WCLC 2025 | Cancer cachexia in locally advanced non small cell lung cancer

Yeah, so basically, cancer cachexia is a wasting syndrome. It shows up in about 50% of all patients with solid tumors, and 30% of, and it’s responsible for 30% of all cancer-related deaths. So in lung cancer, its incidence is about 30 to 40% of all non-small cell lung cancer patients, and it gets higher with advanced disease. And when I say wasting syndrome, it’s basically patients start developing anorexia. They start developing muscle and fat loss. And it’s because we think a directed program from tumors that promote this breakdown in order to supply themselves energy for continued growth. And so unfortunately, there are no FDA-approved regimens for the management of cancer cachexia. There’s no biomarkers ideally used for cachexia determination and prediction. And so our group developed a very comprehensive program to try to better understand cancer cachexia development, try to understand the biology of cachexia in the hopes of developing biomarkers, mechanistic insight into the biology, and ultimately therapeutic interventions. And so one of the early things we did is we established a screen where we looked at tumors that are derived from human patients. We put them back into mice, and some of them caused wasting, some of them did not. And then what we did is we used whole exome sequencing to try to understand if there were any genetic mutations in genes that associated with the tumors that caused cachexia in mice versus the ones that did not. And one of the only major genes that was mutated frequently in the setting of cachexia was STK11, also known as LKB1. And this is an energy-sensing gene. It’s involved in nutrient sensing by the cell. And so when times are good, this gene is not active and the tumor cells proliferate very rapidly. When there’s a deprivation of nutrients, this gene is activated under normal circumstances and tells the tumor cell, hold off on using too much energy. Let’s control our energy to continue to survive. So it’s both a survival gene as well as a nutrient-sensing gene. So in cancers, in 15% of all non-small cell lung cancers, this gene is mutated, and it really is necessary for driving the cancer development. So the fact that we identified mutations in this gene to associate with cachexia was a very unique finding. The second aspect of our research was to say, now that you have a loss of this gene function, what is the downstream result of that? Why do we see cachexia? And what we discovered is that in tumors that have a loss of function of STK11 or LKB1, they actually secrete a molecule called GDF15. And GDF15 is a very important hormone that goes to the brain and activates certain parts of the brain and sends a signal saying, don’t eat. And so it’s a pro-anorexia signal. So we think that this axis of a loss of STK11 leading to the induction of GDF15 and other cytokines are what lead to the cachexia development in our patients. And interestingly enough, there are actually clinical trials now that are trying to block the signaling of GDF15 in order to allow those patients not to have the wasting of the muscle and the fat and the anorexia that we see. And the reason that this is all important is that despite or independent of any tumor-directed therapy, if you have cachexia, you live half as long as the same patient with the same cancer and the same stage of disease who does not have cachexia. So it’s very important that if we reverse or suppress cachexia, then we can improve survival and independent of any tumor-directed therapy. And so that was kind of the gist of the presentation. And then the final thing I pointed out in the presentation is that we sometimes view all of the mutations in a gene as behaving the same. But what we’re finding out in the field of oncology is that not every mutation is quote-unquote created equal. Some mutations retain some function, some retain other functions. And we need to do a better job of understanding exactly what each mutation represents before we start including or excluding patients as part of clinical trials. And so that’s another aspect of the work that we’ve been trying to accomplish.

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