Divide & Conquer: short-circuiting tumor lines of communication

Divide & Conquer aims to prevent cancer cells from sharing resistance mechanisms via multicellular networks

Divide & Conquer aims to capitalize on new tumor biology that would prevent cancer cells from sharing resistance mechanisms and resensitize the tumor to chemo- and radiotherapy.

Medicxi’s David Grainger founded the company in 2018 based on the research findings of co-founders Miroslav Radman and Frank Winkler.

Grainger, who is the company’s executive chairman, told BioCentury that Radman was first to propose that tumor cells, which harbor various mutations that could hinder their survival, must share materials with each other and healthy cells that help them grow and proliferate. Radman is a professor of cell biology at Paris Descartes University and a co-founder of the Mediterranean Institute for Life Sciences.

A Nature paper published in 2015 by Winkler and colleagues at Heidelberg University demonstrated how this sharing occurs. They found glioblastoma cells create passageways, called microtubes, between each other to form large interconnected networks through which they share resources over long distances.

The Winkler paper also showed that radiotherapy was able to kill GBM cells with few or no microtube connections; whereas highly connected cells were resistant.

Grainger suggested that these “highly connected” tumor cells may correspond to the elusive cancer stem cells, a group of tumor cells whose identity has never been revealed but are difficult to eliminate and lead to recurrent disease.

Furthermore, a new Nature paper published Wednesday found these GBM cells also establish microtube connections with neurons that contribute to tumor progression.

In parallel with Winkler’s work, Grainger said the Divide & Conquer team was tackling the question of how these connections make tumor cells resistant to chemo- and radiotherapy.

Grainger noted that the critical requirement for triggering cellular apoptosis is an influx of calcium large enough to activate the caspase cascade.

When attacked by T cells or highly toxic agents that cause such calcium spikes, the highly connected cancer cells are able to shuttle the calcium through the tumor microtubes to other cells in the network, lowering the peak calcium concentration and avoiding apoptosis.

“Imagine what happens if I’m connected to lots of other cells. As soon as the calcium rushes into me, I equilibrate that across a massive network that includes normal cells,” Grainger said. “The most connected cells essentially become invincible, they can never enter apoptosis no matter how hard you hit them, because they have so many connections they are able to share the pain and survive.”

Divide & Conquer aims to resensitize tumor cells to therapy by disconnecting these microtube networks.

Grainger said part of the challenge is that most healthy tissues in the body use similar microtube networks to protect themselves from becoming cancerous in the first place, because the connections impair the ability of any one cell to stray too far from its baseline phenotype.

The hope is that short-term inhibition of the networks will provide a workable therapeutic window. While healthy tissues require the networks for “robustness over the long term, they can cope without it for a short period of time,” said Grainger.

Grainger said Divide & Conquer’s lead therapeutic targets are members of the protein kinase C (PKC) family.

He noted PKC is activated when a cell enters apoptosis, divides or differentiates into a different phenotype. “This immediately withdraws the connections with the cells around it. The cell isolates itself, which allows for autonomy,” Grainger said. “We are only really leveraging the mechanism by which your body is doing this in embryogenesis or a normal adult.”

The idea is to immediately follow the short, re-sensitizing treatment with chemotherapy and radiotherapy to kill the newly vulnerable tumor cells.

While Grainger declined to disclose details regarding Divide & Conquer’s PKC agonist programs, he did say the chemistry was complex enough such that the biotech wasn’t simply repurposing existing PKC agonist compounds.

He said the company has data implicating tumor microtube networking in drug-resistant triple-negative breast cancer (TNBC), and is looking at other hard-to-treat tumor types such as pancreatic, lung and colorectal cancer.

Leo Pharma A/S markets PKC modulator Picato ingenol mebutate gel to treat actinic keratosis, while eight other therapies targeting different PKC enzymes are in the clinic for autoimmune, cancer, dermatology and neurology indications. However, none of them are in development for the same indications Divide & Conquer is targeting.

According to BioCentury’s BCIQ database, 23 other programs have been discontinued targeting PKC, of which nine were in development to treat solid tumors.

Divide & Conquer raised £10 million ($13.1 million) in a series A round last year. Grainger said the capital should fund the company’s lead program through a first clinical trial, which it expects to start next year.

Though the microtube hypothesis is still relatively new, it isn’t wholly new. For example, a group at the University of California San Diego discovered that hematopoietic stem cells were capable of differentiating into macrophages that then used nanotubes to transfer wild-type protein into diseased liver cells (see “All-Purpose HSCs”).

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