The Bernards laboratory found a counterintuitive approach to combating cancer cells. The development of targeted cancer therapies has enabled the selective inhibition of activated oncogenic signaling pathways, with many new drugs inhibiting the processes cancer cells need to divide rapidly. But over time, the cells become resistant to the effect of the drugs and become unresponsive to treatment. Bernards found a counterintuitive approach - a ‘paradoxical intervention’ - which means that instead of attempting to inhibit oncogenic signaling, his laboratory researched the effect of further activating mitogenic signaling to disrupt the labile homeostasis of cancer cells and overload stress response pathways. Such overactivation can be combined with stress targeted drugs to kill overstressed cancer cells.

He found that the inhibition of Protein Phosphatase 2A (PP2A) with Lixte’s drug LB-100 hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identified combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. The data Bernards and his team found suggested that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

“Oncode Institute supports high-risk high-gain research, and we started this research with the support of the Oncode funding” says Bernards. “Initially the idea seemed so unusual, we could have never gotten funds from any other source” he adds.

His collaboration with LIXTE began two years ago. LIXTE owns an unusual drug, LB-100, which was initially developed for different purposes. Bernards and his team discovered that LB-100 can further activate oncogenic signaling in cancer cells, making them grow slower instead of faster. They spent one year trying to understand which of the stress responses are essential, and discovered that using a WEE1 inhibitor, combined with LB-100 results in efficient cancer death.

“LB-100 is an exceptional small molecule, as it is able to both enhance responses to immune checkpoint inhibitors and the action of chemotherapeutic agents. Given that both classes of drugs have limited activity in the clinic, agents that enhance their efficacy are urgently needed” says Bernards.

“The partnership with NKI and Oncode Institute gives us great opportunity to gain new insights into the molecular mechanism that underlie the anti-cancer effects of LB-100. The collaboration was highly successful in the first two years and we are looking forward to working with NKI and Oncode Institute to bring these discoveries to the clinic” says Bas van der Baan, Chief Executive Officer of LIXTE.