RAS drug discovery at Frederick National Laboratory reaches lung cancer patients in a clinical trial

An investigational treatment co-discovered by RAS Initiative scientists at the Frederick National Laboratory (FNL) is now being tested in patients with advanced non-small cell lung cancer driven by mutant KRAS G12C. 

BBO-8520 is being evaluated in a Phase1a/1b clinical trial, the ONKORAS-101 Study. It is a first-in-human study which seeks to determine the drug’s safety and tolerability and to detect potential antitumor activity. It was developed in partnership with BridgeBio Oncology Therapeutics (BBOT) and Lawrence Livermore National Laboratory (LLNL).  

The drug targets KRAS G12C, the most common KRAS variant in lung cancer. Laboratory assays conducted by the team led by Anna Maciag, Ph.D. within the National Cancer Institute’s RAS Initiative at FNL show BBO-8520 blocks the “ON” and “OFF” states of KRAS G12C, resulting in rapid KRAS inhibition. 

Results of more tests in several cancer models indicated the compound locks KRAS G12C in a conformation that is unable to drive tumor growth. And tests that detect the emergence of resistance to a drug showed that BBO-8250 was at least 30 times more potent than existing KRAS G12C treatments. Currently approved drugs block the KRAS G12C “OFF” state only. 

“By binding only to the ‘OFF’ conformation, existing treatments result in a patient developing resistance quite quickly,” resulting in cancer progression,” Maciag said. “This dual inhibitor hits the ‘ON’ and ‘OFF’ states simultaneously, providing 100 percent coverage of the target.”  

How a compound becomes a drug 

NCI established the RAS initiative in 2013 to explore and target the roughly 30% of cancers driven by mutations in RAS genes. FNL is at the center of the hub-and-spoke model of a worldwide collaboration to investigate the complexity of RAS biology and therapy through the RAS Initiative. 

FNL’s RAS Initiative team, led by Dwight Nissley, Ph.D., studies the biology of RAS, its structure and pathways to discover ways to inhibit its ability to drive cancer.  

The investigators are “excited to be part of the first FNL co-led effort that went from discovery of a compound to development of a cancer drug,” said Nissley, who also directs FNL’s Cancer Research Technology Program.  “We are deeply gratified to see many years of effort result in a drug candidate that is being tested in patients.” 

In discovering the compound that ultimately became BBO-8520, scientists used mass spectrometry technology to identify compounds that showed a strong inhibitory response when exposed to the KRAS protein. This process, called high-throughput screening, allows scientists to quickly determine which compound(s) are a “hit” against the KRAS and could be further developed into a drug. 

“We looked into disruption of specific cell signaling, downstream from RAS,” Maciag said. “If we see cell signaling shut down within 30 minutes we are on a good track.” 

Partners bring expertise to further develop a drug 

The “hits” discovered by FNL provided a baseline for BBOT chemists to then develop hundreds more compounds, each tested by FNL, before they landed on the lead compound, BBO-8520. BBOT has worked with FNL since 2017 under a Cooperative Research and Development Agreement to develop drugs that target KRAS. 

LLNL leveraged its high-performance supercomputing capabilities and the Livermore Computer-Aided Drug Discovery (LCADD) platform to simulate how the candidate compounds would function. This enabled the team to quickly and efficiently identify the lead compound. The three entities continue to collaborate on KRAS-related projects. 

“This partnership demonstrates the profound impact that HPC can have on developing innovative therapies to address some of the world’s most challenging diseases,” said LLNL Biochemical and Biophysical Systems Group Leader Felice Lightstone, a principal investigator on the project. 

BBOT is sponsoring the clinical trial, and Chief Scientific Officer Pedro Beltran is also a principal investigator. 

“Thanks to our collaboration with FNL and LLNL, we’ve reached a significant milestone in drug discovery for inhibiting KRAS mutations that lead to cancer.” Beltran said. “The discovery of BBO-8520 exemplifies the power of teamwork.” 

In addition to Maciag and Nissley, FNL RAS Initiative investigators on the BBO-8520 project include Alok Sharma, Albert Chan, Marcin Dyba, Brian P. Smith, Dana Rabara, Erik K. Larsen, Dominic Esposito, Maria Abreu Blanco, John Paul Denson, Patrick Alexander, David Turner, Dhirendra Simanshu, Andrew G. Stephen, and Frank McCormick.