What is chromosomal instability?
At Volastra we are focused on a biological process that is not only a hallmark of cancer, but is its key vulnerability: chromosomal instability, or CIN. CIN is present in 60-80% of all cancers and is associated with poor surivival in many patients. While the genetic mutations that result from CIN have long been the focus of pharma and biotech research, modulating CIN itself has evaded discovery efforts — until now.
When cells undergo mitosis, their chromosomes usually separate in an orderly fashion. The process by which chromosomes incorrectly separate is known as chromosomal instability (CIN). Normal cells can’t tolerate CIN; in fact, inducing CIN in normal cells triggers various mitotic and immune processes that kill the aberrant cell. These innate defense mechanisms protect the body from the development of cancer.
In cancer cells, these cellular processes are turned off or evaded, allowing cancer cells to not only tolerate but also thrive under chromosomally unstable conditions. In cancers where CIN levels are high (CIN-high cancers), there are both genetic and non-genetic cellular consequences that lead to a host of biological glitches. CIN-high cancer cells develop mechanisms to escape cell death and evade immunity, driving primary tumor growth and treatment resistance. These consequences increase a patient’s risk of disease recurrence and death.
We are working to exploit this biogy and turn a deep understanding of CIN and its biological consequences into life-saving therapies. Learn more about our multi-pronged approach to stop cancer in its tracks.
Chromosomal instability leads to cancer growth, but how? Learn more about one of the key immunological consequences of CIN that enables cancer growth…
What drives cancer?
The error: Cancer cells divide rapidly as tumors grow. Chromosomal instability promotes errors in mitosis, leading to genetic and non-genetic consequences. The deposition of chromosome fragments outside the cell’s nucleus in structures known as micronuclei, is one of those consequences.
The rupture: These micronuclei are fragile and prone to rupturing. When they do, their contents become exposed to the cytosol.
The STING: DNA in the cytosol activates a signaling pathway known as cGAS-STING. Normally, activation of this pathway leads to the release of cytokines that simulate an appropriate immune response.
The dodge: Ongoing cellular stress as a result of chromosomal instability changes the STING-dependent signaling outputs. Instead of inducing a potent inflammatory, anti-tumor response, cytosolic DNA in CIN-high tumor cells preferentially activates a non-canonical, pro-metastatic NF-kB pathway.
The result: Cancer cells with high levels of CIN evade immune detection and elimination.
A Multi-pronged Attack
CIN is one of cancer’s most prevalent vulnerabilities and Volastra has developed ways to exploit it. Our nascent understanding of the underlying mechanisms of CIN has revealed vulnerabilities of CIN-high cancer cells, previously under-appreciated in oncology drug discovery. Incorporating both experimental and computational tools, we have been able to uncover novel druggable targets to stop cancer in its tracks.
Having completed the first ever CIN-specific CRISPR target identification screen, Volastra is marching towards the clinic with unique therapies that target the biological consequences of CIN. We are initially focusing our efforts on synthetic lethality and re-activation of the immune system.
Synthetic Lethality: Chromosomal instability increases tumor cell genomic diversity and intratumor heterogeneity. Errors in mitosis can also be lethal to cancer cells. Cells selected for increased rates of mitotic errors, a hallmark of CIN-high cells, have unique genetic dependencies that can be selectively targeted with novel therapies. We are identifying these targets by combining computational analysis with genetic screens on isogenic CIN cancer cell lines. Specifically, we are targeting mitotic checkpoints, centrosome regulation and kinetochore-microtubule dynamics.
Immune Activation: Extrachromosomal DNA often found in CIN-high cells stimulates a potent anti-tumor immune response, however, chromosomally unstable tumor cells evolve mechanisms for evading this immune-mediated destruction. We are integrating computational analyses with CRISPR screens in isogenic CIN-high and CIN-low cells to identify novel, targetable immune-evasive mechanisms that are critical for CIN-high tumor cell survival.
Applying our biological expertise and suite of propriety tools, we are equipped to identify targets more quickly, select the appropriate patients for therapies more effectively and ultimately improve patient outcomes.
- Xu Z, Verma A, Naveed U, et al. Deep learning predicts chromosomal instability from histopathology images. iScience, 2020.
- Cogan D, Bakhoum SF. Re-awakening innate immune signaling in cancer: the development of highly potent ENPP1 inhibitors. Cell, 2020.
- Bakhoum SF, Cantley, LC. The multifaceted role of chromosomal instability and its microenvironment. Cell, 2018.
- Bakhoum SF, Ngo B, Laughney AM, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature, 2018.