What We Do
A New Approach To Cancer Treatment
We develop ecDNA-directed therapies (ecDTx) intended to transform the lives of patients with aggressive gene amplified cancers.
Boundless Bio is committed to improving and extending the lives of patients with oncogene amplified cancers. Our approach to doing so is by turning one of oncogene amplification driven cancer’s most enabling mechanisms, extrachromosomal DNA (“ecDNA”), into one of its critical vulnerabilities. We aim to disable ecDNA in cancer cells by developing a new wave of precision medicines called ecDNA-directed therapies (“ecDTx”).
The oncology field has long known that high copy number oncogene amplifications are associated with aggressive tumor growth and resistance to cancer treatments, but until recently the specific mechanism by which gene amplified cancers evade standard therapeutic intervention was not understood. Boundless Bio’s scientists and company founders discovered that ecDNA are one of the key culprits and are a differentiated feature of cancer cells that do not exist in normal cells.
Through our proprietary Spyglass platform, Boundless Bio has identified three distinct vulnerabilities of ecDNA-driven cancers: (1) ecDNA Replication Stress, (2) ecDNA Assembly and Repair, and (3) ecDNA Inheritance
ecDNA Replication Stress
Cancer cells with oncogene amplifications on ecDNA exhibit elevated levels of replication stress (RS), a cellular condition where the DNA replication process is dysregulated and leads to potentially toxic DNA damage to cells. As a consequence, ecDNA amplified tumor cells undergoing elevated RS invoke certain cellular RS response factors, which renders them hypersensitive to further modulation of those factors.
Our first ecDTx, BBI-355, is a novel, potent, selective, oral drug that inhibits checkpoint kinase 1 (CHK1), one of cells’ master regulators of DNA RS arising from ecDNA-based oncogene amplification. Inhibition of CHK1 by BBI-355 is synthetic lethal in ecDNA-enabled oncogene amplified cancer cells due to their exquisite reliance on CHK1 to manage their intrinsically elevated RS. This results in tumor growth inhibition and tumor regressions in multiple oncogene amplified mouse tumor xenograft models. In early 2023, we expect to enroll the first patient in our first in human (FIH), tumor-agnostic clinical study of BBI-355 in patients with oncogene amplified cancers. The study is called POTENTIATE (Precision Oncology Trial Evaluating Novel Therapeutic Impeding Amplifications Tied to ecDNA).
ecDNA Assembly and Repair
In order to maintain ecDNA, ecDNA-enabled cancer cells have increased demand for the raw materials normally used for DNA replication. Our second ecDTx, BBI-825, is a novel, potent, selective, oral drug that inhibits a rate-limiting enzyme that is essential for ecDNA assembly and repair. IND-enabling studies for BBI-825 are underway.
ecDNA lack centromeres, the structural component of chromosomes that is required for proper segregation during cell division. Thus, segregation and subsequent inheritance of ecDNA is dependent on alternative cellular mechanisms that Boundless Bio has begun to uncover. We have identified and validated a novel protein target essential for ecDNA inheritance whose inhibition is synthetic lethal to ecDNA-enabled cancer cells. We have a drug discovery effort directed to this novel target (ecDTx 3) and continue to leverage our Spyglass platform to identify additional targets required for ecDNA-enabled oncogene amplified tumors.
Boundless Bio, with its world leading understanding of ecDNA, is the only company delivering new therapeutic options to improve and extend the lives of patients with oncogene amplified cancers enabled by ecDNA.
What are ecDNA?
ecDNA are a primary site for activating oncogene amplifications in cancer.
ecDNA are large units of circular DNA that reside within the nuclei of cells yet are physically distinct from chromosomal DNA. They often range in size from 1-3 mega base pairs in length and can encode one or more full-length genes and regulatory regions. ecDNA have accessible chromatin and are highly transcribed, meaning they are fully functional and often more active than chromosomally located genes. ecDNA are one of the primary locations for high copy number focal oncogene amplifications in cancer cells; in fact, more than half of all high copy number amplifications in cancer occur on ecDNA.
Spyglass: the only-in-class platform built to identify vulnerabilities of ecDNA in cancer
Boundless Bio’s Spyglass platform consists of a comprehensive suite of proprietary ecDNA+/- models across tumor types and oncogene amplifications. Leveraging innovative molecular analytical technologies and imaging techniques, Spyglass enables characterization of ecDNA in cancer cells and provides a synthetic lethality-based approach to targeting ecDNA-bearing cancers. Through the use of Spyglass, Boundless Bio scientists have thus far identified and validated four distinct and druggable cellular targets that are essential to the function of ecDNA in cancer cells.
ecDNA are a cancer specific phenomenon
Absent in normal healthy tissue, ecDNA are found in 14% of primary cancers and >40% of metastatic cancers.
Driving high copy number gene amplifications and non-Mendelian genomic adaptation, ecDNA enable tumors to rapidly evolve and switch their oncogene dependency when under therapeutic pressure, thereby rendering current targeted and immunotherapy approaches largely ineffective in patients with gene amplified cancers.
ecDNA are the next frontier of precision medicine
ECHO (ecDNA Harboring Oncogenes) is a proprietary software system for detecting the presence of ecDNA oncogene amplifications using routine clinical next-generation sequencing (NGS). ECHO is the first portable precision medicine tool for identifying ecDNA amplified oncogenes and built to be deployable at clinical trial sites or commercial laboratories.
In our mission to deliver transformative precision therapies to patients with aggressive oncogene amplified cancers, ECHO is a vital tool in the development of our ground-breaking ecDTx candidates.
Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers
Kim, Nguyen, Turner 2020 Nature GeneticsRead
Circular ecDNA promotes accessible chromatin and high oncogene expression
Wu 2019 NatureRead
Extrachromosomal oncogene amplification drives tumor evolution and genetic heterogeneity
Turner 2017 NatureRead
Extrachromosomal oncogene amplification in tumor pathogenesis and evolution
Verhaak 2019 NATURE REVIEWS CANCERRead
Extrachromosomal DNA—relieving heredity constraints, accelerating tumour evolution
Mischel, Swanton 2020 Annals of OncologyRead
Circular DNA Throws Gene Regulation for a Loop
Dolgin 2020 Cancer DiscoveryRead
The rapidly growing field of ecDNA cancer biology helps explain why some oncogene amplified cancers are so aggressive and why traditional approaches to treatment are not working for many patients. This new understanding of ecDNA shines light onto innovative and differentiated therapeutic approaches to help those affected by the most aggressive tumors. I am thrilled that Boundless Bio has assembled a world class team that has been able to leverage ecDNA biology to develop a host of innovative drug candidates that have the chance to improve the lives of patients with oncogene amplified cancer.”
Paul Mischel, M.D.
Scientific Co-Founder and Chairman of the Scientific Advisory Board