For decades, cancer drug developers have focused on inhibition. Now, a GV-backed startup is eyeing activation

One of the backbones of cancer medicine is shutting down key cancer-driving pathways to kill tumor cells. But for years, researchers have noticed hyperactivation of certain signals in these pathways can lead to the same result.

Researchers from Bill Sellers’ lab at the Broad Institute wanted to figure out how widely hyperactivation could be applied to kill tumor cells. They explored over-activating three major cancer-driving pathways across nearly 500 cell lines, and they found that over-activating certain signals in all three pathways could keep tumor cells at bay, according to a new study in Nature Genetics published Monday.

Kevin Marks

The researchers also detailed a new hyperactivation signal that stopped the growth of tumors for a mutation found in 80% of colorectal cancer patients.

Based on the findings, Sellers is co-founding Delphia Therapeutics, with an aim to develop new cancer drugs based on activating key pathways. It’s backed by Google’s venture arm GV and led by GV entrepreneur-in-residence Kevin Marks, according to business filings in Massachusetts. Marks, who spent nearly 12 years at Agios, joined GV last year from Novartis. (David Schenkein, who co-leads GV’s life sciences team, was the founder and longtime CEO of Agios.)

Delphia is still in stealth. “We at Delphia Therapeutics are enthusiastic to leverage activation lethality to create a new class of cancer medicines, and we look forward to sharing more about our plans and projects in the future,” Marks told Endpoints News.

He did not provide additional comments.

Liang Chang

Sellers was previously head of oncology at the Novartis Institutes for BioMedical Research before returning to academia in 2016. Liang Chang, who recently completed his PhD in Sellers’ lab and is the study’s first author, told Endpoints they devised the project for his dissertation. “We wanted to do something that was big and forward-looking,” Chang said.

Chang, who is now an associate at Cure Ventures, declined to comment on Delphia, noting that he was not directly involved with the startup.

Chang said past studies found that tumors that develop resistance to BRAF inhibitors are essentially “addicted to the drug.” So when the drug is taken away, the cells start to die. In other words, the cells become vulnerable to additional activation of the pathway that the inhibitors blocked.

The researchers developed a method to test 488 cancer cell lines at the same time. They decided to activate certain signals in each of the three pathways, and what they found was that overactivation substantially slowed the growth of cells with certain mutations for each pathway.

“The cells already with higher basal levels are the ones that are most vulnerable,” Chang said.

For instance, PI3K activation was most lethal for endometrial cancer cells with a specific double mutation that had the highest levels of PI3K signaling at baseline. In colorectal cancer cells with APC mutations, overactivation of another pathway called Wnt also slowed tumor cell growth.

The researchers then took the study one step further. In patient-derived organoids, they found that overexpression of a signal in that pathway harmed the organoids with APC mutations, but not the organoid without the mutation. And in mice with a xenografted APC-mutant tumor, the overexpression of the same signal slowed tumor growth.

That said, there are safety concerns with overactivation. In the paper, the study’s authors note that the risk associated with activating these pathways in normal tissue cells is not yet known.

The research is still in its early stages. “This is high-risk, high-reward, and a lot of hard work still needs to be done,” Chang said. “But I think that there’s a very interesting possibility ahead to think about how to do cancer therapeutics differently.”

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