A novel cancer therapy approach, termed 'paradoxical intervention,' is set to enter clinical trials, aiming to exploit cancer cells' inherent vulnerabilities by intentionally stressing them to the point of self-destruction. This strategy, developed by researchers at the Netherlands Cancer Institute (NCI), seeks to overload cancer cells with excessive oncogenic signaling, making them more susceptible to existing therapies.
The Paradoxical Approach
The core concept involves using one drug to increase oncogenic signaling beyond a critical threshold, thereby overwhelming the cancer cells' stress response pathways. This is then followed by a second drug that targets these overstressed cells, preventing them from repairing DNA damage and forcing them into cell death. Matheus Henrique Dias, Ph.D., a senior scientist at the NCI, likens this to "boosting the speed of cars already moving too fast and spilling oil on the track," causing them to lose control and crash.
Clinical Trial Details
The upcoming phase 1b clinical trial, sponsored by the Netherlands Cancer Institute, will enroll over 30 patients with advanced colorectal cancer. The trial will evaluate the combination of LB-100, a protein phosphatase 2A (PP2A) inhibitor developed by Lixte Biotechnology, and adavosertib, a WEE1 inhibitor from AstraZeneca. LB-100 is designed to activate oncogenic signaling, while adavosertib prevents the cancer cells from repairing DNA damage, ultimately leading to their demise.
Preclinical Evidence
Preclinical studies, published in Cancer Discovery, demonstrated the effectiveness of this approach in mice. The combination of LB-100 and adavosertib prevented tumor growth in xenograft models derived from heavily pretreated colorectal cancer patients. According to Dias, the cancer cells, when faced with overactivated oncogenic signaling, attempted to block the cell cycle to cope with the stress. However, inhibiting WEE1 prevented them from doing so, forcing them into mitosis with DNA damage.
Overcoming Resistance
Interestingly, cancer cells that developed resistance to this treatment did so by deactivating oncogenic pathways, essentially reverting to a state resembling healthy cells. These resistant cells were no longer able to form tumors when injected into mice, suggesting a less aggressive phenotype. This is in stark contrast to current therapies, where resistance often leads to more aggressive and treatment-resistant cancer cells.
Broader Implications
The 'paradoxical intervention' strategy may have applications beyond colorectal cancer. Marcelo Santos da Silva, a professor at the University of São Paulo’s Institute of Chemistry, is exploring the use of this principle to eliminate parasites that cause neglected tropical diseases. The idea is to stimulate the proliferation signaling pathway in parasites, causing DNA damage, and then administer a drug to prevent DNA repair, thereby eliminating the parasite without harming host cells.
Dias emphasizes that this approach represents a fundamental shift in how we think about cancer therapy. By targeting the core differences between cancer and normal cells, it may be possible to develop a new arsenal of therapies with fewer toxic side effects. He also noted that lithium chloride, used to treat bipolar disorder, has been linked to a lower incidence of colorectal cancer, potentially due to its activation of the WNT/β-catenin signaling pathway.
