Volastra Therapeutics CEO Charles Hugh-Jones, MD, FRCP

Soon after Samuel F. Bakhoum, MD, PhD, presented a plenary session on “Chromosomal Instability and Tumor Evolution” at the American Association for Cancer Research (AACR) Annual Meeting 2021, numerous biopharmas contacted the startup he co-founded to develop cancer treatments based on that research.

“After Sam gave that presentation, the phone started really ringing off the hook,” Volastra Therapeutics CEO Charles Hugh-Jones, MD, FRCP, told GEN Edge.

One of them was Bristol Myers Squibb (BMS), which on Monday joined Volastra in launching an up-to-$1.13 billion multi-year collaboration to discover and develop treatments for unspecified cancers targeting chromosomal instability (CIN) using Volastra’s proprietary CINtech platform.

Hugh-Jones said the companies will partner to identify at least two, and possibly three, CIN-related, synthetic lethal targets as drug candidates.

The targets to be partnered do not include Volastra’s lead synthetic lethal target—KIF18A, a mitotic kinesin-8 motor protein shown to play a role in promoting the viability of CIN cancer cells. KIF18A regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. Volastra anticipates launching first-in-human studies of its KIF18A-targeting cancer candidate in early 2023.

Last year a University of Vermont research team led by Jason Stumpff, PhD, research in Nature Communications showing that inhibiting KIF18A caused CIN tumor cells to delay mitosis, as well as the multipolar spindle formations characteristic of cancer cells, leading to increased cancer cell death.

Volastra is not the only drug developer interested in treating cancer by targeting KIF18A. Amgen is recruiting patients for a Phase I trial (NCT04293094) assessing the safety of its small molecule KIF18A inhibitor AMG 650 in up to 140 adults with advanced solid tumors, and determining the maximum tolerated dose and/or recommended dose for Phase II studies.

On March 14, a team of researchers from Amgen published a paper in Journal of Medicinal Chemistry reporting what the authors said was the first disclosure of KIF18A inhibitors with in vivo activity. The authors identified a pair of compounds that caused significant mitotic arrest in vivo that was sustained for 24 hours, followed by cell death either in mitosis or in the subsequent interphase.

On its website, Amgen Oncology has identified KIF18A among four targets for its small molecule cancer drug pipeline; the other three are KRASG12C, MCL-1, and proteasome.

Volastra has four other synthetic lethal targets in development, none of which it will disclose, though Hugh-Jones did say they “look at different mechanisms that have synthetic lethal vulnerabilities that we can target.”

“Really ambitious plans”

“We have really ambitious plans for the company,” Hugh-Jones said. “I can see a company two to three years from now where we have a wide range of targets across those two or three strategic areas.”

One of those strategic areas Volastra is focused on is synthetic lethality, a genetic approach of target discovery designed to exploit vulnerabilities in tumor cells, in order to induce tumor cell death while sparing normal cells. Volastra says it has shown in preclinical models that synthetic lethal approaches can effectively fight tumors with high levels of CIN.

“You find chromosomal instability in about 70 to 80% of cancers, and it’s pretty much across the board with all tumors. Some cancers—ovarian, lung, breast—have a higher rate of chromosomal instability than others, but there is a broad applicability across a wide range of tumors,” Hugh-Jones explained.

Volastra Therapeutics says its CINtech platform is designed to exploit chromosomal instability (CIN) as cancer’s most targetable vulnerability, with the goals of developing new first-in-class oncology therapies by identifying relevant targets more quickly. CINtech integrates proprietary data sciences technologies (imaging and genomics, computational screens, merged data analytics); cancer biology (paired CIN cell lines, CIN CRISPR screens, and organoid systems); and medicinal chemistry (2D and 3D design tools, biological and ADME assays, and structure activity analysis). [Volastra Therapeutics]
While normal cells don’t tolerate chromosomal abnormalities, he said, “with the cancer cells, it’s a bit of a Goldilocks situation:  If you get the right amount, they can leverage that genetic complexity, and start to hijack some mechanisms within the cell to allow them to survive. And that includes some mitotic machinery, the structures that allow for cell separation. And they can also hijack some of the immune evasion pathways.”

