Cancer–neuronal crosstalk and the startups working to silence it

Investors back ‘cancer neuroscience’ outfits as the field breaks out from academia.

Two new biotech startups are taking aim at the neuronal signaling that drives cancer growth and progression. Cygnal Therapeutics emerged from the venture capital firm Flagship Pioneering last October with $65 million and a plan to disrupt communication channels between the body’s nerves and cells implicated in cancer, inflammation and other ills. A month earlier, Divide & Conquer likewise spun out of Medicxi with $13 million and a focus on short-circuiting the connections tumor cells make between each other and with neurons.

Cancer cells migrating along nerves: cancer cells, yellow; neurons of the dorsal root ganglion explant culture, cyan. Credit: Cygnal Therapeutics

Cancer neuroscience is a burgeoning new field, and both companies hope to capitalize on their head start in what is still mostly an academic pursuit. “Even two years ago, it was regarded as peripheral that nerves could participate in cancer initiation and progression,” says Hubert Hondermarck, a cancer neurobiologist at the University of Newcastle in Australia. “Now, it is slowly becoming mainstream.”

The surprising phenomenon of cancer cells hooked up to neurons came to wider attention in September when a team co-led by neuro-oncologist Frank Winkler and neurophysiologist Thomas Kuner of Heidelberg University in Germany reported that incurable brain tumors called gliomas often form synaptic junctions with healthy nerve cells. By linking finger-like extensions that protrude from cancer cells to glutamate-releasing neurons, the brain tumors seemed to feed off existing neural networks, the researchers found. And decoupling those connections with a marketed antiepileptic agent — perampanel (Fycompa), which targets postsynaptic AMPA-type glutamate receptors — helped blunt tumor growth in mice.

That study, along with an earlier demonstration from the Heidelberg team that the same types of tumor protrusion help connect cancer cells to each other, laid the scientific foundation for Divide & Conquer, which counts Winkler as a co-founder. (A similar report documenting synaptic connectivity in a range of aggressive brain tumor types provided independent validation for the strategy of disabling cancer’s social network; however, lead study author Michelle Monje, a pediatric neuro-oncologist at Stanford University in California, is advising Cygnal and is not involved in Divide & Conquer.)

The Medicxi-backed startup is broadly focused on targeting “the connections that the tumor cells make with each other and with the surrounding normal tissue,” says executive chairman and cofounder David Grainger. In glioblastoma, Divide & Conquer’s top therapeutic priority, those connections are between cancer cells and neurons. With its lead small-molecule candidate, the company aims to block the signaling pathway involved in activating growth-associated protein-43, a crucial regulator of synaptic plasticity that Winkler has found is also essential to the formation and function of tumor protrusions. A phase 1 trial is anticipated for early 2021.

Cells from other types of cancer form connections with cells other than neurons, though. In triple-negative breast cancer, for example, Divide & Conquer has unpublished data showing that the intercellular exchanges driving tumor aggressiveness and therapeutic resistance occur between malignant cells and surrounding fibroblasts, Grainger says. And the company is also looking to sever the ties that bind pancreatic cancer, a disease recently shown by cell biologist Henry Higgs of the Dartmouth College Geisel School of Medicine in Hanover, New Hampshire, who is unaffiliated with Divide & Conquer, to form interconnected protrusions, too.

“We are positioning ourselves as the global leaders in this ‘disconnection biology,’” says Grainger, also chief scientific advisor of Medicxi.

Cygnal, meanwhile, has its sights set squarely on blocking peripheral nerve signaling to cells that underpin disease. The company’s lead programs are in cancer, but it also has drug candidates in the works for inflammatory bowel conditions in which enteric nerve impulses are thought to contribute to disturbed gut health. Other therapeutic areas — including fibrosis, metabolism and endometriosis — are under consideration as well. The peripheral nervous system “is relevant in all these settings and needs to be decoded,” says Cygnal’s president and CEO Pearl Huang.

In oncology, most previous nerve-targeted drug research has centered on repurposing a common class of heart medicines called β blockers. Prompted by dozens of retrospective and observational studies showing that cancer patients who regularly take β blockers — ostensibly for high blood pressure or some other cardiovascular problem — typically have better prognoses than patients who do not take the drugs, clinicians recently started prospectively evaluating these agents as potential adjuncts to other anticancer therapies.

In Australia, for example, a team co-led by Erica Sloan, a cancer biologist at the Monash University in Melbourne, tested whether preoperative treatment with propranolol — the world’s first β blocker, developed in 1964 — could reduce the invasive potential of residual disease cells, and thus lower rates of recurrence, among women undergoing surgery for early-stage breast cancer. Late last year, she and her colleagues reported that one week of β blockade leading up to surgery lowered the expression of biomarkers associated with metastasis and promoted immune cell infiltration in the excised tumor tissue.

“We got really lucky,” Sloan says of this drug repurposing strategy. “Propranolol is a way we can do something for patients now.” But, she adds, “if we understand the biology, perhaps we can really improve that and do something much better.”

