In recent years, there have been exciting new advances in targeting the KRAS G12D mutation. As one example, a recent study showed that a molecularly targeted therapeutic directed against the mutation shrank tumors or stopped their growth in preclinical animal models of pancreatic cancer (727). Notably, the drug also allowed the cancer-fighting immune cells to enter the tumor microenvironment. Researchers are now planning to combine this drug with an immunotherapeutic to evaluate whether the combination will be even more effective against pancreatic cancer. In a phase I/II clinical trial, treatment with another KRAS targeted therapeutic, sotorasib, shrank tumors in about 20 percent of participants (728). Sotorasib, which has already been approved to treat patients with lung cancer, is directed against a different KRAS mutation called G12C (see Figure 16, p. 84), which is present in approximately 1 to 2 percent of patients with pancreatic cancer. Findings from these studies are encouraging and underscore the continued efforts to develop effective treatments against an intractable form of cancer. Immunotherapy, especially adoptive cell therapy and vaccines, has shown great promise against pancreatic cancer. As of March 2022, multiple CAR T-cell therapies, targeting various proteins such as CD133, EGFR, HER2, and MSLN, were in clinical trials for treatment of pancreatic cancer (729). Together, these research efforts are ushering effective methods for early detection and treatment of pancreatic cancer into a new era, with immense potential of bringing hope to patients with this aggressive form of cancer. Targeting the Microbiome in Cancer Treatment The human microbiome is the collection of all microorganisms (e.g., bacteria and fungi) and viruses that live in the gut, skin, and mouth, among other parts of the body. Most The Gut Microbiome: A New Frontier in Cancer Prevention, Early Detection, and Treatment The gut microbiome is an exciting new area in cancer research. Investigations are underway to study whether it is possible to harness the human gut microbiome to prevent, detect, diagnose, or optimize cancer treatment. Manipulating the microbiome through lifestyle modifications such as changes in diet, might aid in reducing the risk of developing cancer by suppressing chronic inflammation, while detection of certain microbial species that are frequently associated with cancer incidence may help in the early detection or diagnosis of disease. The gut microbiome may also have a dramatic impact on the efficacy of anticancer immunotherapies and chemotherapies. Modulating the microbiome in patients with cancer through advanced probiotics, fecal transplantation, or pharmacologic interventions may open up new opportunities to improve patient outcomes and further precision medicine. Adapted from (489). FIGURE 21 Drug discovery Microbiome-derived compounds or microbiometargeted drugs as cancer therapeutics Precision medicine Microbiome analysis to create patient’s personal profile Early detection Microbiome analysis to identify biomarkers Prevention Modifying microbiome through diet or medication Therapy optimization Modifying microbiome to augment responses to treatment AACR Cancer Progress Report 2023 Envisioning the Future of Cancer Science and Medicine 150
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