Volastra Therapeutics, Inc.

A hallmark of cancer cells is aneuploidy, when a cell has too few or too many chromosomes. This happens during cell division, when chromosomes can get left behind and not incorporated into the nucleus of a new daughter cell. In 2022, on the alpine shores of Lake Maggiore in northern Italy, longtime friends Samuel Bakhoum, M.D., Ph.D., and Stefano Santaguida, Ph.D., were catching up. Pandemic restrictions had prevented the two from seeing each other for years, but, at a small conference in the lakeside town of Stresa, they seized the opportunity to share what they’d been working on recently—the collapse of micronuclei in cancer cells.“We were so happy and excited to be together in real life,” Santaguida, a molecular biologist at the European Institute of Oncology and the University of Milan, told Fierce Biotech in an interview. “We were working on two separate aspects at the very beginning, without knowing of each other’s work.”Teaming up to tackle the problem has now resulted in two papers published Aug. 29 in the journal Science. The studies explain in mechanistic detail how micronuclei rupture and collapse in cancer cells, an important process that drives cancer progression. By getting tangled with mitochondria, micronuclei are exposed to reactive oxygen species that alter the behavior of a key repair protein and over-activate a protein-destroying pathway. A hallmark of cancer cells is aneuploidy, when a cell has too few or too many chromosomes. This happens during cell division, when chromosomes can get left behind and not incorporated into the nucleus of a new daughter cell. A stranded chromosome forms a shoddy nuclear membrane around itself, which is much smaller and less functional than the main nuclear envelope that surrounds the nucleus. These micronuclei can then break apart, leaving the chromosome exposed to the cellular elements.“That rupture process underlies a lot of the means by which micronuclei seem to drive cancer progression,” Bakhoum, a cell biologist at Memorial Sloan Kettering Cancer Center in New York City, told Fierce in an interview.Enzymes in the cytoplasm break chunks off the free-floating DNA, leading to mutations that can spur new cancer traits or alter how genes are expressed. And the cell can also confuse the loose chromosome for a virus, sparking inflammation that can lead the tumor to evolve immune resistance.Melody Di Bona, Ph.D., a cancer biologist working in Bakhoum’s group, was observing cervical cancer cells under the microscope when she noticed that micronuclei tended to get tangled up with mitochondria. “My hypothesis when I started to look at cells was that mitochondria were actually entering the micronucleus,” Di Bona told Fierce in a joint interview with Santaguida.Investigating further, she instead found that the chance of rupture greatly increased as the micronucleus was exposed to more and more toxic forms of oxygen-containing molecules leaking from the mitochondria, called reactive oxygen species (ROS). Through a series of experiments, she pieced together how the membrane unraveling unfolds.Tumors tend to be low on oxygen, which the mitochondria normally need to function; when oxygen is low, nitric oxide binds in its place instead, which produces ROS as a byproduct. ROS are unstable and can steal electrons from other molecules, messing with their forms and functions. Di Bona found that ROS take electrons away from amino acids called cysteines in the protein CHMP7, changing its form so that it abnormally binds to another protein called LEMD2 that sits inside the micronuclear membrane. What’s more, ROS damage also prevents CHMP7 from being kicked out of the cell.“LEMD2 is already in the membrane,” Bakhoum said. “And now imagine a protein that's aggregating inside, right underneath, and pulling it away.” The force of CHMP7 tugging at LEMD2 causes the micronucleus’s membrane to collapse and rupture.Di Bona first looked at CHMP7 because it’s normally a key part of a nuclear membrane repair enzyme called ESCRT-III. But this enzyme is prevented from patching up the rupturing micronucleus due to the actions of another protein called p62.“p62 is a protein that has its own life,” Santaguida said. “It works in the cells by recognizing proteins or organelles that have to be degraded,” targeting them for a process called autophagy.Santaguida’s team found that ROS from mitochondria also alter p62, ramping up its activity to send proteins down the autophagy pathway. This overreactive p62 degrades the repair enzyme ESCRT-III, further dooming the micronuclear membrane to collapse. To connect p62 with cancer prognosis, the team analyzed data from the tumors of 875 gastric cancer patients and found that higher levels of p62 were correlated with shortened survival.“The higher the levels of p62, the higher the likelihood to get a worse prognosis,” Santaguida said. “It's a prognostic marker that can be employed in the clinic tomorrow.” In addition to the prognostic power of p62, the collapse mechanism presents several other potential targets for new drugs. Therapies could target cysteines in CHMP7 and push them away from a pathological path, Bakhoum said. And numerous other molecules play bit parts in the process too, like kinases in the nuclear factor κB pathway—targeting them could reduce the odds of micronuclei rupturing and causing cancer progression.Chromosomes in cancer cells are starting to attract more attention from biotechs. Bakhoum is a co-founder and scientific adviser of Volastra Therapeutics—a biotech focused on chromosomal instability—and also serves on the scientific advisory board of precision oncology company Meliora Therapeutics.“We can't suppress chromosome instability [in cancer] because the cat's out of the bag, but can we at least kneecap it?” Bakhoum said. “Can we intervene in a way that prevents all the bad consequences and sequela of micronuclear rupture?”

