‘Pan-KRAS’ drug aiming at KRAS-related cancers lacking targeted therapies now being tested in humans

Patients with intractable cancers driven by mutations of the KRAS oncogene have few available therapies. Yet, an investigational compound co-developed by Frederick National Laboratory for Cancer Research (FNL) scientists and now in clinical trials may one day be a targeted treatment for KRAS-driven cancers. 

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BBO-11818 is a “pan-KRAS” inhibitor that acts against several KRAS mutants, including the most common KRAS^G12D and KRAS^G12V  in both their “ON” and “OFF” states.  Drugs targeting KRAS^G12C, the most common KRAS mutant in lung cancer, have shown promise in the clinic with two approved by the U.S. Food and Drug Administration and many others in development, including BBO-8520 co-developed at FNL. 

However, there are no approved targeted therapies against major cancer types driven by the other KRAS variants, including pancreatic, colorectal and non-small lung cancer. More than 90% of pancreatic ductal adenocarcinomas, the most common type of pancreatic cancer tumors, are driven by KRAS mutations. 

“The incidence of pancreatic cancer continues to rise, with approximately 50% of patients presenting with metastatic disease. There is no early screening for this cancer, like those available for colorectal or breast cancers,” said Anna Maciag, who led the FNL scientists in the pre-clinical study. “Targeted therapeutics hitting the driver mutation hard, in this case specific KRAS inhibitors targeting multiple mutans – so called pan-KRAS inhibitors – are an unmet clinical need.”   

BBO-11818 is the third drug candidate targeting RAS-related cancers developed by FNL scientists in the National Cancer Institute’s RAS Initiative, in partnership with BridgeBio Oncology Therapeutics (BBOT) and Lawrence Livermore National Laboratory (LLNL). Carlos Stahlhut, associate director at BBOT, presented a poster on preclinical studies of BBO-11818 at the American Association for Cancer Research annual meeting in April. The team is preparing the paper for publication. 

Clinical trials are also underway for investigational drugs BBO-8520, which targets KRAS^G12C, the most common KRAS variant in lung cancer and BBO-10203, which disrupts the cancer-driving signaling pathway caused by mutated RAS and PI3Ka proteins. 

“These three new drugs significantly expand the arsenal of agents and therapeutic approaches that can be studied and deployed against cancer,” said Dwight Nissley, who directs the RAS Initiative at FNL. “This work is the culmination of a strategic investment by NCI and FNL which was amplified through collaboration with BBOT and LLNL to push RAS Initiative discoveries into the clinic.” 

 BBO-11818 is being evaluated in a phase 1 clinical trial to evaluate its safety, and preliminary antitumor activity in patients with locally advanced unresectable or metastatic KRAS-mutant solid tumors.  

FNL scientists led by Maciag conducted biochemical and cell-based assays that confirm BBO-11818 is a strong force against several cancer-driving KRAS mutants, interrupting the signaling pathways that drive tumor progression.  

BBO-11818 alone substantial anti-tumor activity against pre-clinical models of KRAS-mutant pancreatic, non-small cell lung and colorectal cancers. When combined with BBO-10203 or targeted cancer drug cetuximab, BBO-11818 was even more effective against the KRAS^G12D and KRAS^G12V mutations in the examined models. It also showed considerable efficacy when paired with the immunotherapy anti-PD-1 treatment. 

In addition to Maciag, FNL authors include Roger Ma, Patrick Alexander, Megan Rigby, Alok Sharma, Albert Chan, Brian Smith, Dana Rabara, Erik Larsen, Andrew Stephen, Dhirendra Simanshu, Nissley and Frank McCormick.