A closer look at Volastra’s lead program: KIF18A inhibitor

September 29, 2022

By Christina Eng, Ph.D., VP, Head of Biology

Earlier this month at the FASEB Consequences of Aneuploidy conference, we shared the first preclinical data from our KIF18A inhibitor program targeting chromosomally unstable tumors. The data are highly encouraging, as they showed treatment with our KIF18A inhibitor led to substantial, dose-dependent inhibition of tumor growth in lung and ovarian cancer models, with no effect on normal cell growth.

As we advance this program to a planned Phase 1 study in 2023, I wanted to take an opportunity to share a bit more background on our rationale for targeting KIF18A and the results we’ve seen to date.

Chromosomal instability (CIN), our focus here at Volastra, is a major hallmark of cancer and a critical vulnerability of many cancers. It is defined by persistent errors in chromosome segregation during cell division (mitosis). Despite its widespread prevalence across many cancer types, not many drug targets have been identified that can capitalize on this cancer-specific vulnerability.

To identify vulnerabilities unique to the survival of chromosomally unstable tumor cells, we conducted computational mining using gene dependency data from over 1,000 tumor cell lines. Among the genes required for cells with CIN, KIF18A stood out as especially promising. KIF18A is a protein that helps usher cells through mitosis by helping to align chromosomes. Normal cells can divide without KIF18A, but cells high in CIN have increased mitotic adaptation and errors, and are therefore, we believe, more dependent on KIF18A to successfully divide.

Our recent data support this mechanism. Using the unique and proprietary paired cell lines of our CINtech platform, we were able to model different levels of CIN and confirmed that cells with higher CIN are more dependent on KIF18A. Our KIF18A inhibitor traps chromosomally unstable tumor cells in mitosis — preventing them from proliferating, and ultimately leading to cell death — with minimal effects on normal, healthy cells.

This selectivity is important since therapies that interfere with mitosis broadly — like many chemotherapies do today — can have toxic effects on normal dividing cells, making them difficult to tolerate by patients due to their adverse effects. Thus, we believe that KIF18A inhibitors represent a unique class of mitotic regulators that will be efficacious against tumor cells but tolerated by normal cells.

These data represent a very exciting milestone for Volastra. Not only is this the result of immense dedication across our team for the last several years, but it is a testament to the power of our CINtech platform to discover and validate promising new drug targets. We’re excited to share future updates on this program and on our ongoing efforts to change the cancer treatment landscape by leveraging a uniquely deep understanding of CIN.