Lecture : Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States. By the year 2030, PDAC is projected to be the second leading cause of cancer deaths. There is an unmet therapeutic need for developing new therapies, which include novel immunotherapies, stroma-directed and targeted therapies. Understanding the molecular pathways involved in the carcinogenesis, progression, metastases, and tumor microenvironment (TME) changes are important in novel therapeutic development, thereby improving PDAC patient survival and quality of life. The treatment paradigm for PDAC changed in 2011 when FOLFIRINOX demonstrated a survival benefit compared to single-agent gemcitabine. And nab-paclitaxel plus gemcitabine established another first-line treatment option after revealing a survival benefit over gemcitabine. Current ongoing trials are investigating this regimen with an immune checkpoint inhibitor plus Vitamin D; however, tolerability beyond several cycles might become an issue due to cumulative toxicities. It is hypothesized that cisplatin can disrupt the stroma and allow for more efficient drug delivery, however, this has not been confirmed yet. NGS of PDAC has provided tumor biology insights by identifying driver oncogenes/tumor suppressors. This information helps to guide and develop more effective therapies than the current standard of care treatments. WGS also demonstrated four subtypes of PDAC, with unique patterns of chromosomal structural variants classified as stable, locally rearranged, scattered and unstable. Sequential NGS studies after progression of each treatment would be helpful in identifying the genetic makeup of resistant clones of PDAC and could help in the design of novel therapeutic treatments and clinical trials. TME is an integral part of PDAC pathogenesis. Understanding its role in shaping and reshaping the fibrotic reaction (desmoplasia) will help further development of tumor-stroma directed treatments. TME consists of different cell types, including the transformed cells, their normal counterparts, and infiltrating cells that are key to the innate and adaptive immune response.. Conversely, PEGPH20 when combined with gemcitabine plus nab-paclitaxel in a randomized phase II trial demonstrated improved PFS, although a SWOG trial demonstrated detrimental outcomes when combined with FOLFIRINOX [120,121]. Hence, perhaps targeting new stromal drivers such as CEACAM6 and the JAK-STAT pathway are potentially exciting new therapeutic opportunities. Immune checkpoint therapies for PDAC are in its infancy and thus far have demonstrated null or modest efficacy. We believe the role of immunotherapy in PDAC needs further scientific investigation. In addition to MSI-H and high tumor mutational load, patients with DNA damage repair mutations (BRCA1/1, PALB2, CHEK1/2, FANCA, ATM, and PALB2) are also likely to respond to immune checkpoint therapies. This could potentially increase the power and potential of immunotherapies for a large number of PDAC patients. Lastly, a new treatment modality, Tumor-Treating Fields involves low-intensity, intermittent frequency, alternating electrical fields delivered through non-invasive transducer array that abrogates cancer cell division, has demonstrated efficacy in pre-clinical and clinical trials in solid tumors and is currently FDA approved in gliomas. The aforementioned has led to the development of a large randomized trial in patients with locally advanced pancreatic cancer and we look forward to the results (NCT03377491).