Abstract
Pancreatic cancer is the most common lethal malignancy, with little improvement in patient outcomes over the decades. The development of early detection methods and effective therapeutic strategies are needed to improve the prognosis of patients with this disease. Recent advances in cancer genomics have revealed the genetic landscape of pancreatic cancer, and clinical trials are currently being conducted to match the treatment to underlying mutations. Liquid biopsy-based diagnosis is a promising method to start personalized treatment. In addition to genome-based medicine, personalized models have been studied as a tool to test candidate drugs to select the most efficacious treatment. The innovative three-dimensional organoid culture platform, as well as patient-derived xenografts can be used to conduct genomic and functional studies to enable personalized treatment approaches. Combining genome-based medicine with drug screening based on personalized models may fulfill the promise of precision medicine for pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with an average 5-year survival rate of less than 10% [1]
Increased dosage of mutant KRAS is sufficient to induce basallike features [32, 87]. These results suggest that mutant KRAS plays an important role in oncogenesis in PDAC, but other epigenetic or microenvironmental factors are critical in regulating molecular phenotypes
Therapeutic strategies based on gene alterations in cancer cells, including Homologous reconbination deficiency (HRD) and mismatch repair deficiency (MMR-D)/MSIH, have improved the survival of PDAC patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with an average 5-year survival rate of less than 10% [1]. The Cancer Genome Atlas Research Network reported that the KRASWT tumors had significantly elevated tuberous sclerosis complex/mammalian target of rapamycin (TSC/mTOR) signaling pathway activity compared with KRAS mutant tumors, indicating that functional activation of the mTOR signaling pathway may be an alternative oncogenic driver in KRASWT pancreatic cancer [15] These data suggest that larger multicenter clinical trials are needed to fully investigate the therapeutic efficacy of the inhibition of upstream and downstream signaling of RAS in KRASWT patients with other oncogenic mutations. Expression profiling based on speciesspecific RNA sequencing of PDXs provides a unique opportunity to distinguish mouse stroma-derived transcripts from human cancer cell-derived transcripts without physically separating the two components prior to RNA extraction [87] Novel approaches, such as short-term primary cultures or organoids, are being developed and are expected to be applied to preclinical screening studies [24]. Clinical trials using PDOs are ongoing [25], and PDX-derived organoids are useful for drug screening
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