“What we’re doing,” Hugh-Jones added, “is trying to define which of those mechanisms it’s hijacking, and then use synthetic lethal approaches to target them.”

The company is targeting mitotic checkpoints, centrosome regulation and kinetochore-microtubule dynamics, reasoning that 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. Volastra says it is identifying these targets by combining computational analysis with genetic screens on isogenic CIN cancer cell lines.

Volastra is also pursuing immune reactivation, based on research showing that extrachromosomal DNA often found in CIN-high cells stimulates a potent anti-tumor immune response. Yet chromosomally unstable tumor cells evolve mechanisms for evading this immune-mediated destruction.

The company says it is 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.

How large of a pipeline does Volastra envision developing?

“I can see within two to three years, a Phase II candidate, a number of active INDs, and several candidates in late-stage discovery,” Hugh-Jones projected.

Volastra’s ambitious plans, he added, include expanding Volastra’s staff of about 35. The company isn’t quantifying its projected increase, though Hugh-Jones said the company’s headcount will grow “in line with building clinical capabilities and additional biology capabilities to support that pipeline, and then also data science capabilities to do a lot of our computational and data work.”

In November, Volastra named former Regeneron Pharmaceuticals oncology clinical development executive Scott Drutman, MD, PhD, as senior vice president, head of translational science, while former Pfizer oncology business development executive Rachel Zolot Schwartz, MBA, was appointed vice president, head of business development and commercial.

As staff expands, he said, so will Volastra’s space. The company has grown in New York City from a bench at JLABS@NYC, the Johnson & Johnson Innovation health sciences incubator housed at the New York Genome Center in SoHo, to 15,000 square feet at the 150,000-square-foot Mink Building in West Harlem, including a 4,000-square-foot expansion announced last year.

“We’re getting to starting to fill out the space and we will be looking to expand going forward,” Hugh-Jones said.

Big apple to the core

That expansion, he said, will keep Volastra in the Big Apple, where a sub-cluster of biotech startups and biopharma giants has emerged in recent years, aided by the city government and its public-private Economic Development Corp. (NYCEDC) last year doubling to $1 billion  the Big Apple’s planned spending on life sciences programs through 2026.

“New York City is a fantastic place to run a small biotech for a number of reasons,” Hugh-Jones said. “Location-wise, we get fantastic talent out of both academic and industry. We’ve been really able to hire top talent. Location-wise, we get people from the whole tri-state area [New York, New Jersey, and Connecticut].  And on top of that, we have access to academic institutions, financial institutions, and all the support services you need to run an effective biotech. It’s a great place to work.”

Volastra is named for a village in Italy’s Cinque Terre National Park that has a population of some 200 residents and a close personal connection to one of the company’s co-founders.

“And in many ways it became an aspirational idea that not only it was a town, but also, it means reach for the stars,” Hugh-Jones said. “I think if it’s a nice way of pivoting the company as an idea.”

Lewis C. Cantley, PhD, of Weill Cornell Medicine, a Volastra co-founder and the discoverer of the phosphoinositide 3-kinase (PI3K) signaling pathway.

Volastra’s origins stretch back to 2016, when Bakhoum joined the lab of Lewis C. Cantley, PhD, the discoverer of the phosphoinositide 3-kinase (PI3K) signaling pathway in 1984 and a professor at Weill Cornell Medicine. Bakhoum’s research was focused on how chromosome behavior drove cancer metastasis.

Cantley and Bakhoum recruited Olivier Elemento, PhD, to Weill Cornell, where he is now a professor and Director of the Englander Institute for Precision Medicine (EIPM), among other positions. Elemento’s lab combines big data analytics, including artificial intelligence and mathematical modeling, with experimentation to develop entirely new ways to help prevent, diagnose, understand, treat and ultimately cure cancer.

The three began working on a path toward targeting CIN as a root cause of cancer metastasis. In 2018, the three, joined by 30 colleagues, published a study in Nature showing for the first time how CIN allowed cancerous cells to evade the immune system and spread.

‘It really just became such an obvious therapeutic opportunity that they felt that they could drive that most effectively by founding Volastra,” Hugh-Jones recalled.

