As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs.
We’re joined for our latest interview by Zachary Hornby, President and CEO of Boundless Bio, a next-generation precision oncology company who raised an oversubscribed $105 million in Series B Financing last year to develop innovative therapeutics directed against extrachromosomal DNA (ecDNA) in aggressive cancers. Earlier this month, Boundless Bio announced a partnership with Sophia Genetics to further develop Boundless’s proprietary precision diagnostic method called ECHO (ecDNA Harboring Oncogenes) to detect ecDNA in a patient’s routine tumor sequencing data to select appropriate patients for treatment in the in clinical trials of the first ecDNA-directed therapies (ecDTx).
Greetings Zachary! In your opinion, what are the top therapeutic challenges in the field of oncology?
Zachary: Within the field of oncology, the top therapeutic challenge is the fact that patients with oncogene amplified tumors, which account for 400,000 new patients per year in the US, have no standard of care therapies and have significantly worse survival than the cancer population at large. The underlying biology that accounts for this poor prognosis of patients with oncogene amplified tumors is the phenomenon that oncogene amplifications, in contrast to other types of oncogenic alterations, frequently do not occur on linear chromosomal DNA and instead occur on circular extrachromosomal DNA (ecDNA). ecDNA are large (1-3 mega base pair), circular units of nuclear DNA that are physically distinct from chromosomes, highly transcriptionally active, and do not adhere to Mendelian principles of genomic inheritance. They are the primary site of high copy number focal oncogene amplifications, and they propel primary tumor oncogenesis and secondary tumor resistance through rapid amplification and genetic evolution. ecDNA are observed only in cancer cells and not in healthy cells. Until now, the industry has not previously understood ecDNA biology and its role in cancer nor how to appropriately treat cancers that leverage this biology for growth and resistance.
Indeed, ecDNA is becoming a new focus of the cancer field. How might your approaches lead to better cancer therapeutics?
Zachary: Boundless Bio’s novel technological approach to treating patients with oncogene amplified cancers is to therapeutically exploit the unique cellular vulnerabilities associated with cancer cells’ reliance on ecDNA. Boundless has built an only-in-class platform called Spyglass that allows us to exquisitely characterize oncogene amplified cancer models and determine how, when, and why they rely on ecDNA for growth and survival. In thoroughly interrogating ecDNA’s role in these cancer cells, we have learned the lifecycle of ecDNA—how they form, replicate, transcribe, segregate, and degrade. Through our understanding of the ecDNA lifecycle, we have identified nodes of vulnerability that represent pharmacological intervention points where we can develop small molecule inhibitors that disrupt the formation and function of ecDNA and render them inaccessible to cancer cells’ benefit. No other company in the biopharma industry is dedicated to improving and extending the lives of patients with oncogene amplified cancers, and no other company is exploiting ecDNA biology to develop novel therapeutics.
To realize the full potential of your ecDNA platform, do you anticipate any critical challenges? What about recent milestones?
Zachary: One key challenge is that ecDNA represents novel biology that has not previously been therapeutically targeted. Most of the targets that Boundless is pursuing are novel or have not been successfully drugged to date. A second challenge is that ecDNA is a novel biomarker for which no clinical detection methods exist. Boundless is developing a novel companion diagnostic clinical trial assay (CTA) called ECHO (ecDNA Harboring Oncogenes) that uses routine clinical NGS (next generation sequencing) data to detect ecDNA in patient tumor specimens. A key milestone for Boundless will be to demonstrate clinical proof of concept with our first ecDNA directed therapy (ecDTx), BBI-355, in its first in human (FIH) clinical study, due to begin in Q1:2023, which will be a precision oncology trial leveraging ECHO to select appropriate patients for treatment.
If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry?
Zachary: In 10-15 years, we will be discussing the first drugs ever designed specifically for, and approved and commercialized for, patients with high unmet need oncogene amplified cancers. We will talk about how an advanced understanding of the underlying molecular biology, not just the genetic driver (e.g., EGFR amplification), but the genetic topology (i.e., circular extrachromosomal DNA) afforded insight into cancer specific synthetic lethality. We will eagerly look forward to the additional indications, possibly beyond cancer, that our new understanding of topology-dependent synthetic lethality enables for targeted treatment.
In your opinion, what will be the next big scientific breakthrough in life science industry?
Zachary: The next big scientific breakthrough is the concept of topology-dependent synthetic lethality (i.e., where genes are architecturally located in the nuclear genome); this concept is in contrast to genomic synthetic lethality (i.e., what genes encode). Topology-dependent synthetic lethality is an utterly new concept and is based on the observation that circular ecDNA creates profound accessibility of the DNA encoded on the circle and those DNA remain accessible throughout the cell cycle. Open accessible DNA is available to the cellular machinery for DNA replication and for RNA transcription. Normally, these processes are tightly coordinated so that cells don’t try to replicate and transcribe regions of DNA at the same time. When they do occur at the same time, transcription-replication collisions also occur. These collisions damage the DNA and cause a shortage of precursors for synthesizing new DNA. Consequently, tumor cells that have ecDNA are under a great deal of replication stress, which creates a unique, druggable, cancer-specific liability.
Zachary (“Zach”) Hornby has served in executive and director roles for multiple private and public biotechnology companies. He is currently a Director at Aardvark Therapeutics, Novome Biotechnologies, and Radionetics Oncology. Prior to joining Boundless Bio, Zach was Chief Operating Officer at Ignyta, where he oversaw development of the company’s portfolio of four clinical stage therapeutics and was the team leader for the company’s lead program, RozlytrekTM (entrectinib), which was the first drug in pharmaceutical history to garner the coveted BTD (FDA), PRIME (EMA). and Sakigake (PMDA) designations. In that role, he also led the business development process that resulted in Ignyta’s acquisition by Roche for $2 billion; after the Roche acquisition, Zach served as the Ignyta site head where he was responsible for overseeing the integration into Roche. Before assuming the COO role, Zach was Ignyta’s Chief Financial Officer, helping the company go public and raise $120 million in capital. Prior to joining Ignyta, Zach served in roles of increasing responsibility across business development, marketing, new product planning, finance, and regulatory affairs at Fate Therapeutics, Halozyme Therapeutics, Neurocrine Biosciences and Transkaryotic Therapeutics (“TKT;” now the Human Genetic Therapies division within Takeda/Shire) and was a life sciences consultant at L.E.K. Consulting.
Zach holds B.S. and M.S. degrees in biology, with a concentration in neuroscience, from Stanford University and an MBA from Harvard Business School