Cancer thrives by hijacking the body's own basic survival systems, making it hard to attack tumors without collateral damage and side effects. Now, researchers at Cornell's Weill Institute for Cell and Molecular Biology have discovered what may be a less invasive strategy that shows promise as a potential therapeutic pathway.
New research has uncovered molecules that can preserve crucial cellular processes while blocking malignant proteins from their preferred attachment points on the healthy cell. The findings indicate a new approach to fighting cancer, one that triggers apoptosis-the self-destruct process-in melanoma and bone cancer cells.
The study, published Oct. 6 in the Journal of Medicinal Chemistry, was led by graduate student Nathan Frederick in collaboration with Jeremy Baskin, associate professor and Nancy and Peter Meinig Family Investigator in the Life Sciences in the Department of Chemistry and Chemical Biology in the College of Arts and Sciences, and the Weill Institute for Cell and Molecular Biology. It describes the discovery of the first compounds that directly target a family of proteins called PLEKHA, which help cancer cells grow and spread by interpreting lipid "messages" on cell membranes.
Inside every cell, phosphatidylinositol phosphate (PIP) lipids act like address labels, guiding proteins to the right locations and telling them when to act. Many cancers hijack these signals to keep dividing. Existing drugs that block the enzymes making PIPs can slow tumors but also disrupt vital processes that keep healthy cells functioning-particularly those controlling metabolism, immunity, and the ability for tissues to maintain a stable internal environment. These disruptions then lead to serious side effects, Frederick said.
The team in the Baskin lab flipped the problem around. Rather than turning off PIP production, they aimed to jam the signal receivers-the pleckstrin homology (PH) domains that allow PLEKHA proteins to grab onto lipid molecules. "We wanted to stop the lipid message from being read instead of silencing the entire system," Frederick said.
Using computer modeling, the researchers screened more than 90,000 drug-like compounds to find those that could fit into the PH domain of PLEKHA4, a protein linked to melanoma growth. They discovered one molecule, called NF1, that bound tightly to the lipid pocket and competed with PIPs for space.
The team then created and tested chemical variations to fine-tune how well the compounds bound PLEKHA both in isolation and within cells. One version, NF14, worked especially well. They found it starts as an inactive "prodrug" that easily enters cells, and then once inside cells it's converted into NF1 by natural enzymes, activating its cancer-killing potential.
When tested on melanoma and bone cancer cell lines, NF14 disrupted PLEKHA proteins' grip on the cell membrane, triggering a chain reaction whereby the cells stopped dividing and triggered their own death through apoptotic pathways. Importantly, it showed little effect on cancer cells that make few PLEKHA proteins, suggesting it was hitting its intended target.
PLEKHA molecules are competed off the plasma membrane of SK-MEL2 cells by NF14
The results mark one of the first proofs that PH domains-long considered too tricky for drug design-can be selectively targeted, Baskin said. Because PH domains vary subtly among protein families, this approach could lead to more precise cancer drugs with fewer side effects.
"This shows that lipid signaling can be controlled in a more surgical way," Baskin said. "Instead of shutting down an entire pathway, we can go after just the part that's participating in cancer cell reproduction."
The researchers are now exploring how to optimize these compounds for potency and safety. Beyond melanoma and bone cancer, similar strategies might one day help treat immune or metabolic disorders caused by faulty lipid signaling.
The research was supported by funding from the National Institutes of Health, the Weill Institute of Cell and Molecular Biology, and made use of the Cornell University NMR Facility in the Department of Chemistry and Chemical Biology, which is supported in part by the National Science Foundation.
Henry C. Smith is the communications specialist for Biological Systems at Cornell Research and Innovation.
