[co-authors: Kim Beane, and Daniel Meckley]
Photo by National Cancer Institute on Unsplash
Cancer is a horribly painful and debilitating illness, but would you ever call it “diabolical”? What about “conniving”? You might after you hear about the latest research out of Vanderbilt University showing that cancer cells adjust their metabolic profile to evade the effects of treatment. A team of scientists has shown certain melanomas that initially respond well to a particular treatment, ultimately reprogram their metabolism to defeat the ongoing exposure to that same treatment and continue to grow. The good news is that this discovery opens the door to learning how the cells do this, and then, how to stop them.
It is well known that some bacterial infections can be resistant to specific antibiotics.
MRSA, or Methicillin-resistant Staphylococcus aureus, is a bacterium that causes infections that are resistant to penicillin-related antibiotics. These cells that “resist” the antibiotic treatment, in this case, Methicillin, also have an altered metabolism. The Vanderbilt researchers have found a similar principle at work with melanoma.
Their article, “An Integrative Gene Expression and Mathematical Flux-Balance Analysis Identifies Targetable Redox Vulnerabilities in Melanoma Cells,” was published in the journal Cancer Research this past October. It sounds complicated, but in its most basic form, they figured out which cancer cells wouldn’t die with treatment, and determined how they got their energy to stay alive.
Analyzing cancer cells that were responsive to treatment, as compared to cancer cells that were resistant to treatment, they looked at the energy the cells utilized before and after therapy. Using metabolomics (meh·tuh·buh·laa·muhks), which is the measurement of certain substances necessary for metabolism, and machine learning to classify the cells, they discovered that the source of energy for the drug-resistant cells was “centered around redox balance and NOX5, an enzyme that is elevated in melanomas resistant to treatment.” Translation: the resistant melanoma cells were using the NOX5 enzyme to generate energy, maintain their chemical balance, evade treatment and stay alive.
The next step for the Vanderbilt team is to either find a way to destroy the NOX5 enzyme entirely, or inhibit its antioxidant ability. Doing either of these things should make the cells that became resistant to the treatment become responsive to the treatment, i.e., cut them off at the pass.
And while this study was for melanoma, it opens the door for other cancer researchers and scientists to identify enzymes that may be enabling the growth of cancers with drug-resistant cells to stay alive. After that, moving in to exploit the cells’ vulnerabilities and creating new therapeutic strategies may not be far behind.
Dr. John McLean, professor and chair of the Department of Chemistry at Vanderbilt, believes that the data their team found regarding NOX5 and redox balance as the basis for survival of the treatment resistant cancer cells is going to “change the way that the entire cancer research community thinks about curing cancer.”
Melissa Shapiro. Interdisciplinary melanoma research brings understanding of cellular resistance to cancer treatment, opening doors to new cures, (https://news.vanderbilt.edu/author/shapim2/) Oct. 21, 2020
B. Bishal Paudel, Joshua E. Lewis, Keisha N. Hardeman, Corey E. Hayford, Charles J. Robbins, Philip E. Stauffer, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Melissa L. Kemp, and Vito Quaranta. An Integrative Gene Expression and Mathematical Flux Balance Analysis Identifies Targetable Redox Vulnerabilities in Melanoma Cells, Cancer Res; 80(20) October 15, 2020.
Dongya Jia, B. Bishal Paudel, Corey E. Hayford, Keisha N. Hardeman, Herbert Levine, José N. Onuchic and Vito Quaranta. Drug-Tolerant Idling Melanoma Cells Exhibit Theory-Predicted Metabolic Low-Low Phenotype, Frontiers in Oncology Volume 10, Article 1426, August 2020.