Stress and obesity found to fuel early pancreatic cancer growth

There has been a regulatory drive to reduce animal testing for some time, including through frameworks such as the European Union’s REACH directive. More recently, we have seen this strengthened with roadmaps to phase out animal testing for chemical safety. In silico and in vitro methods are likely to be central to that transition. These tools can provide efficient, human-relevant, and multiscale evidence. One could imagine an approach similar to the carcinogenicity weight-of-evidence approach, in which in vitro and in silico data are gathered to justify reduced or no animal testing at specific points in the approval process. Regulatory acceptance remains challenging because standards vary around the world. For AI, there are also questions about model approval, model updates, benchmarking, and version control. It will be very interesting to see how regulators test and define these pathways.

With the current drug discovery paradigm, it takes up to 15 years to translate an idea, such as hypothesizing a certain protein is important in a disease and testing this with targeting the protein with a drug, all the way through to proof of concept. The drug has to be filed with the regulatory authorities, having done all the safety and efficacy testing. It's a long process and it's also very costly. Estimates vary, but it's currently reckoned to cost over 1 billion dollars per drug. That’s partly because you have to pay for all the drugs that didn't make it. By the time you've taken a protein target and you've made a whole load of molecules that affect that target in the way you want them to, you've probably already spent a couple of years on it and then you have to take the best molecule through the appropriate safety testing in animals before proceeding to phase 1 testing in people. Even if you get to phase 1 testing, where you are just giving it to human volunteers for the first time, not even patients, about 95% of the compounds at the stage then fail to make it all the way through to the market. So, you’ve only got a 5% success rate. The odds are not good and, essentially, it is why so many companies have had to merge because, over time, this is becoming less and less sustainable as a business model.

Biologically, vitamins are absorbed within hours and have instant metabolic effects, such as antioxidants that protect cells or compounds that are building blocks for making hormones. But, many factors impact their efficiency and could keep your body from fully absorbing them. Absorption and effects depend on each individual and what combination of vitamins they take. Gender, age, digestive health, medical conditions, and diet all play a role. One helpful practice to detect deficiencies is to look for the symptoms deficiencies create. Then, look for improvement in your symptoms with supplement intake. You are unlikely to see or feel changes if you do not lack nutrients. If you are chronically tired or see signs of unhealthy nails, hair, or skin, supplements may help as these are indicators that you are lacking nutrients in your diet. If you are unsure, your doctor can order tests to check for deficiencies in your blood.

More specifically, the study showed that the female patient produced very few cathelicidins, which is a natural toxin found in the immune cells of the lungs needed to fight tuberculosis. In most people infected by tuberculosis, tuberculosis bacteria attack the immune cells of the lungs. The immune cells fight the bacteria by eating them. But the tuberculosis bacterium has developed various evasive mechanisms that reduce the immune cells’ ability to digest and thus to kill the Mtb. “You could say that the tuberculosis bacterium has developed a way to lull the immune cells to sleep. This enables the disease the hide inside the immune cells, making it invisible to other parts of the immune system,” Martin Kongsbak-Wismann explains. This is where vitamin D enters the picture. Because vitamin D is able to counteract the soporific effect of the tuberculosis bacteria by making the immune cells produce more of the cathelicidin toxin. “Cathelicidin is like a microscopic needle that is able to pierce the tuberculosis bacteria. And when it does, it weakens the bacteria’s soporific effect on the immune cells. This restores the immune cells’ ability to kill tuberculosis bacteria,” says Martin Kongsbak-Wismann and adds: “We were amazed by the effect of vitamin D. In immune cells from healthy control subjects, vitamin D improved the cells’ ability to fight Mtb, whereas in the female patient’s immune cells we saw no response to vitamin D. This shows that vitamin D is key to the immune system’s ability to fight Mtb and prevent tuberculosis.” Al-Jaberi, F.A.H., et al. (2022) Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report. Frontiers in Immunology. doi.org/10.3389/fimmu.2022.1038960.

The medication, called daraxonrasib, is the first drug that targets cancer-causing mutations in pancreas cells. The drug targets a mutation in the KRAS gene, part of the RAS genetic family. KRAS mutations are present in 92% of pancreatic cancers. KRAS genes normally act as an "on-off" switch for cell growth. Mutated KRAS genes are stuck in the "on" position and send out a signal that causes cells to divide and grow uncontrollably, allowing cancer to form. Daraxonrasib blocks the KRAS signal by fitting into a keyhole-type spot on the gene. That spot has a complex shape and is difficult to reach within the cell. The drug gets around this problem by using a "passenger protein" as a Trojan horse. When the cell allows this protein in, daraxonrasib tags along.