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 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.

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.

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.

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.