A New Approach To Cancer Treatment

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.

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.

(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.

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.