Depriving cancer cells of vital nutrients is a well-established strategy in cancer treatment. However, what if we took a different approach and disrupted the cancer cells by blocking their ability to eliminate toxic substances that can accumulate within them? This groundbreaking concept is at the core of the Nature paper recently published by Dohoon Kim, PhD, and his team, as well as their associated project supported by the BRIDGE Innovation and Business Development Office's Bridge Fund.
When cancer cells undergo metabolism, they convert enzymes into metabolites (substances generated within cells during chemical reactions). Some of these metabolites are toxic and pose a hazard at higher levels, necessitating their breakdown for cell survival. Normally, the cells produce an enzyme that detoxifies these metabolites, acting as a safeguard. However, what if we intervened by inhibiting this detoxifying enzyme's function?
By developing a drug to block this detoxifying enzyme, we can induce the death of cancer cells. Importantly, healthy cells do not produce excessive amounts of these toxic metabolites. Therefore, any inhibitor designed to block the detoxifying enzyme will selectively target and eliminate cancer cells.
"We are pioneers in our approach. While other teams focus on depriving cancer cells of essential nutrients, we are exploring the other side of the coin—identifying what accumulates when you remove the enzyme responsible for detoxifying these toxic metabolites,"explains Dr. Kim.
Clogging the kitchen sink
To illustrate their strategy, the team draws an analogy to a kitchen sink, where the faucet represents the upstream metabolic enzyme producing the toxic metabolite, and the drain symbolizes the detoxifying enzyme. In cancer cells, the faucet is gushing toxic levels of metabolites, while in healthy cells, it's barely dripping. By inhibiting the detoxifying enzyme, we're clogging the drain allowing the metabolite to accumulate to toxic levels in cancer cells.
Both the recent Nature paper and the translational project supported by the BRIDGE fund, focus on lung cancer. In this particular cancer type, lung cancer cells often express unusually high levels of an enzyme known as UDP-glucose 6-dehydrogenase (UGDH), resulting in a high production rate of UDP-glucuronic acid (UGPDA). Normally, another downstream enzyme called UDP-glucuronic acid decarboxylase 1 (UXS1) detoxifies UDPGA. When UGPDA isn't cleared, the Golgi apparatus, a crucial part of the cell involved in processing and transporting proteins to the cell surface, malfunctions, leading to cell death.
Cancer cells express high levels of the enzyme UGDH (right). If the detoxifying enzyme UXS1 is blocked, toxic levels of the metabolite UDPGA will accumulate, killing the cancer cells. Normal cells (left) can live because they don’t express nearly as much UGDH.
Exploring translational potential
This project holds promise for clinical translation for several reasons. UGDH is highly expressed in many lung cancers and can serve as a biopsy biomarker to identify patients who might benefit from a drug-blocking UDPGA neutralization. Secondly, Dr. Kim’s team identified that UGDH is elevated in chemoresistant cancer cells, suggesting that targeting UXS1 may be particularly attractive in treatment-resistant tumors. Furthermore, because UXS1 is an enzyme, it is inherently "druggable" equipped with a catalytic pocket where drugs can attach and work their magic.
Dr. Kim's team will begin by screening numerous compounds to identify those that can effectively block UXS1. They'll then make small adjustments to enhance the drug's suitability for human use, such as increasing solubility and reducing toxicity. The ultimate goal is to identify one or two compounds with potential for clinical trials for cancer treatment.
Dr. Kim explains the significance of the BRIDGE Fund, saying, “The BRIDGE Fund gives me an excellent opportunity because even though my lab uncovered multiple new cancer targets, without these funds, I face a barrier to turning [our discoveries] into workable compounds ready for clinical trials."
The approach of inducing an accumulation of toxic substances within cancer cells during their metabolic processes is a novel strategy applicable to a wide range of cancer types. As Dr. Kim notes, the more cancers that feature overproduced enzymes, the more Achilles' heels they can identify. They plan to apply this innovative method not only to cancers that overexpress UGDH but also to other cancer types, expanding the arsenal in the fight against cancer, and pushing it to the sidelines
