What is Pancreatic Cancer?

Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, has one of the highest case fatality rates of all known solid malignancies. Over the past decade, several landmark studies have established mutations in KRAS and TP53 as the predominant drivers of PDAC pathogenesis and therapeutic resistance, though treatment options for PDACs and other tumors with these mutations remain extremely limited. Hampered by late tumor discovery and diagnosis, clinicians are often faced with using aggressive and non-specific chemotherapies to treat advanced disease. Clinically meaningful responses to targeted therapy are often limited to the minority of patients with susceptible PDACs, and immunotherapies have routinely encountered roadblocks in effective activation of tumor-infiltrating immune cells. Alternative RNA splicing (ARS) has recently gained traction in the PDAC literature as a field from which we may better understand and treat complex mechanisms of PDAC initiation, progression, and therapeutic resistance. Here, we review PDAC pathogenesis as it relates to fundamental ARS biology, with an extension to implications for PDAC patient clinical management.

Purpose: Metformin combined with the mTOR inhibitor rapamycin showed potential synergistic anti-tumor activity in preclinical studies in pancreatic ductal adenocarcinoma (PDA). This phase 1b study (NCT02048384) was conducted to evaluate the feasibility and activity of metformin +/– rapamycin in the maintenance setting for unselected patients with metastatic PDA (mPDA) treated with chemotherapy.

Materials and Methods: Eligible patients with stable or responding mPDA after ≥ 6 months on chemotherapy were randomized 1:1 to metformin alone (Arm A) or with rapamycin (Arm B), stratified by prior treatment with FOLFIRINOX. Fluorodeoxyglucose (FDG) PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses.

Results: 22 subjects (11 per arm) received treatment per protocol. Median PFS/OS were 3.5 and 13.2 months respectively, with 2 year OS rate of 37%; there were no differences between arms. No responses were observed by RECIST; however, decreases in FDG avidity and/or CA19-9 were observed in several long-term survivors. Treatment related adverse events of Grade ≥ 3 occurred in 0% vs 27% of patients in Arm A vs B and were asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Improved survival was associated with low baseline neutrophil: lymphocyte ratio, baseline lack of assessable disease by PET, and greater expansion of dendritic cells following treatment.

Conclusions: Metformin +/– rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of these agents in the maintenance setting and to enhance patient selection for such approaches.

Pancreatic cancer is considered one of the most lethal cancers in the US. It contributes to an estimated 47,000 deaths annually and is predicted to surpass prostate, breast and colorectal cancers as the leading cause of cancer-related death. Although major advancements in cancer treatment have improved outcomes for many cancer types, survival rate for pancreatic cancer has not improved in nearly four decades despite tremendous effort. One attribute of pancreatic cancer that is considered a major barrier to effective treatment is the formation of fibrotic tissue around tumor cells known as desmoplasia. A number of promising approaches have been developed to deplete fibrotic components in pancreatic tumors to enhance drug delivery, some of which have been tested in clinical trials of advanced, unresectable pancreatic cancer. Here, we discuss previous efforts, shortcomings and new considerations for developing more effective agents to eliminate desmoplasia.

The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the Kras^LSL.G12D/+; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the Kras^LSL.G12D/+; Tp53^R172H/+; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.

Although early detection and diagnosis are indispensable for improving the prognosis of patients with pancreatic cancer, both have yet to be achieved. Except for pancreatic cancer, other cancers have already been screened through scent tests using animals or microorganisms, including Caenorhabditis elegans. While such a method may greatly improve the prognosis of pancreatic cancer, no studies have investigated the same, mainly given the difficulty of collecting suitable samples from patients with early-stage pancreatic cancer. In this study, we organized a nationwide study group comprising high-volume centers throughout Japan to collect patients with very-early-stage pancreatic cancer (stage 0 or IA). We initially performed an open-label study involving 83 cases (stage 0–IV), with subsequent results showing significant differences after surgical removal in stage 0–IA (×10 dilution: p < 0.001; ×100 dilution: p < 0.001). Thereafter, a blinded study on 28 cases (11 patients with stage 0 or IA disease and 17 healthy volunteers) was conducted by comparing very-early-stage pancreatic cancer patients with healthy volunteers to determine whether C. elegans could detect the scent of cancer for the diagnosis of early-stage pancreatic cancer. Preoperative urine samples had a significantly higher chemotaxis index compared to postoperative samples in patients with pancreatic cancer [×10 dilution: p < 0.001, area under the receiver operating characteristic curve (AUC) = 0.845; ×100 dilution: p < 0.001, AUC = 0.820] and healthy volunteers (×10 dilution: p = 0.034; ×100 dilution: p = 0.088). Moreover, using the changes in preoperative and postoperative chemotaxis index, this method had a higher sensitivity for detecting early pancreatic cancer compared to existing diagnostic markers. The clinical application C. elegans for the early diagnosis of cancer can certainly be expected in the near future.

