By Deborah Borfitz 

August 14, 2024 | Cancer cells are “not like superheroes that have no vulnerabilities,” says Matheus Henrique Dias, Ph.D., senior scientist at the Netherlands Cancer Institute (NCI) who has spent the last few years homing in on their most exploitable weakness—excessive oncogenic signaling. Most current therapies try to block the signaling to prevent cancer’s uncontrolled division, but inevitably tumor cells resist the blockage and become far less responsive to subsequent therapy. 

“For the last 30 years we’ve been struggling to find inhibitors for basically all pathways in a cancer cell and we still have people dying from cancer,” he points out. “It’s about time to at least try something different.”  

His proposal is a “paradoxical intervention” whereby tumor cells are purposefully stressed to the point of ruin, much like a speeding car on an oil-slicked track. In the case of colorectal cancer, tumors would be hit with an activator known as LB-100, a protein phosphatase 2A (PP2A) inhibitor made by Lixte Biotechnology. This would effectively prime the cancer cells for elimination by another drug, WEE1 inhibitor adavosertib (AstraZeneca), which targets the protein responsible for repairing tumor DNA damage. 

The approach worked remarkably well in mice, as described in a story published recently in Cancer Discovery (DOI: 10.1158/2159-8290.CD-23-0216). Treatment with the two drugs prevented tumor growth in xenograft models derived from patients who were heavily pretreated with current therapies. “We observed overactivated oncogenic signaling and then the cells would try to block the cell cycle to deal with the stress, and if you inhibit WEE1 they can no longer do that,” says Dias. “They are forced into mitosis with DNA damage.” 

The most interesting part, he adds, is that cancer cells developed resistance by deactivating oncogenic pathways; that is, they could survive only by “behaving like healthy cells.” 

Colorectal, pancreatic, and bile duct cancers were all examined in vitro as well as in vivo (excepting pancreatic) to test the efficacy of the two-drug combo, says Dias. Resistance was tested only in the colorectal cancer models.   

Dias and his team opted to work with Lixte’s lead LB-100 signal activating compound because it was already being tested in a phase 1 clinical trial seeking to confirm its ability to make lung tumors sensitive to chemotherapy drugs. WEE1 inhibitors were also cleared for use in early-phase trials. 

Both types of compounds will again be used in a phase 1b clinical trial getting underway soon at the sponsoring Netherlands Cancer Institute, enrolling over 30 patients with advanced colorectal cancer, he says. “We need to dose escalate with the two drugs in combination because we only have the right dose for each drug as a single agent.”  

Game-Playing With Cancer 

Dias and his colleagues are effectively targeting the most basic difference between cancer and normal cells. But it’s important to remember that to exist and grow cancer cells must deal with the stress of excessive oncogenic signaling, he says. 

With that in mind, the question arose: Would it be possible to use one drug to increase the signaling over a given threshold so that cancer cells become overstressed, and combine that with another drug that targets those overstressed cells? This would be like boosting the speed of cars already moving too fast and spilling oil on the track, says Dias. They’d lose control and crash. 

It has been known for many years that too much oncogenic signaling can be toxic to cancer cells, as inferred by the oft-used term “oncogene-induced senescence” by scientists in the field, he continues. It was later recognized that this might be leveraged for therapeutic purposes. “There was a natural fear that doing so might cause normal cells in the body to turn cancerous. However, the notion that normal cells have ways to control excessive mitogenic signaling for their homeostasis has recently become clear.” 

In a 2021 perspective piece published in Molecular Oncology (DOI: 10.1002/1878-0261.12979), he and the NCI’s René Bernards proposed “playing cancer at its own game” by activating oncogenic signaling and thereby overloading stress response pathways so cancer cells can be killed with stress-targeted drugs. 

They dubbed this a “paradoxical intervention,” a term used in psychotherapy to describe treatments where a pathological behavior is reinforced to improve a clinical condition, he explains. Others investigating the approach have alternatively called it “activation lethality.” 

