SAN DIEGO--(BUSINESS WIRE)--Boundless Bio, a clinical stage next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in oncogene amplified cancers, today will present at the American Association for Cancer Research (AACR) Annual Meeting 2023, held in Orlando and virtually from April 14-19, 2023. The poster “Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition” is available for in-person presentation on April 17, 2023 at 9:00 a.m. - 12:30 p.m. ET.
"We are excited to unveil CHK1 as the ecDNA-essential target for our first novel ecDNA-directed therapy (ecDTx),” said Christian Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. “Leveraging our proprietary ecDNA-centric research platform, Spyglass, we identified CHK1 as an essential regulator of replication stress associated with oncogene amplification on ecDNA, revealing a unique, druggable, and cancer-specific liability. Our research revealed that ecDNA-enabled cancers have an exquisite reliance on CHK1 to manage intrinsically elevated replication stress, and this important discovery has led to the development of the first ecDTx, BBI-355. BBI-355, a potentially best-in-class, oral, and selective CHK1 inhibitor, is the subject of a recently initiated first-in-human Phase 1/2 clinical study.”
Patients with tumors that harbor oncogene amplification on ecDNA have poor prognosis and generally do not respond well to targeted therapies and possibly immunotherapies. Boundless Bio has previously presented the relationship between oncogene amplification on ecDNA and DNA replication stress, a known form of genomic instability that contributes to oncogenesis and tumor evolution. Today we present data showing that cancer cells with oncogenes amplified on ecDNA are hyper-reliant on CHK1 to survive and that inhibition of CHK1 in ecDNA-enabled cancer cells is synthetically lethal. Using our Spyglass platform, we identified CHK1 as an ecDNA essential drug target through a CRISPR genetic screen and further pharmacologically validated its essential role in multiple ecDNA model systems across various tumor types and oncogene drivers.
We designed BBI-355, an orally available, highly potent, and selective inhibitor of CHK1 to target this unique genetic susceptibility in ecDNA-bearing cancer cells. In January of this year, the FDA accepted our investigational new drug application to enable the BBI-355-101 Phase 1/2 clinical trial of BBI-355, which is now open for enrollment of patients with oncogene amplified solid tumors.
About Extrachromosomal DNA (ecDNA)
ecDNA are circular units of nuclear DNA that are physically distinct from chromosomes and are found only within cancer cells. ecDNA encode full length genes, including oncogenes and regulatory regions, are highly transcriptionally active, and lack centromeres. ecDNA replicate and express within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and gene copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells can increase or decrease copy number of select genes located on ecDNA to enable survival under selective pressures, including targeted therapy, chemotherapy, or radiation, thereby making ecDNA one of cancer’s primary mechanisms of growth and treatment resistance. ecDNA are not found in healthy cells but are present in many cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.
BBI-355 is a potentially best-in-class checkpoint kinase 1 (CHK1) inhibitor and the first ecDNA-directed therapy (ecDTx) being investigated to treat patients with oncogene amplified cancers. CHK1 is a master regulator of DNA replication stress (RS), which frequently arises from oncogene amplification on extrachromosomal DNA (ecDNA). Inhibition of CHK1 by BBI-355 is synthetic lethal in cancer cells with oncogene amplification on ecDNA due to their heightened RS. CHK1 was identified and validated as an ecDNA essential target via Boundless Bio’s proprietary Spyglass platform and led to the development of BBI-355, an orally available, potent, and selective inhibitor of CHK1. BBI-355 is currently being evaluated in a first-in-human trial designed to evaluate the safety, maximum tolerated dose, and recommended Phase 2 dose of BBI-355 as a single agent and in combination with select therapies in patients with locally advanced or metastatic solid tumors with oncogene amplifications.
About Boundless Bio
Boundless Bio is a clinical stage next-generation precision oncology company dedicated to the discovery and development of new drugs targeting a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies intended to improve and extend the lives of patients with oncogene amplified cancers.
For more information, visit www.boundlessbio.com.