On December 10, 2024 Leapfrog Bio, a clinical-stage precision oncology company identifying novel therapies for undruggable cancer-driving mutations, reported that Tomas Babak, PhD, the Company’s Chief Scientific Officer, will present evidence that Leapfrog Bio’s Precision PGx Platform discovered a clinically significant link between the EP300 gene and bromodomain and extra-terminal domain (BET) protein inhibitors (Press release, Leapfrog Bio, DEC 10, 2024, View Source [SID1234648988]). The presentation titled, "EP300 loss of function is a pan-cancer sensitizer to BET inhibition," will take place at the AACR (Free AACR Whitepaper) Special Conference in Cancer Research in Toronto, Canada and will focus on the discovery, characterization and clinical development plan for Leapfrog Bio’s BET inhibitor LFB-190 to treat solid tumors with EP300 loss of function.
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Loss of transcriptional control is a hallmark of cancer and can be an essential driver of cancer initiation and progression. BET proteins regulate the expression of multiple cancer-related genes and pathways; several molecules targeting this family of proteins have been tested in early phase clinical trials, although these molecules had shown limited clinical success as monotherapies. After conducting hundreds of pharmacogenetic screens using its Precision PGx Platform, Leapfrog Bio discovered an interaction between BET protein inhibition and the EP300 gene loss of function (LOF) similar to PARP-BRCA1/HRD in significance. The Company believes it has also discovered the mechanism of action for this synthetically lethal relationship between BET protein inhibition and EP300 LOF.
"It was gratifying to identify this essential interaction, as there has been so much research and activity related to BETs inhibitors," said Tomas Babak, PhD, CSO of Leapfrog Bio. "Discovering a strong interaction between BET proteins and the mutated EP300 gene resulting in LOF—as well as the mechanism that drives it—using the Precision PGx Platform is a meaningful validation of the platform’s ability to identify therapies for previously undruggable cancers caused by LOF mutations. Two-thirds of all cancers are caused by mutations in tumor suppressor genes, such as what we see here with EP300, yet less than one percent of LOF tumor suppressor genes have been drugged to date. With Leapfrog Bio’s platform, we can repeatedly uncover candidates that address the unmet needs of patients with cancers caused by LOF mutations."
Leapfrog’s Lead Candidate, LFB-190, exploits the relationship between BET inhibition and EP300 LOF mutations. The Company’s Phase 2-ready compound was clinically studied prior to Leapfrog’s research and a recommended Phase 2 dose has been established.
Greg Vontz, CEO of Leapfrog Bio added, "This discovery demonstrates the ability of the Precision PGx Platform to uncover potential therapeutic solutions for the 10M patients with cancers driven by LOF mutations. We have filed IP around this discovery and are currently preparing for LFB-190’s entry into Phase 2 in lung, colon and bladder cancers in 2025."