Besides Lixte Biotechnology, U.S.-based startup Delphia Therapeutics (based on the work from the lab of Bill Sellers, director of the cancer program at the Broad Institute of MIT and Harvard) is one of a small but growing number of companies in the business of developing activators of oncogenic signaling, Dias says. Earlier this year, Delphia announced completion of its $67 million Series A financing. 

Hopping Continents

The paradoxical intervention idea began to develop while Dias was doing postdoctoral research at Butantan Institute in São Paulo, Brazil, studying cell cycle and fibroblast growth factor 2 (FGF2). Puzzlingly, FGF2 was decreasing rather than increasing the proliferation of cancer cells under study, he says. The reason, he was soon to learn, was because FGF2 was over-activating their oncogenic signaling. 

Given that cancer cells all have increased oncogenic signaling and defective feedback to that signaling, “the implication was pretty obvious,” says Dias. If they could block the proliferation of cancer cells by over-activating oncogenic signaling, it could be game-changing for cancer therapy. 

Current chemotherapies have toxic side effects “precisely because they do what they’re supposed to do, but normal cells also depend on most of the pathways affected by these drugs,” he says. “We can potentially have cancer cells being very upset by activation while normal cells are actually healthier because they depend on that signaling.” 

During his postdoc in Brazil, which included time at the University of Liverpool in the UK, he published a paper, published in Molecular Oncology (DOI: 10.1002/1878-0261.12402), about how FGF2 lethality sensitizes cancer cells to stress‐targeted therapeutic inhibitors. In hopes of translating that notion to a clinical trial, Dias says, he joined the lab of René Bernards at the NCI who was studying oncogenic signaling and its toxicity at high levels. Together, they began in earnest to advocate for paradoxical intervention and moved from hypothesis to identification of the drugs they should use for testing in animal models. 

They also hypothesized that the mechanism of resistance to the approach would lead to less aggressive phenotypes “because it goes exactly in the opposite direction” as current therapies, says Dias. “That was exactly what happened.” The resistant cells, when injected in mice, were no longer able to form tumors. 

Inhibitors of specific pathways are often used to treat cancer, but here the tactic is to target the phenotype itself, he reiterates. If a tumor becomes resistant to a current line of therapy, there appears to be no reason the same paradoxical intervention approach wouldn’t result in more normal-looking cancer cells. 

Possibilities with Parasites

The rationale is “much broader” than the LB-100 and WEE1 drug combination the study team is currently investigating and based on solid knowledge in the field, says Dias. Thinking about cancer therapy from this alternative perspective “kind of changes everything... we may come up with a whole new arsenal of therapies that have never, ever been tested.” 

It may also apply to more than just cancer. Study co-author Marcelo Santos da Silva, a professor at the University of São Paulo’s Institute of Chemistry and the one who developed an assay to quantify stress in tumor cells, now plans to apply the paradoxical intervention principle to eliminate parasites that cause neglected tropical diseases to replicate quickly inside host cells, says Dias. 

The idea, in this case, is to use a drug to stimulate the proliferation signaling pathway in parasites to cause the same kind of DNA damage, and then administer another drug to prevent DNA repair—thereby eliminating the parasite without harming host cells. As friends who frequently discuss science, it was “inevitable” that they’d draw parallels between the behavior of parasites and cancer cells, in terms of the speed of their reproduction and super-effective means of protecting their DNA integrity, Dias says. 

Silva just submitted a grant to investigate the possibility of pushing certain parasites “over the edge” by preventing them from slowing or stopping their cell cycle, the way they would normally escape therapeutic targeting, and combining that with a drug aimed at their DNA damage stress mechanism, he adds. If the concept proves true, paradoxical interventions might also become treatments for various parasitic diseases.  

Much more data points in that therapeutic direction for cancer, says Dias, citing one intriguing example. Contrary to expectations, it was recently learned that people with bipolar disorder being treated for years with lithium chloride have a lower incidence of colorectal cancer compared to individuals treated with other types of drugs. The paradoxical part is that lithium chloride activates the WNT/β-catenin signaling pathway known to play a causal role in colorectal cancer.