In November 2014, biologist Miroslav Radman was thinking a lot about social networks, but not the kind we obsess over on our computers and phones. Instead, he was interested in the social networks of cells. Radman hypothesized that physical connections between cancer cells might allow them to share molecules with each other and resist treatments that ought to kill them.
During a visit to Cambridge, England, Radman explained the idea to his friend and business partner David Grainger, a venture capitalist at Medicxi. “He talked to me for about an hour,” Grainger recalls. “Very strikingly, without much evidence.”
A year later, a team of scientists led by Frank Winkler at the German Cancer Research Center in Heidelberg published a paper showing that structures called tumor microtubes help brain tumors resist radiation therapy. These structures protrude from cancer cells and form tunnels between them. When microtube formation was blocked, the cancer cells were susceptible to treatment and died (Nature 2015, DOI: 10.1038/nature16071).
Radman’s ideas were no longer hypothetical. And to him and Grainger, the implications were obvious.
The pair began working on plans for a biotech company that would make drugs that break down those cellular communication networks in cancer. Together with Winkler and another Medicxi partner, Moncef Slaoui, they cofounded Divide & Conquer in the spring of 2018. Now, the company is officially emerging from stealth mode with $13.1 million in series A financing from Medicxi and plans to test its first experimental therapy in humans by the end of next year.
With Grainger as its director, the start-up has developed a small molecule that its founders hope will disassemble tumor microtubes. That molecule is designed to turn on an enzyme called protein kinase C, which Grainger describes as “the master regulator of how well-connected a cell chooses to be to its neighbors.” When protein kinase C is activated, it phosphorylates and disables another protein that’s important for the growing ends of tumor microtubes and causes the structures to fall apart.
Grainger and Winkler have an elegant theory that explains why these microtubes are so critical to tumors. Most cancer therapies kill cancer by activating apoptosis, the process of cellular suicide. A key trigger for apoptosis is calcium, Grainger explains, and when calcium levels get too high, apoptosis begins. Cancer microtubes allow cells to easily distribute excess calcium, allowing those damaged by cancer treatment to survive.
In the clinic, Grainger hopes that Divide & Conquer’s protein kinase C activators will break down cancer microtubes and leave tumors susceptible to apoptosis after being bombarded with chemotherapy or radiotherapy. “We are disconnecting and removing their cloak of invincibility,” he says.
Winkler’s team has continued studying the role of cancer microtubes, particularly in glioblastoma. His group, and two others, recently independently published three papers in Nature showing that tumors can use their microtubes to plug into healthy neurons of the brain as well (Nature 2019, DOI: 10.1038/s41586-019-1564-x, DOI: 10.1038/s41586-019-1563-y, DOI: 10.1038/s41586-019-1576-6).
For now, Divide & Conquer is focusing on glioblastoma, where the importance of cancer microtubes is most apparent. But Grainger says microtubes may also be important in other notoriously tough-to-treat tumors, such as triple-negative breast cancer.
It will be a couple years at least before the start-up has an idea of whether its cellular-communication-jamming strategy will work. As a founding partner of Medicxi, Grainger has evaluated a lot of ideas for companies. “I always said I would never invest in a cancer company,” he says. “And yet here I am doing this.”