A new model of cancer-related cachexia promises to help scientists understand why patients with cancer show severe wasting, which in turn may drive the development of better therapies.
Cachexia refers to the excessive weight loss and the characteristic wasting due to loss of skeletal muscle, seen in at least half advanced cancers. It is often associated with systemic inflammation and anorexia. 70% of patients with pancreatic cancer show severe weight loss, but it is also seen in cancers of the lung, esophagus and colon. The reasons for this syndrome are poorly understood, leading to a paucity of options to treat it. In fact, supplementary nutrition fails to prevent or treat it.
Skeletal muscle is the most plentiful tissue in the body. Cachexia is important because it not only causes the body to consume away, chiefly by the loss of skeletal muscle tissue, but also hinders cancer treatment by weakening the patients. This reduces their ability to tolerate the frequently harsh adverse effects of cancer therapy, and causing increased resistance to treatment.
One bottleneck in cancer cachexia research may now have been addressed with the development of the new mouse model of adenocarcinoma of the pancreas. The model, called KPP, shows a close similarity to human cancer cachexia, with increasing wasting as the cancer progresses. This was achieved by genetic engineering methods and results in a novel model which is not subject to the usual limitations of studying cachexia in animal models. For instance, in animals cachexia is associated with widespread or large tumors, weighing 10% or more of the body mass, unlike in humans. They also cause cachexia to occur within weeks as opposed to a longer timescale in humans.
The new model allows scientists to induce the expression of specific cancer mutations as desired, to produce different types of pancreatic cancer at the planned point of time. This inducible model causes tumors of the pancreas to develop in two months rather than two weeks with conventional models, giving the scientists more time to observe the actual march of events that are eventually responsible for cachexia, and to test out new therapies. According to researcher Denis Guttridge, “Because of the timescale of the model, we believe the model will be useful for performing preclinical studies that possibly lead to identifying new drugs that can be translated to the clinic.”
Guttridge, whose team developed the KPP model at the Hollings Cancer Center, explains, “We believe that the KPP mouse model better captures what patients go through when afflicted with pancreatic cancer and suffer from cachexia.” This is evident when the patterns of gene expression in muscle tissue taken from cachecticis compared with that found in KPP mouse model tissues and with that taken from other traditional animal models. In other words, he says, “Collectively, we conclude from these data that [other traditional] models are not optimal to recapitulate the muscle wasting phenotype of human cancer-induced cachexia,” whereas the KPP model “mimics the human condition.”
Of course, the model will have to be refined to allow researchers to compensate for certain specific differences that have become obvious. One such is the increased inflammatory markers that are found in the KPP model compared to human patients. Again, KPP mice show loss of normal pancreatic tissue which may contribute to the skeletal muscle wasting. Again, this model may not be useful for other cachectic tumors, though this is not likely.
Guttridge has made an intensive study of cancer cachexia, which is ultimately responsible for death in one out of three cancer patients, and produces immense stress on caregivers as well. Pancreatic cancer is rising in incidence, and leads to death within 5 years in over 90% of patients. This is partly due to drug resistance and late detection. However, treatment intolerance due to cachexia also plays a role.
On a more human note, Guttridge speaks of some reminiscences shared by the wife of the actor Patrick Swayze who suffered from this syndrome before dying of pancreatic cancer in 2009. According to Guttridge, “She remembered that he would go in for his checkup and was always more concerned about why he was losing so much weight rather than the progression of his cancer, because maintaining a quality of life and his fitness was so important to him.”
This is why the study is important. In Guttridge’s words, “Although we understand that cachexia is a consequence of cancer, for such cancers like pancreatic, an effective treatment does not yet exist. So trying to combat cachexia to provide the patient a better quality of life is a big deal.” He wants to see other researchers using this model to contribute to the pool of knowledge in this field, by finding out what is causing the cachexia and thus helping other scientists find the right targets to prevent it.
The study was published in the journalon August 8, 2019.