Background: Modern anesthesia strives to offer personalized concepts to meet the patient’s individual needs in sight of clinical outcome. Still, little is known about the impact of anesthesia on the plasma metabolome, although many metabolites have been shown to modulate the function of various immune cells, making it particularly interesting in the context of oncological surgery. In this study longitudinal dynamics in the plasma metabolome during general anesthesia in patients undergoing pancreatic surgery were analyzed.

Materials and Methods: Prospective, observational study with 10 patients diagnosed with pancreatic (pre-) malignancy and subjected to elective resection surgery under general anesthesia. Plasma metabolites (n = 630) were quantified at eight consecutive perioperative timepoints using mass spectrometry-based targeted metabolomics.

Results: 39 metabolites significantly changed during the perioperative period. Tryptophan concentrations decreased by 45% with the maximum decrease after anesthesia induction (p = 6.24E-07), while taurine synthesis increased (p = 1.46E-04). Triacylglycerides and lysophosphatidylcholines were significantly reduced with increased liberation of free monounsaturated fatty acids (p = 0.03). Carnitine levels decreased significantly (p = 9.30E-04).

Conclusions: The major finding of this study was perioperative tryptophan depletion and increased taurine synthesis. Both are essential for immune cell function and are therefore of significant interest for perioperative management. Further studies are needed to identify influencing anesthetic factors.

Objective: Pancreatic cancer is the most aggressive common cancer and is desperately in need of novel therapies. Unlike many other common cancers, there have been no new paradigm-changing therapies in the past 40 years beyond multi-agent chemotherapy. In this study, we perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies.

Materials and Methods: We queried https://clinicaltrials.gov/ for registered pancreatic cancer clinical trials. Studies were curated and categorized according to phase of study, clinical stage of the study population, type of the intervention under investigation, and biologic mechanism targeted by the therapy under study.

Results: As of May 18, 2019, there were 430 total active therapeutic interventional trials testing 590 interventions. The vast minority of trials (n = 37, 8.6%) are in phase III testing. 189 (31%) interventions are immunotherapies, 69 (11%) target cell signaling pathways, 154 (26%) target cell cycle or DNA biology, and 35 (6%) target metabolic pathways. Of the late phase trials, only 14 are currently testing novel interventions. Rather, 23 phase III trials examine new ways to deliver existing FDA-approved drugs, procedures, or pain management.

Conclusions: A large number of novel therapeutic strategies are currently under investigation. They include a broad range of therapies targeting diverse biologic processes. However, only a small number of novel therapies are in late-stage testing, suggesting that future progress is likely several years away, and dependent on the success of early-stage trials.

Resectable pancreatic adenocarcinoma (PC) is generally managed with surgery followed by chemotherapy, but the role of postoperative chemoradiation (pCRT) is controversial. We sought to identify a microRNA (miRNA) expression profile associated with higher risk for local-regional recurrence (LRR), which might help identify patients that may benefit from pCRT. Total RNA was isolated from viable tumor from 88 patients who underwent PC resection with or without chemotherapy, but did not receive radiation. Digital miRNA expression profiling was performed and risk scores were calculated based on the expression levels of the four most significantly correlated miRNAs, and dichotomized about the median to detect correlations between risk group, LRR and overall survival (OS). Two cohorts from The Cancer Genome Atlas (TCGA) and Seoul National University (SNU) were used for validation. Patients with high-risk scores had significantly worse LRR (p = 0.001) and worse OS (p = 0.034). Two-year OS rates for the high- and low-risk groups were 27.7% and 52.2%, respectively. On multivariable analysis, the risk score remained significantly associated with LRR (p = 0.018). When validated on TCGA data, a high-risk score was associated with worse OS on univariate (p = 0.03) and multivariable analysis (p = 0.017). When validated on the SNU cohort, a high-risk score was likewise associated with worse OS (p = 0.042). We have developed a 4-miRNA molecular signature that is associated with risk of LRR and OS after PC resection and validated on two separate cohorts. This signature has the potential to select patients most likely to benefit from pCRT, and should be tested further.

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.