What We Do

An Entirely New Approach to Cancer Treatment

 

We develop ecDNA-directed therapies (ecDTx) intended to improve and extend the lives of patients with oncogene amplified cancers.

Our Pipeline

BBio_Pipeline_Diagram_Spyglass

Through our proprietary Spyglass platform, we have identified three distinct vulnerabilities of ecDNA-driven cancers: (1) ecDNA Replication Stress, (2) ecDNA Assembly and Repair, and (3) ecDNA Segregation.

ecDNA Replication Stress: BBI-355

Cancer cells with oncogene amplifications on ecDNA exhibit elevated levels of replication stress (RS), a cellular condition where the DNA replication process is dysregulated and leads to potentially toxic DNA damage to cells. As a consequence, tumor cells with ecDNA undergoing elevated RS invoke certain cellular RS response factors, exposing a synthetic lethal vulnerability, which renders them hypersensitive to inhibition of such factors.

Our lead ecDTx, BBI-355, is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1), one of cancer cells’ master regulators of RS. BBI-355 is designed to exploit the elevated RS in ecDNA-enabled oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS, and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells. The preclinical and clinical development of BBI-355 was designed with the aim to effectively treat ecDNA-enabled cancers and overcome weaknesses of prior CHK1 inhibitors

BBI-355 is currently being studied in a first-in-human Phase 1/2 clinical trial in patients with oncogene amplified cancers. The study is called POTENTIATE (Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA).

For patients and caregivers:  to learn more about the POTENTIATE study, please visit ClinicalTrials.gov Study Identifier  NCT05827614.

In addition to BBI-355, we have identified a second CHK1 inhibitor candidate with a differentiated profile from BBI-355. This novel compound, BBI-098, is an oral, selective CHK1 inhibitor that demonstrates central nervous system (CNS) penetrance in preclinical models. BBI-098 has the potential to be developed in the future as a treatment for patients with CNS cancers such as glioblastoma or brain metastases.

ecDNA Assembly and Repair: BBI-825

In order to maintain and perpetuate ecDNA, ecDNA-enabled cancer cells have increased demand for the raw materials used for DNA synthesis and replication. As a consequence, disruption of the supply of raw materials necessary for ecDNA assembly and repair can lead to death of cancer cells that rely on ecDNA.

Our second ecDTx, BBI-825, is a novel, oral, selective inhibitor of ribonucleotide reductase (RNR). RNR is the rate-limiting enzyme essential for production of deoxyribonucleotide triphosphates (dNTPs), the building blocks of DNA required for ecDNA assembly and repair; inhibition of RNR is synthetically lethal to ecDNA-enabled cancer cells. BBI-825 has demonstrated single agent activity, and synergistic activity when combined with specific targeted therapies in amplification-enabled tumor models, in particular cancer models that develop resistance amplifications in response to mitogen activated protein kinase (MAPK) pathway targeting therapies, such as KRASG12C or BRAF inhibitors.

BBI-825 is currently being studied in a first-in-human Phase 1/2 clinical trial in patients with resistance gene amplifications. The recently initiated study is called STARMAP (Study Treating Acquired Resistance: MAPK Amplifications).

For patients and caregivers: to learn more about the STARMAP study, please visit ClinicalTrials.gov Study Identifier NCT06299761.

ecDNA Segregation: ecDTx 3

ecDNA lack centromeres, the structural component of a chromosome that is required for proper segregation during cell division. Thus, segregation and subsequent inheritance of ecDNA in cancer cells is dependent on alternative cellular mechanisms. Our third ecDTx program is directed to a previously undrugged kinesin target. This novel target is essential for ecDNA segregation, and inhibition of this kinesin is synthetically lethal to ecDNA-enabled cancer cells. We have identified inhibitors of this target and intend to advance these compounds to ecDTx candidate identification.

New ecDNA Targets and Vulnerabilities

We leverage our proprietary Spyglass platform (see description below) to identify and preclinically validate additional ecDNA-essential targets. These candidate targets span multiple, diverse ecDNA synthetic lethal nodes in oncogene amplified cancers and are intended to be the aim of our future ecDTx discovery efforts.

Spyglass: the only platform built to identify vulnerabilities of ecDNA in cancer

Spyglass diagram FEB2024

The Spyglass platform consists of a comprehensive suite of proprietary ecDNA+/- models that span many tumor types and amplified oncogenes. Leveraging innovative molecular analytical technologies and imaging techniques, Spyglass enables characterization of ecDNA in cancer cells and reveals a synthetic lethality-based approach to targeting ecDNA-enabled cancers. Through Spyglass, Boundless Bio scientists have thus far identified and validated several distinct and druggable cellular targets that are essential to the function of ecDNA in cancer cells.

ecDNA are the next frontier of precision medicine

ECHO

ECHO (ecDNA Harboring Oncogenes) is a proprietary software algorithm for detecting the presence of ecDNA using routine clinical next-generation sequencing (NGS) data. ECHO will be the first ecDNA diagnostic used in clinical trials.

In our mission to deliver transformative precision therapies to patients with oncogene amplified cancers, ECHO is a vital tool to select appropriate patients for treatment with our ground-breaking ecDTx candidates.

The rapidly growing field of ecDNA cancer biology helps explain why some oncogene amplified cancers are so aggressive and why traditional approaches to treatment are not working for many patients. This new understanding of ecDNA shines light onto innovative and differentiated therapeutic approaches to help those affected by the most aggressive tumors. I am thrilled that Boundless Bio has assembled a world class team that has been able to leverage ecDNA biology to develop a host of innovative drug candidates that have the chance to improve the lives of patients with oncogene amplified cancer.

Paul Mischel, M.D.

Scientific Co-Founder and Chairman of the Scientific Advisory Board

P. Mischel

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