LONDON – Divide & Conquer Ltd. has been launched to develop a new class of cancer drugs that disrupt networks through which malignant cells communicate and share materials.

The company's scientific founders have produced evidence that cells in glioblastoma and other aggressive solid tumors are in a state of cellular parabiosis, sharing information and exchanging resources.

The stabilizing effect of that functional complementation allows tumor cells to override the impact of a high mutation load and to continue to proliferate.

The founders have shown in mouse models that the best-connected glioma cells are resistant to chemo- and radiotherapy. Those highly networked cells increase their connectivity in response to cancer therapies and then go on to form another tumor, as seen in human patients.

"The way to think about this is as a social network of cancer cells. By having the ability to share, it gives them a cloak of invincibility," said David Grainger, co-founder and director of Divide & Conquer.

Cancer cells grow really rapidly, making mistakes and inducing mutations that ruin critical proteins they need to survive. "If they didn't make connections, they would die out as a result," Grainger said told BioWorld. Those contacts and sharing not only occur between cancer cells, but also with healthy stromal cells.

Cell-to-cell communication

Cambridge, U.K.-based Divide & Conquer was formed in 2018 with a £10 million (US$12.5 million) series A from venture capital firm Medicxi. The company is advertising its existence and objectives for the first time to coincide with the publication in Nature of the latest research by co-founder Frank Winkler, professor of experimental neuro-oncology at the University of Heidelberg, Germany.

In the paper, Winkler reports the existence of a direct communication channel between glioma cells and neurons in different disease models and human tumors. Those neurogliomal synapses form on tumor microtubes, which are long cellular protrusions on glioma cells that are known to be crucial for communication, and for the invasion and proliferation of those cells.

The research shows neurogliomal synapses consistently formed in the microtubes of incurable human gliomas and were reproducibly and frequently found in the tumor infiltration zone. Structurally, they have all the hallmarks of a glutamatergic chemical synapse, for example, featuring AMPA glutamate receptors.

In comparison, Winkler found that in oligodendroglioma and meningioma, primary brain tumors that can be cured, it was not possible to detect synapses between neurons and tumor cells. That suggests neurogliomal synapses make a specific contribution to the malignant nature of glioma, Winkler said.

In support of that, Winkler and colleagues showed calcium can enter glioblastoma cells via AMPA receptors, sending calcium signals across the cancer cell network.

The subpopulation of glioma cells that was functionally connected to neurons in vivo was significantly more invasive than glioma cells without direct connections. Meanwhile, episodes of tumor cell migration correlated with the frequency of calcium signals.

Confirming a causal link, when AMPA receptor signaling was genetically perturbed, glioma cell invasion was reduced.

The research also showed the approved antiepileptic drug perampanel, an AMPA receptor antagonist, decreased proliferation of glioma cells in xenografted mice.

Divide & Conquer cites papers dating back to 1941 in support of the hypothesis that cell-to-cell communication induces cellular parabiosis and makes tumor cells resistant to cancer therapies. Now, Winkler's latest research takes the field "to the next level," Grainger said.

Disconnecting cells

Since its formation, Divide & Conquer has been carrying out research needed to translate those findings to the clinic.

"What we lacked when we formed the company was understanding of the molecular pathways that formed the connections and how to target them," Grainger said. "We have been working hard over the past 18 months to understand the fundamental biology and create a mechanism to disconnect [glioblastoma cells] so they then become vulnerable."

The company has built up "compelling evidence" that it is possible to disrupt cellular parabiosis. "We have several small-molecule candidates that disconnect the microtubes," Grainger said. "We can cure mice of glioma."

The act of disconnecting cells has no real appreciable effect on its own, though some cancer cells die. "It is not designed to be toxic – the aim is to remove the invincibility cloak," said Grainger.

The intention is that the company's drugs are administered some weeks in advance of conventional chemo- or radiotherapy.

Part of the motivation for Divide & Conquer to remove its mask is the publication of Winkler's latest research. "But it's also because we are on a straight-line path to the clinic," Grainger said.

He expects the first patient to have been treated by the end of 2020. There is increasing evidence for the role of cellular parabiosis in a range of other solid tumors, including triple-negative breast cancer, and pancreatic and lung cancer, and the £10 million series A also gives Divide & Conquer the scope to advance programs in those indications.

According to Grainger, Divide & Conquer is at the forefront of attempts to treat cancer by disrupting cellular parabiosis and has biological insights into what controls the underlying communications networks that are not published. "But I'm certain a year from now, it will be the next big thing in cancer," he said.

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