That is exactly what Cygnal intends to do. To that end, the company has tapped Sloan as well as Hondermarck, Monje, and other academic researchers — including Paul Frenette, a stem cell scientist at the Albert Einstein College of Medicine in New York City, whose lab in 2013 published concrete evidence that nearby nerves are essential to the proliferation of tumors in mice — to serve on its scientific advisory board. In December, the company also funded an invitation-only meeting at the Cold Spring Harbor Laboratory’s Banbury Center in New York state to discuss the emerging principles of cancer neuroscience with leading thinkers in the field.

There, and in posters presented at assorted cancer meetings last year, the company described how its scientists are coculturing primary neurons with both tumor and immune cells; using advanced imaging techniques to visualize tumor innervation; manipulating tumor-associated neurons with viral vectors; performing CRISPR-based screens of neuronal genes involved in regulating membrane potential, synapse formation, neurotransmission and axonal guidance; and deploying neurally focused bioinformatics, among other approaches, to find drug targets affecting cancer growth.

Manuel Fankhauser, a scientific consultant to Cygnal and the CSO of the Seerave Foundation, a cancer-focused non-profit, applauds the company for exploring the interconnectedness between tumors, the immune system and neurons in an unbiased, systematic fashion. “There’s lots of feedback going on, and it’s often unclear what’s the chicken and what’s the egg,” he says. “This exciting platform allows you to appreciate that complexity, but at the same time still take the reductionist approach that you need in drug development.”

Cygnal has disclosed one target identified in this way: CYFIP1 (cytoplasmic FMR1-interacting protein 1), a protein involved in regulating synaptic connectivity between neurons. Dysregulation of CYF1P1 has been implicated in autism, schizophrenia and other neuropsychiatric disorders, and lab experiments detailed at the 2019 International Conference on Molecular Targets and Cancer Therapeutics in Boston showed that knocking out CYFIP1 markedly delayed cancer initiation. However, the effect on tumor maintenance was much less pronounced — and “this target is not Cygnal’s primary focus for the moment,” Huang says.

“We shared this target at the meeting to illustrate how we use our platform to discovery new biology,” she explains. The same platform also helped the company pinpoint α6-subunit-containing nicotinic acetylcholine receptors and the purinergic receptor P2X 2, among other synaptic proteins, as potential candidate targets, patent filings show.

Collectively, the targets discovered to date reveal that “as tumors become really deranged and they get more advanced, there’s a selection for tumors that are expressing these nerve functions because it gives them a growth advantage,” Huang says. “So what we’ve identified are targets that are neural in origin — that is, they were first described in neural systems — that are now acting like oncogenes in tumors.”

Huang intends to announce two development candidates later this year. For now, she would only say that one is a small-molecule drug aimed at a neurotransmission target with expression levels that are amplified across multiple tumor types and are predictive of patient survival in various cancers, including those of the uterus and bladder. The other candidate is an antibody drug directed against an undisclosed target.

Few if any other companies beside Cygnal and Divide & Conquer have publicly disclosed plans to develop drugs targeting neuron–cancer interplay, but there are a handful of ongoing academic efforts. Monje, for example, will begin a human trial early this year that builds on her team’s 2017 finding from mouse xenograft models that pharmacologically blocking the release of a neuron-secreted adhesion molecule into the tumor microenvironment can hamper the proliferation of brain cancer. Her team is planning to give patients with high-grade gliomas a small-molecule drug called aderbasib, an inhibitor of ADAM (a disintegrin and metalloprotease) enzymes. Incyte previously tested the drug for breast cancer before suspending further development.

Timothy Wang, a gastrointestinal cancer researcher at the Columbia University Medical Center in New York City and a member of Cygnal’s scientific advisory board, also has a pilot study ongoing to test whether presurgical treatment with bethanechol (Urecholine), an activator of muscarinic acetylcholine receptors typically prescribed for bladder problems, can help patients with pancreatic cancer. The trial — run jointly with oncologists Susan Bates of Columbia and Paul Oberstein of New York University — has accrued five patients so far, and, according to biomarker analyses, “there are some very encouraging findings,” says Wang. In 2018, he and his colleagues showed that cholinergic nerves, as mediated by muscarinic receptors, regulate the progression of pancreatic tumors in mice.

Earlier research from Wang’s lab had additionally found that PLX7486 — an experimental small molecule from Plexxikon (a subsidiary of Daiichi Sankyo) that impedes nerve growth signaling by blocking tropomyosin receptor kinases — inhibits tumor development in mouse models of gastric and pancreatic cancers. Plexxikon had launched a clinical trial to test whether the same is true in patients. The study was stopped, however, for business reasons — “much to my own disappointment,” says Gideon Bollag, the company’s CEO.

“We were never able to properly explore the role of nerves in cancer growth,” Bollag says. “It’s nice to see that others are pursuing that link.”

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Dolgin, E. Cancer–neuronal crosstalk and the startups working to silence it. Nat Biotechnol 38, 115–117 (2020). https://doi.org/10.1038/s41587-020-0411-9

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