What We Do
A New Approach To Cancer Treatment
Our goal is to treat the most intractable cancers by turning one of cancer’s enabling mechanisms into one of its critical vulnerabilities.
Transform Care For Patients With Cancer
We aim to treat the most aggressive cancers, which are frequently driven by ecDNA. Our initial therapeutic programs will pursue specific solid tumor types where ecDNA are highly prevalent.
Pioneer ecDNA Science
Boundless Bio is paving the way for a new understanding of extrachromosomal DNA, or ecDNA, one of the key drivers of the most aggressive cancers—specifically, those characterized by high copy number amplification of oncogenes.
Develop Medicines Targeting ecDNA Biology
Building upon these insights, we have undertaken efforts to discover and develop proprietary treatments that exploit ecDNA’s unique vulnerabilities in precisely targeted patient populations.
Cancers driven by high copy number amplification of oncogenes can be some of the most aggressive and difficult-to-treat
High copy number amplified oncogenes refer to a significant increase in the number of copies of cancer-promoting genes. Rapid replication of oncogenes leads to excess copies of cancer-promoting proteins, which allow cancer cells to grow and divide at hyper-speed, enabling their proliferation and survival.
Copy number driven cancers are a clearly defined subset of aggressive, difficult-to-treat cancers. Across many cancers, copy number can predict poor prognosis and relapse. However, medicines capable of targeting gene amplification have not yet been developed, and there remains a significant unmet need in this area.
Boundless Bio’s scientific founders have built new DNA maps that enable us to see not just which genes have high copy number amplifications in cancer, but where in the cell those high copy numbers reside. We have found that oncogenes with high copy numbers frequently reside not within the chromosomes, as previously assumed, but rather on extrachromosomal DNA, or ecDNA; furthermore, oncogenes expressed on ecDNA have higher transcription rates, meaning even more cancer-causing protein.
Patients with cancers characterized by amplifications on ecDNA have worse disease-free survival than cancers with non-circular amplifications or no amplifications
Across All Tumor Types, Patients with Cancer Characterized by Copy-Number Alterations Have Worse Survival than Those with No Copy Number Alterations. Patients with ecDNA-Driven (Circular) Copy Number Amplifications Have the Worst Survival of All.Learn More
Extrachromosomal DNA (ecDNA) are circles of DNA outside the chromosomes but still within the nucleus of a cell. ecDNA typically contain multiple genes, and they also encode regulatory and other types of sequences. If the ecDNA encode genes that translate to proteins that are advantageous for cell survival, such as oncogenes, the ecDNA provide a distinct advantage to cells that contain several copies; this can then drive tumor growth, progression, and resistance to standard treatment options.
The ecDNA themselves can be rapidly replicated within the cell, causing high numbers of oncogene copies. High copy number is a trait that can be passed down to daughter cells in asymmetric ways during cell division. Cells then have the ability to upregulate or downregulate the ecDNA and resulting oncogenes to ensure survival under various selective pressures, including existing therapeutic approaches like chemotherapy or radiation. ecDNA therefore become one of cancer cells’ primary mechanisms of recurrence and treatment evasion. Typically, ecDNA are not found in healthy cells, but their presence has been identified with high frequency in nearly half of all solid tumor cancers.
ecDNA are large circles of DNA found off chromosomes and can be observed via imagingLearn More
Where Do ecDNA Come From and How Do They Work?
In normal human cells, our genes, and the regulatory control elements that govern when and how they are expressed, reside on chromosomes. Chromosomes evolved so that when cells divide, they pass the same genetic information to their daughter cells. This is required for a multi-cellular organism’s body to form and maintain properly. When ecDNA form, this process becomes corrupted. The genes and their control elements jump onto extrachromosomal DNA circles passing genetic information from mother cells to daughter cells in an uneven fashion when cells divide. As a consequence, cells differ genetically from each other in ways that ensure that a tumor constantly acquires new genetic diversity, enabling it to adapt rapidly in response to changing conditions, including treatments. With genetic diversity, some cells will be more optimally fit to thrive, and those cells will gain a growth and survival advantage. This unusual form of non-chromosomal inheritance of ecDNA allows certain tumors to evolve and change rapidly to become increasingly aggressive and resistant to treatment. The circular architecture of extrachromosomal DNA also contributes to aggressive cancer growth, by changing how the genes on an ecDNA are expressed. Most of the genes in a cell are not expressed because the DNA is not accessible to the cellular machinery that transcribes the messages encoded by that DNA. On ecDNA, the genes and their regulatory regions become highly accessible, and the circles generate new interactions, which, when coupled with the very high copy number of the circular ecDNA elements, contributes to super high levels of expression of oncogenes that drive tumor growth.
How ecDNA in cancer form remains an open question, but evidence points to at least two independent mechanisms that may contribute. In one proposed mechanism, when cells divide and the chromosomes are duplicated and equally distributed to daughter cells, sometimes a chromosome gets “stuck” and shatters into pieces, that can come together to form a circular ecDNA. In a second contributory mechanism, segments of a chromosome can sometimes break and form a circle. It is also suspected that there may be other mechanisms that can contribute to ecDNA formation.
Novel Mapping of ecDNA
Boundless Bio's scientific founders developed directed assembly techniques using short-read sequencing data to reconstruct the architecture of ecDNA. The copy number of the reads mapping to ecDNA segments (colored boxes) is proportional to the average number of ecDNA copies per cell and reveals itself as copy number amplification in the mappings (Verhaak, Bafna, Mischel 2019 Nature Reviews Cancer).Learn More
Increased Expression of ecDNA
Oncogenes encoded on ecDNA are some of the most highly expressed genes tumors, linking increased copy number with high transcription levels. ecDNA lacks higher order compaction that is typical of chromosomes and display significantly enhanced accessibility to transcriptional machinery.Learn More
Why Target ecDNA?
ecDNA alter cancer cell behavior, enabling tumors to grow and evolve in response to selection pressures – including cancer treatments like chemotherapy, targeted therapy, immunotherapy or radiation. ecDNA may provide the tools for cancers to become resistant to current treatments.
High copy number amplification-driven cancers are distinct from cancers driven by specific somatic mutations or fusions. While the scientific community has made progress in developing treatments targeting point mutations and fusions using a precision medicine approach, current therapies do not generally work against high copy number amplification-driven cancers. These are often the most aggressive and hardest-to-treat cancers.
We believe that targeting ecDNA – one of cancer’s most powerful drivers and evasive mechanisms – will enable us to effectively treat cancers previously thought to be intractable.
How We Target ecDNA Spyglass™ Drug Discovery Platform
Boundless Bio’s Spyglass™ platform is a comprehensive suite of proprietary ecDNA-driven and pair-matched tumor models along with proprietary imaging and molecular analytical tools that enables Boundless’s researchers to interrogate ecDNA biology to identify a pipeline of novel oncotargets essential to the function of cancer cells that are enabled by ecDNA. The Spyglass platform facilitates Boundless innovation in the development of precision therapeutics specifically targeting ecDNA-driven tumors, thereby enabling selective treatments for patients whose tumor genetic profiles make them most likely to benefit from our novel therapeutic 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
We have drawn a new map of the cancer genome, elucidated by ecDNA, that explains why some cancers are so aggressive and why traditional approaches to treatment are not working for many patients. This new understanding paves novel pathways in which to develop effective treatments for those affected by the most aggressive tumors. I am thrilled that Boundless Bio has fully committed to the challenge of interrogating ecDNA biology and put a pioneering team in place to improve the lives of patients with cancer.”
Paul Mischel, M.D.