October 3, 2022

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Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?



 

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

 

As early as the 1960s and 1970s, scientists discovered a class of tiny chromosomes in cancer cells, and later found that these DNA elements without centrioles and telomeres are circular and several Mb in size.

 

Until 2013, Professor Paul Mischel published a paper in the journal Science [1] , pointing out that extrachromosomal DNA (ecDNA) is related to cancer and drug resistance to targeted therapy.

Since then, Professor Paul Mischel has published a series of research papers on ecDNA and cancer.

 

With advances in sequencing and bioinformatics, we now know that ecDNA is a tumor-specific DNA element that is circular in shape and approximately 1-4 Mb in size.

They are ubiquitous in cancer cells and rarely detected in normal cells, suggesting that the presence of ecDNA is characteristic of some cancers.

 

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

Extrachromosomal DNA (ecDNA) observable by microscopy

 

Recent studies have shown that ecDNAs are closely related to cancer, and they can promote chromatin accessibility, promote oncogene amplification, drive genetic heterogeneity, and promote cancer cells to escape immune surveillance, and are associated with poor prognosis in various cancers.

Therefore, ecDNA has great potential as a cancer detection marker and a therapeutic target.

 

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

Professor Paul Mischel


In 2019, Professor Paul Mischel and others founded Boundless Bio , which is dedicated to discovering new targets from ecDNA and developing targeted cancer therapies.

The company closed a $46 million Series A in September 2019 and a $ 105 million Series B in April 2021 .

 

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

 

At the beginning of its establishment, Zachary Hornby , CEO of Boundless Bio , said that chemotherapy born in the 1940s, targeted therapy born at the end of the last century , and immunotherapy born in recent years are the three revolutions in cancer treatment, and ecDNA will bring The fourth revolution in cancer treatment.

 

He said that ecDNAs are extrachromosomal DNA loop elements that contain functional genes and are highly transcriptionally active.

ecDNAs are present in many solid tumors and are key drivers of the most aggressive and refractory cancers, especially those with high oncogenes.

Cancers characterized by copy number amplification, and ecDNA is usually not present in healthy cells.

Over the past few years, the team has developed the proprietary Spyglass™ platform to study ecDNA in cancer and discover key therapeutic targets in cancers driven by ecDNA-driven gene amplification.

In addition, the team is developing corresponding diagnostic tests to identify ecDNA-driven cancers.

 

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?Cancer patients with oncogene amplification on ecDNA have worst survival

 

On April 11, 2022, Boundless Bio presented new findings on the association between ecDNA and replication stress at the American Association for Cancer Research Annual Meeting (AACR), revealing that replication stress in ecDNA – driven cancer is a unique vulnerability as a therapeutic strategy for gene-amplified cancers.

 

Previous research by Boundless Bio has demonstrated that cancers with ecDNA-amplified oncogenes are associated with poor clinical outcomes and are often unresponsive to targeted therapy, suggesting an urgent need to define clinical strategies for the treatment of ecDNA-amplified cancers.

 

In the report, Boundless Bio presented data on the relationship between ecDNA and DNA replication stress for the first time .

DNA replication stress is a known form of genomic instability, and excessive replication stress can lead to widespread DNA damage and cancer cell death.

Their data show that ecDNA-driven colorectal cancer cells have significantly elevated replication stress and are highly sensitive to replication stress inducers.

This finding highlights replication stress as a potential synthetic lethal approach in ecDNA-driven cancers.

 

 

 

Based on this finding, hyper-level transcription and replication of ecDNA in cancer cells increases replication stress and reliance on nucleotide biosynthesis, where replication stress inducers can serve as a synthetic lethality approach, resulting in ecDNA driven cancer cell death.

 

Zachary Hornby , CEO of Boundless Bio, said that Boundless Bio ‘s goal is to become the foremost biopharmaceutical company researching ecDNA to provide treatments for patients with difficult-to-treat cancers.

Their vision is to pioneer a new paradigm in cancer treatment, helping patients with ecDNA-driven cancers gain access to powerful anti-cancer therapies that improve and prolong their lives.

 

 

 

 

 

References :

https://www.science.org/doi/abs/10.1126/science.1241328

https://www.nature.com/articles/s41587-022-01332-z

https://www.nature.com/articles/s41598-022-07530-8

https://boundlessbio.com/what-we-do

Will the ubiquitous ecDNA in cancer cells bring about a new revolution in cancer treatment?

(source:internet, reference only)


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