products.
SignalChem strives to support scientists in academia, pharma and biotech companies around the world by creating effective research tools to advance the basic research in life sciences and to facilitate the efforts in drug discovery and development.
For more information, please visit https://www.signalchemlifesciences.com.
Forward-Looking Statements and Information
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Zaihui Zhang, PhD
CSO, VP R & D
SignalChem Lifesciences Corp.
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