Chromosomal instability (CIN), a distinguishing attribute of solid tumors, is marked by persistent chromosome segregation errors across consecutive cell divisions. CIN leads to gains and losses (numerical CIN) or rearrangements (structural CIN) of chromosomes.1-3 Given its ability to generate genomic heterogeneity, CIN is considered to be a major driver of cancer evolution.4 In addition, recent evidence has demonstrated that CIN is a source of chronic inflammation in cancer. Persistent inflammatory signaling enables metastasis, immune evasion, and therapeutic resistance.3
Despite the widespread prevalence of CIN in cancer (it is estimated in 60% to 80% of human tumors), CIN remains one of the major unresolved challenges in cancer therapy.3
Volastra aims to extend the lives of patients with cancer by leveraging unique insights into chromosomal instability. Moving away from primary tumor models to target the site of metastasis in the toughest-to-treat solid tumors, we are altering the treatment paradigm for metastatic cancers.
A world-renowned biologist and biochemist, Dr Cantley has set a course for new cancer therapies based on novel enzyme targets. The Cantley lab at Weill Cornell Medical College investigates cancer metabolism and phosphoinositide signaling. It was the first lab to identify the link between chromosomal instability and cytosolic DNA signaling in cancer metastases. Dr Cantley is celebrated, in particular, for his discovery of the phosphoinositide 3-kinase (PI3K) signaling pathway in the 1980s.
Dr Bakhoum is both a practicing radiation oncologist who specializes in the treatment of breast cancer and a leading investigator into the role of chromosomal instability in tumor evasion. The Bakhoum lab at Memorial Sloan Kettering Cancer Center has pioneered the development of cell and animal-based models to explore the role of CIN in therapeutic resistance and metastasis.
A professor of Physiology and Biophysics, Dr Elemento develops new methodologies for the prevention, diagnosis, and treatment of cancer by combining ultrafast DNA sequencing, proteomics, high-performance computing, mathematical modeling, and artificial intelligence/machine learning. Work at the Elemento lab at Weill Cornell Medical College includes examination of how genes are regulated in cancer cells, determination of whether 3D chromatin architecture can predict where mutations are most likely to occur, and investigation of mutated genes and their mediation of genome-wide, epigenomic patterns.
Volastra’s research into genomic instability is distinguished by an experienced interdisciplinary team. Our team is poised to address the underlying cell biology of CIN through cellular analyses, computational approaches, state-of-the-art animal modeling, and a collection of unique, patient-derived organoids.3 Our goal is to develop therapeutic strategies to tackle metastasis and therapeutic resistance driven by CIN.
Doctors Cantley, Bakhoum, and Elemento identified a unique mechanism that drives the formation and migration of metastatic cancer cells. They discovered that high levels of CIN within cancer cells enable cell migration and alter key immunologic processes to evade immune system detection. These chromosomally unstable cells migrate from the primary tumor and invade distant tissues, which produces metastatic colonies resistant to a wide array of therapies.
It has long been assumed that CIN could not be targeted directly. Volastra harnesses unique druggable pathways that inhibit genomic instability and the underlying disease process. By targeting altered biologic pathways in cells with high levels of CIN, we hope to halt and potentially prevent metastasis in difficult-to-treat solid tumors for which there are limited therapeutic options. Our approach also aims to render aggressive tumors sensitive to immunotherapy.
To accelerate the drug development and enhance its precision, we will utilize a library of patient-derived, metastatic tumor organoids. This platform will be used to validate our compounds, discover novel targets, and perform high-throughput single-agent and combination drug screens. The library will support patient selection and stratification in combination with advanced analytics.
Our experts in metastatic disease, CIN, drug discovery and development, and pharmaceutical commercialization are primed to deliver therapeutic solutions to patients.
If you'd like to join a team with the goal of rapidly advancing therapeutic options for patients with metastatic cancer, please submit your information below.
References: 1. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501(7467):338-345. 2. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396(6712):643-649. 3. Bakhoum SF, Cantley LC. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell. 2018;174(6):1347-1360. 4. Primo LMF, Teixeira LK. DNA replication stress: oncogenes in the spotlight. Genet Mol Bio. 2020;43(1)(suppl 1):1-14.