On September 5, 2024 Leapfrog Bio, a clinical-stage precision oncology company, accelerating oncology drug development by identifying novel therapies for undruggable cancer-driving mutations, reported a publication in Nature PJ Precision Oncology describing and validating its Precision PGx Platform, a novel pharmacogenomic approach to screening and discovering drug-genotype combinations that are clinically actionable and demonstrate the potential to significantly impact overall survival for cancer patients (Press release, Leapfrog Bio, SEP 5, 2024, View Source [SID1234646371]). The platform evaluates cancers resulting from LoF mutations and leverages real driver biology to expose hidden vulnerabilities that accompany these mutations and finds the drugs that exploit those vulnerabilities to destroy cancer cells.
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As outlined in the paper, the approach employs driver-focused CRISPR screens with and without drug in a pool of isogenically controlled cell lines, using next-generation sequencing (NGS) to identify genes that cause cells to ‘drop out’ of the pool when mutated and treated with a particular drug. Proof-of-concept experiments using PARP (poly-ADP ribose polymerase) inhibitors – the only drug class currently directed at cancers with LoF mutations – allowed the team to technically optimize their pharmacogenetic approach. They then applied the platform to approved cancer drugs for which real-world data was available and showed that platform-discovered genetic sensitizers impacted patient survival.
"This was a pivotal moment for me," says Tomas Babak, CSO of Leapfrog Bio and corresponding author. "Not only did we see 100% validation in mouse xenografts, but our platform was able to point out which patients would respond best to specific drugs based on the genetic drivers of their tumors. Unlike traditional synthetic lethality screening, which is based on testing combinations of gene knockouts, pharmacogenomic interactions capture the effects of drugs, which can be far more complex than a simple genetic knockout."
"Two-thirds of cancers are caused by a loss of function mutation in a tumor suppressor gene, where the absence of a functional protein results in tumor growth. Due to the challenge of developing a targeted drug that treats a disease caused by the absence of a protein target, most patients with tumors caused by loss-of-function mutations do not have access to genetically targeted therapies," said Greg Vontz, CEO of Leapfrog Bio. "Our precision PGX Platform addresses this area of tremendous patient and clinician need."
Mr. Vontz continued, "There are more than 2,400 clinical stage cancer therapeutics that have not advanced to FDA approval due to lack of efficacy but were generally safe and well tolerated. After screening only a small portion of these molecules, Leapfrog has identified several compelling opportunities and has filed corresponding intellectual property applications around the discoveries."