A new investigational drug co-developed by Frederick National Laboratory for Cancer Research (FNL) scientists blocks an intracellular RAS signaling pathway known to drive the growth of many types of cancer and is now being tested in humans.
BBO-10203 is the second drug candidate targeting RAS-related cancers developed by the RAS Initiative in partnership with BridgeBio Oncology Therapeutics (BBOT) and Lawrence Livermore National Laboratory (LLNL). This compound is being evaluated in a phase 1 clinical trial, the BREAKER-101 study, a first-in-human trial to assess its safety, tolerability, and potential antitumor activity.
This clinical trial is currently enrolling adult patients with advanced solid tumors like metastatic breast cancer, lung cancer, and colorectal cancer.
The drug blocks the cancer-driving RAS-PI3K pathway, which is notoriously challenging.
KRAS and PIK3CA are among the most frequently mutated genes in human cancer. The PIK3CA gene produces the phosphatidylinositol 3-kinase alpha (PI3Kα) protein.
Scientists have known for 30 years that mutated RAS and PI3Ka proteins interact as part of a signaling pathway that promotes cancer growth. To develop a drug to disrupt this pathway, scientists first needed to determine the 3D structure of the RAS and PI3Kα bound to each other.
This was difficult to achieve because the interaction between these two proteins is weak and falls apart during protein crystallization, a technique used to resolve molecular structure.
Dhirendra Simanshu, Ph.D., who leads the RAS structural biology group within the RAS Initiative at FNL, spent years working with his team to determine the RAS-bound PI3Kα structure. In 2019, pharmaceutical company Daiichi Sankyo Co. shared with RAS Initiative lead consultant Frank McCormick, Ph.D. several of its compounds that acted like glue and strengthened RAS-PI3Kα binding. With this “molecular glue” stabilizing RAS and PI3Ka during crystallization, Simanshu and his team solved the first structure of this complex.
Upon analyzing the structure of the RAS-PI3Ka complex bound to glue, Simanshu and team noted that more than 80 percent of the compound was bound to PI3Ka. This gave him the idea to chemically alter the molecular glue to instead force the two proteins apart, creating a “breaker” compound to disrupt the RAS-PI3Ka interaction and block this cancer-driving pathway.
This project became a strategic objective of the FNL RAS Initiative. It was folded into an existing Collaborative Research and Development Agreement (CRADA) with BBOT and LLNL for medicinal chemistry, pharmacology, and computational chemistry support. This collaborative effort focused on improving the compound through several iterations, ultimately developing BBO-10203. Unlike other cancer treatments that target PI3Kα, BBO-10203 slows tumor growth without affecting blood sugar levels.
As part of the standard preclinical evaluation of a potential drug, the team tested the compound across various human cancer cell lines. While it demonstrated substantial activity against KRAS- and PIK3CA-mutant cancer cells, the most pronounced response was observed in a breast cancer cell line with HER2 (human epidermal growth factor receptor 2) amplification.
This was unexpected, as this cancer type is not typically driven by oncogenic RAS, Simanshu noted.
“This suggests there is an aspect of HER2 in breast cancer biology that we still do not fully understand, which this compound appears to be exploiting,” said Simanshu, adding that many scientists are investigating why it is particularly effective in this cancer type.
Currently, BBO-10203 is being evaluated in clinical trials as a monotherapy as well as in combination with trastuzumab, which targets the HER2 protein.
The RAS Initiative at FNL is 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, established by the National Cancer Institute. Led by Dwight Nissley, PhD at FNL, the RAS Initiative investigates RAS biology, its structure, and related pathways to identify strategies for blocking its cancer-driving activity.
“Structural analysis of RAS, alone and bound to other proteins, has advanced the understanding of the molecular mechanisms that regulate RAS function,” said Nissley, who also leads the FNL’s Cancer Research Technology Program. “Simanshu and his team have made fundamental discoveries in RAS structure published in high-impact journals, enabling advances by FNL scientists and collaborators in the RAS Initiative.”
While it's uncommon for an idea to become a clinical candidate in just a few years, “it requires a dedicated, multi-disciplinary team of scientists working together to make it happen," Simanshu said. He has been part of the RAS Initiative since 2014.
Simanshu credits the eventual development of BBO-10203 to the collective efforts of numerous scientists from FNL, BBOT, and LLNL, who have worked in a highly collaborative manner over the past five years. This study has recently been accepted for publication in Science.
Along with Simanshu, other FNL RAS Initiative investigators involved in the RAS-PI3Kα breaker project include Daniel J. Czyzyk, Wupeng Yan, John-Paul Denson, Brian P. Smith, Maria Abreu-Blanco, Swapnil Singh, Jayasudhan Reddy Yerabolu, Dana Rabara, Marcin Dyba, Erik K. Larsen, Nicole Fer, Albert Chan, Sathiya Dharmaiah, Trent Balius, Allison Champagne, Dominic Esposito and his team at the Protein Expression Laboratory, David M. Turner, Andrew G. Stephen, Anna E. Maciag, Dwight V. Nissley, and Frank McCormick.
Several scientists from BBOT, including Rui Xu, James Stice, Kerstin Sinkevicius, Eli Wallace, and Pedro Beltran, played a major role in the development of the breaker, with BBOT currently sponsoring the clinical trial. Yue Yang and Felice Lightstone from LLNL contributed by utilizing the laboratory's advanced supercomputing resources to support the development of the breaker.
FNL, BBOT, and LLNL also collaborated on BBO-8520, an investigational inhibitor that targets KRAS G12C, the most common KRAS variant in lung cancer, and which began testing in clinical trials in June 2024.
Mary Ellen Hackett Manager, Communications Office 301-401-8670