Sovilnesib is one of Volastra’s two class-leading, clinical-stage KIF18A inhibitors that are specifically designed to treat cancers characterized by high levels of chromosomal instability NEW YORK--(BUSINESS WIRE)-- Volastra Therapeutics, a clinical-stage biotechnology company, today announced it has dosed the first patient in its Phase Ib clinical trial evaluating sovilnesib in patients with platinum-resistant or refractory high-grade serous ovarian cancer (HGSOC). This trial (NCT06084416) is a randomized dose optimization study of once-daily oral sovilnesib at different dose levels to establish the recommended Phase 2 dose. Sovilnesib was granted Fast Track designation in this indication by the U.S. Food and Drug Administration (FDA) based on its initial clinical data as well as the high unmet need in this population. Volastra in-licensed sovilnesib (formerly AMG-650) from Amgen in February 2023. The company is also progressing its internally developed KIF18A inhibitor, VLS-1488, in an ongoing Phase 1 clinical trial (NCT05902988). “Advancing our two chemically differentiated KIF18A inhibitors in parallel Phase 1 clinical trials presents the rare opportunity to efficiently gather comparative clinical data,” said Charles Hugh-Jones, M.D., FRCP, Chief Executive Officer at Volastra. “We believe our strategy will allow us to select the first, and potentially best-in-class, medicine for patients to advance to late-stage development for treatment of platinum-resistant or refractory HGSOC.” In the U.S. alone, there are more than 20,000 new cases of ovarian cancer each year, over 75% of which are advanced. The majority of these patients will see disease progression on platinum-based therapy. “Patients with advanced HGSOC have poor treatment response rates after disease progression on platinum-based chemotherapy, and as a result have a significant need for new treatment options,” Dr. Joyce Liu M.D., MPH, Associate Chief and Director of Clinical Research in the Division of Gynecologic Oncology at Dana Farber Cancer Institute and a principal investigator on the trial, commented. “We are excited to participate in this trial evaluating a unique treatment approach in hopes of advancing new options for patients.” In addition to clinical development of novel therapeutics, Volastra is deploying multiple unique biomarker approaches to measure chromosomal instability and other predictors of response to KIF18A inhibitors through partnerships with companies including Microsoft, Tailor Bio, and Function Oncology. About Volastra Therapeutics, Inc. Volastra Therapeutics is a New York-based clinical-stage biotechnology company pioneering novel approaches to treating cancer by targeting chromosomal instability. The company was founded in 2019 by Lewis Cantley, Ph.D., Samuel Bakhoum, M.D., Ph.D., and Olivier Elemento, Ph.D., and is funded by investors including Polaris Partners, Arch Ventures, Droia Ventures, Vida Ventures, Catalio Capital Management, and Eli Lilly & Company. Volastra is developing new techniques to understand the biology of chromosomal instability and leveraging these insights to drive a pipeline of therapies towards innovative targets. The company leads the field with two differentiated clinical-stage KIF18A inhibitors, VLS-1488 and sovilnesib (formerly AMG-650). A robust discovery pipeline targeting novel approaches to chromosomal instability, progresses internally and in collaboration with Bristol Myers Squibb. For more information, please visit .

SAN DIEGO--(BUSINESS WIRE)-- Function Oncology, a company transforming the operating system of precision medicine with CRISPR-powered platform technology, today announced an innovative research and development partnership with Volastra Therapeutics, a company pioneering novel approaches to treating cancer by targeting a tumor vulnerability known as chromosomal instability (CIN). The collaboration brings together Function’s CRISPR-enabled personalized functional genomics technology with Volastra’s expertise in CIN to expand patient selection for Volastra’s KIF18A inhibitors across an array of solid tumors indications. Function is leveraging its CRISPR-enabled platform to understand disease in unprecedented and patient-specific detail. By moving beyond traditional gene sequencing to measuring gene function, the Volastra and Function teams aim to identify which patients would benefit from treatment with Volastra’s KIF18A inhibitors. This technology has the potential to accelerate clinical development through predictive biomarkers, as well as novel target identification and validation, and ultimately lead to better patient and trial outcomes. “This collaboration serves as validation of our CRISPR-based approach to deciphering patient-specific drug target vulnerabilities in solid tumors. We are excited to partner with the world-class team at Volastra to accelerate the development of promising medicines that will impact the lives of patients and their families,” said Srinath Sampath, M.D., Ph.D., M.Phil., Co-founder and Chief Executive Officer of Function Oncology. Added Scott Drutman, M.D., Ph.D., Chief Medical Officer and Head of Research and Development at Volastra, “KIF18A inhibition holds tremendous promise for treating chromosomally unstable tumors. CRISPR technology has transformed precision medicine, and we are excited by the potential of Function’s innovative platform to expand the pool of patients that will benefit from KIF18A inhibitors.” About Function Oncology Function is a San Diego-based precision medicine company advancing CRISPR-powered personalized functional genomics to understand serious diseases in unprecedented and patient-specific detail. The company was founded in 2019 and is funded by Andreessen Horowitz, Section 32, Casdin Capital, and ARE. Function’s platform moves beyond measuring gene sequence to instead measure gene function directly in clinical samples using CRISPR. This provides unique insight into patients and diseases, enabling identification of optimal treatment strategies for current patients, as well as driving development of an exciting internal pipeline of novel therapeutics. To learn more, please visit and follow us on LinkedIn. View source version on businesswire.com: Contacts Function Oncology Media Contact Katie Engleman, 1AB katie@1abmedia.com Source: Function Oncology View this news release online at: