On April 28, 2025 Edgewood Oncology, a clinical-stage biotechnology company focused on delivering BTX-A51 to patients with hematologic malignancies and genetically-defined solid tumors, reported the presentation of new preclinical data presented by Dana-Farber Cancer Institute and Hebrew University-Hadassah Medical School in support of an ongoing investigator-sponsored Phase 1 study of BTX-A51 in liposarcoma (LPS) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 25-30, 2025, in Chicago (Press release, Edgewood Oncology, APR 28, 2025, View Source [SID1234652229]).
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BTX-A51 is a first-in-class, small molecule kinase inhibitor that co-targets casein kinase 1 alpha (CK1a) and cyclin-dependent kinases 7 and 9 (CDK7 and CDK9), three master regulators of cancer cell survival and transcriptional control.
The presentation, "Therapeutic potential of combined targeting of casein kinase 1 alpha (CK1a) and CDK7/9 with the inhibitor BTX-A51 in human liposarcomas," highlights new mechanistic and efficacy data in patient-derived cell lines and xenograft models. One of the most significant findings from the presentation is that CK1a is an essential gene for the growth of liposarcomas based on genome-scale RNAi perturbation analysis. The study also used RNAi knockdown and targeted small molecules to confirm that inhibition of CK1a, CDK7, and CDK9 has synergistic impacts on LPS cell survival. As a single agent, BTX-A51 blocked MDM2 and induced P53 expression, stimulating potent apoptosis in LPS models while significantly inhibiting tumor growth in patient-derived xenografts at well tolerated dose levels.
"Well-differentiated and dedifferentiated liposarcomas (WD/DDLPS) remain among the most challenging soft tissue sarcomas to treat," said Geoffrey I. Shapiro, M.D., Ph.D., Professor of Medicine, Harvard Medical School, and director of the Early Drug Development Center at Dana-Farber Cancer Institute. "This study identifies novel, targetable vulnerabilities in LPS and offers a compelling justification for the clinical evaluation of BTX-A51 in this patient population."
BTX-A51 is currently being evaluated in an open-label, investigator-sponsored Phase 1 pilot study at Dana-Farber Cancer Institute in patients with metastatic and/or recurrent liposarcomas characterized by Murine Double Minute Clone 2 (MDM2) amplifications. Additional details about the study can be found at clinicaltrials.gov under the identifier NCT06414434.
"These findings strengthen the rationale for BTX-A51’s mechanism of action and support its potential across a spectrum of genetically defined cancers," said David N. Cook, Ph.D., Chief Executive Officer of Edgewood Oncology. "We’re encouraged by the strength of these preclinical findings, which further support the ongoing clinical advancement of BTX-A51."
Additional Details about the Study
Through computational and experimental methods, including DepMap screening, siRNA silencing, and small-molecule inhibitor profiling, the study confirmed that CK1α, CDK7, and CDK9 are essential for LPS survival. CK1a knockdown by itself was shown to be toxic to LPS cell lines and CDK9 inhibition alone suppressed LPS cell growth and induced apoptosis by downregulating MDM2 and activating p53. When CK1α depletion and CDK9 inhibition were combined, the potency of the individual approaches was amplified. In addition, combining CDK7 and CDK9 inhibitors synergistically inhibited LPS cell lines. These observations led to the evaluation of BTX-A51, which inhibits all three kinases with nanomolar potency. BTX-A51 robustly reduced MDM2 expression and induced expression of p53 and PUMA. The compound also lowered MCL1 expression and sensitized cells to apoptotic signaling through BIM and PUMA, as confirmed by BH3 profiling. In vivo studies in two LPS PDX models demonstrated that BTX-A51 is well tolerated and inhibits tumor growth under clinically relevant dosing conditions.