Volastra was founded in 2019 and emerged from stealth mode the following year, when it announced its formal launch with a $12 million seed financing. That seed financing expanded the following year to $44 million; the company has raised a total $45 million in capital to date.

“We are suitably capitalized to do everything that we need to,” Hugh-Jones said. Volastra won’t disclose how long its cash runway will extend before it will need additional financing, though he did say the company was evaluating financial options and raising capital as part of that strategy.

Three blockbusters, one approval

BMS wowed Hugh-Jones and other Volastra executives with its focus on developing and/or commercializing therapies for various cancers. BMS’ considerable oncology portfolio is anchored by three blockbuster drugs: Revlimid (lanalidomide), which was acquired with Celgene in 2019  (and generated $12.821 billion in sales last year); Opdivo® (nivolumab, $7.523 billion in 2021 sales); and Yervoy® (ipilimumab; $2.026 billion).

Another BMS cancer drug is headed for the market. On Friday, the FDA approved Opdualag (nivolumab and relatlimab-rmbw) for the treatment of patients 12 years of age or older with unresectable or metastatic melanoma. Opdualag is a first-in-class, fixed-dose dual immunotherapy combination of Opdivo, a PD-1 inhibitor, and the LAG-3-blocking antibody relatlimab.

During the virtual J.P. Morgan 40th Healthcare Conference, BMS Chairman and CEO Giovanni Caforio, MD, said in a presentation Opdualag would be one of the company’s three planned launches this year and was “a critical foundational element for the company’s sustained growth,” along with six therapies approved since 2020.

“We ended up talking to a number of different companies, but we really felt the relationship and the capabilities of both sides with Bristol-Myers Squibb made for an ideal partnership,” Hugh-Jones said. “As we went into the fall and towards the end of the year, we really started to cement this partnership. And we’re pleased that over the last few weeks, we’ve been able to sign and finalize it.”

BMS agreed to pay Volastra $30 million upfront, and up to $1.1 billion in payments tied to achieving development, regulatory and commercial milestones. Volastra is also eligible to receive royalties on net global sales of any product developed through the collaboration that is commercialized by BMS.

Volastra agreed to oversee activities for undisclosed targets, as well as conduct all research activities for select targets through development candidate selection. BMS said it “may take on the responsibilities” for all subsequent development, regulatory and commercialization activities of the companies’ development candidates.

“We look forward to collaborating with Volastra and utilizing their chromosomal instability targeting platform to identify important drug discovery insights,” said Rupert Vessey, BM BCh, FRCP, DPhil, BMS’ executive vice president, research & early development. “New therapies targeting CIN have the potential to enhance treatment selectivity and improve patient outcomes.”

R&D, organoid partnerships

BMS becomes the first big-name biopharma to partner with Volastra. In March 2021, Volastra inked an R&D partnership of undisclosed value with Dewpoint Therapeutics to discover novel modulators of biomolecular condensates, with the goal of preventing cancer progression and metastasis. The Dewpoint partnership is initially focused on early drug discovery, with the option for future joint development and commercialization.

A month later, Volastra began collaborating with Microsoft to develop machine learning tools to detect drivers of tumor growth and predictors of outcomes, by integrating Microsoft’s Azure AI portfolio of AI services designed for developers and data scientists with Volastra’s insights into tumor biology. The companies have committed to creating automated tools capable of rapidly and accurately measuring the rate and state of chromosomal instability and other features of tumor growth and progression.

Two additional Volastra collaborations focus on three-dimensional tissue models called organoids. The company has an ongoing license agreement with Weill Cornell Medicine for access to its primary and metastatic organoids, as well as a license agreement with HUB Organoids enabling the company to grow organoids in its lab for use in preclinical research.

HUB was founded by the Hubrecht Institute, the University Medical Center Utrecht and the Royal Netherlands Academy of Arts and Sciences to refine organoid development and foster organoid adoption globally. Hans Clevers, one of HUB’s founders, is a member of Volastra’s scientific advisory board—as are all three Volastra co-founders.

“We’re focused at the moment on these collaborations. But we have ambitious plans for the company, and we’re always interested in potential additional opportunities,” Hugh-Jones added.