Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside
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<jats:title>Abstract</jats:title><jats:p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.</jats:p>
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Bao, Xuhui, Yongjun Liang, Hanman Chang, Tianji Cai, Baijie Feng, Konstantin Gordon, Yuekun Zhu, Hailian Shi, et al. (n.d.). Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduction and Targeted Therapy, 9(1). 10.1038/s41392-023-01690-3 Retrieved from https://hdl.handle.net/10161/29666.
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Xuhui Bao
Cancer remains a significant global public health challenge and is the second leading cause of mortality in the United States. While traditional treatments such as surgery, chemotherapy, and radiotherapy have seen incremental advancements, the prognosis for many cancer patients continues to be poor. Over the past decade, the advent of novel targeted therapies, combination treatments, and immunotherapies has revolutionized the clinical approach to cancer care, offering new hope and changing treatment guidelines.
These innovative therapies have been successful in significantly prolonging the lives of 10-30% of patients, marking a milestone in cancer treatment. However, the majority of cancer patients still do not benefit from these novel immunotherapies, highlighting a clear need for more effective treatment modalities. The urgency to improve patient outcomes has sparked intense research into the discovery of new antitumor targets, a deeper understanding of resistance mechanisms to current immunotherapies, and the intricate dynamics of the tumor microenvironment.
Looking forward, the focus is on developing precision oncology strategies that can address these challenges. This includes not only identifying novel therapeutic targets but also unraveling the complex interactions within the tumor microenvironment that contribute to therapeutic resistance. By doing so, we aim to expand the arsenal of effective treatments and pave the way for more personalized and successful cancer therapies in the future.
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