A groundbreaking study published in the European journal of pharmacology on January 14, 2024, by a team led by researchers from the Tianjin Medical University, China, has brought new hope for individuals suffering from pancreatic cancer (PC). This malignant disease is known for its lethal agility, presenting one of the lowest survival rates among cancers. However, the scientists have made a significant leap forward by identifying potential drug candidates for repurposing as PC therapy through a combination of virtual screening and experimental validation.
Pancreatic cancer stands as an ominous specter in the oncology community, notoriously difficult to treat due to its aggressive nature and tendency for late detection. With a disheartening 5-year survival rate hovering around 11%, research and development in this field are of paramount importance and urgency. The disease’s hostile tumor microenvironment, characterized by a stiff interstitium and constricted blood vessels, coerces cancer cells into relying excessively on glycolysis for energy—a phenomenon famously known as the “Warburg effect.”
Central to this metabolic shift is the enzyme PFKFB3, which catalyzes a crucial step in glycolysis. It produces fructose-2,6-bisphosphate, a potent activator of another enzyme, PFK1, that accelerates glycolytic flux. By inhibiting PFKFB3, there could be a reduction in the glycolytic rate, thus hampering the tumor’s growth potential by throttling its energy supply.
With this knowledge at hand, researchers, including Cao Xin, Jiang Xiao, Zhong Zhi-Xin, and others, undertook a massive computational trek through the archives of the FDA-approved compound library to discover candidates that could inhibit PFKFB3. Their journey led them to identify 14 promising inhibitors via molecular docking techniques—a method of computer simulation to predict how a drug binds to its target enzyme.
Lomitapide and Cabozantinib S-malate emerged as the stars of this exploration. Subsequent experimental studies coalesced these computational predictions with reality—the two drugs were confirmed to possess an exceptional ability to stifle PFKFB3’s activity.
The team didn’t stop there. They pressed on to test the effectiveness of these inhibitors in biological systems. In a significant revelation, the combination of Lomitapide with the chemotherapy agent Gemcitabine showed an amplified anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This result indicates a potential synergy between the repurposed drug and standard chemotherapy, opening avenues to enhance treatment efficacy dramatically.
The study’s DOI, 10.1016/j.ejphar.2024.176330, serves as a digital identifier linking directly to the published work, allowing interested scholars and medical professionals to delve into the specifics of this promising discovery.
The authors, who disclosed no competing interests, hint at a radical shift in therapeutic strategy for pancreatic cancer. Much-deserved credit also goes to researchers Ni Tian-Wen, Liu Lu, Li Xiao-Lei, Yu Yang, Chen Ying, Qin Nan, and Duan Hong-Quan, who contributed to this transformative work.
This cutting-edge research, a model of drug-repurposing by virtual and experimental screening, provides a much-needed glimmer of hope in a field that has seen frustratingly slow progress in treatment development. Such innovative endeavors underscore the significance of multidimensional research, integrating computational prowess with clinical insight to outmaneuver one of the most formidable cancers known to man.
Keywords
1. Pancreatic Cancer Treatment
2. PFKFB3 Inhibitors
3. Drug Repurposing
4. Lomitapide
5. Cabozantinib S-malate
References
1. Cao X., et al. (2024). Drug-repurposing by virtual and experimental screening of PFKFB3 inhibitors for pancreatic cancer therapy. European Journal of Pharmacology, 176330. doi:10.1016/j.ejphar.2024.176330
2. American Cancer Society. (2023). Cancer Facts & Figures 2023. American Cancer Society. [Online resource].
3. Siegel, R. L., Miller, K. D., & Jemal, A. (2023). Cancer Statistics, 2023. CA: A Cancer Journal for Clinicians, 73(1), 7-30. doi:10.3322/caac.21708
4. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930), 1029-33. doi:10.1126/science.1160809
5. Röhrig, F., & Schulze, A. (2016). The multifaceted roles of fatty acid synthesis in cancer. Nature Reviews Cancer, 16(11), 732-749. doi:10.1038/nrc.2016.89
The quest to cure pancreatic cancer continues with renewed vigor as researchers relentlessly seek ways to outsmart this cunning adversary. Long may this spirit of innovation and dedication thrive, lighting the path toward a future where cancer no longer marks an intractable death sentence but a challenge surmountable by human ingenuity.