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 biggest 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 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 reside not within the chromosomes, as previously assumed, but rather on extrachromosomal DNA, or ecDNA.
Patients with a High Proportion of Copy-Number Alterations in Non-Small-Cell Lung Cancer (NSCLC) have worse Disease-Free Survival
In patients with Non-Small-Cell Lung Cancer, there was no significant association between the proportion of subclonal mutations and relapse-free survival (P=0.70) (Panel B), but patients who had tumors with a high proportion of subclonal copy-number alterations were at significantly higher risk for recurrence or death than those with a low proportion (P=4.4x10^-4) (Panel C) (Jamal-Hanjani et al. 2017 NEJM).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?
(Or How Do ecDNA Work?)
ecDNA-driven cancers copied the playbook from bacteria in terms of their ability to grow and survive. Bacteria have extrachromosomal, circular plasmid DNAs that can replicate independent of the chromosomes. Circular plasmids help bacteria grow rapidly and in this way protect bacteria from environmental stressors, such as antibiotics. Some plasmids can also integrate back into the linear host chromosome to quietly survive through multiple generations. Similar to bacteria, ecDNA-driven cancers can aggressively replicate, invading the surrounding tissue and driving tumor growth and resistance.
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
Why Target ecDNA?
ecDNA alter cancer cell behavior, enabling tumors to adapt and evolve in response to selection pressures – including cancer treatments like chemotherapy, 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 work against high copy number amplification-driven cancers. These are often the most aggressive and hardest-to-treat cancers. There are no effective treatments directed at high copy number amplifications.
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.
Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA
Nathanson 2014 ScienceRead
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
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.