Researchers at Cornell University’s Weill Institute for Cell and Molecular Biology have unveiled a promising strategy to combat cancer. Their study, published on October 6, 2023, in the Journal of Medicinal Chemistry, reveals a novel approach that targets specific proteins involved in cancer cell growth while preserving essential cellular processes.
Targeting Cancer’s Communication Signals
Cancer cells often exploit the body’s basic survival mechanisms, making treatment challenging and frequently resulting in collateral damage to healthy tissues. The research team, led by graduate student Nathan Frederick and Jeremy Baskin, an associate professor and investigator in the Life Sciences, discovered molecules that can disrupt malignant proteins’ interactions without shutting down vital cellular functions.
The focus of the study is on the PLEKHA family of proteins, which play a crucial role in interpreting lipid signals on cell membranes. These lipids, specifically phosphatidylinositol phosphate (PIP), act as guiding messages, directing proteins to their appropriate locations within cells. Many cancers leverage these signals to promote uncontrolled growth. Traditional therapies that inhibit the enzymes producing PIPs can hinder tumor growth but also affect normal cellular activities, leading to significant side effects, according to Frederick.
Innovative Approach to Drug Design
Instead of blocking PIP production, the research team aimed to obstruct the signal receivers, known as pleckstrin homology (PH) domains, that allow PLEKHA proteins to bind to lipid molecules. “We wanted to stop the lipid message from being read instead of silencing the entire system,” Frederick explained.
Utilizing advanced computer modeling, the researchers screened over 90,000 drug-like compounds to identify those capable of binding to the PH domain of PLEKHA4, a protein associated with melanoma progression. They discovered a compound named NF1, which competes with PIPs for binding sites, effectively blocking the cancer-promoting signals.
Further refinement led to a more effective variant, NF14, which acts as a prodrug. This means it can easily enter cells and is converted into the active NF1 form by natural enzymes once inside. Laboratory tests on melanoma and bone cancer cell lines demonstrated that NF14 disrupts the adhesion of PLEKHA proteins to cell membranes, initiating a self-destruct process known as apoptosis. This mechanism halted cell division and triggered the demise of cancer cells.
Importantly, NF14 exhibited minimal effects on cells with low PLEKHA expression levels, indicating its targeted action. According to Baskin, the results represent a significant advancement, suggesting that PH domains, previously deemed difficult for drug design, can indeed be selectively targeted.
This research offers hope for developing more precise cancer therapies, potentially leading to treatments with fewer side effects. “This shows that lipid signaling can be controlled in a more surgical way,” Baskin noted. “Instead of shutting down an entire pathway, we can go after just the part that’s participating in cancer cell reproduction.”
The team is now focused on optimizing these compounds for both potency and safety. Beyond melanoma and bone cancer, similar methodologies may prove beneficial in treating immune or metabolic disorders arising from dysfunctional lipid signaling.
This significant research effort was supported by funding from the National Institutes of Health, the Weill Institute for Cell and Molecular Biology, and utilized resources from the Cornell University NMR Facility, partially funded by the National Science Foundation.
As cancer treatments continue to evolve, this innovative approach could pave the way for a new generation of therapies that effectively combat malignancies with greater precision.
