Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in many cancers, but thus far have yielded little clinical benefit in PDAC. Based on recent combined targeting of programmed cell death protein-1 (PD-1) and C-X-C chemokine receptor 4 (CXCR4) in patient-derived xenografts (PDXs) and a pilot clinical trial, we sought to elucidate potential interactions between PD-1 and CXCR4. We observed concomitant expression and direct interaction of PD-1 and CXCR4 in PDAC cells. This interaction was disrupted upon CXCR4 antagonism with AMD3100 and led to increased cell surface expression of PD-1. Importantly, CXCR4-mediated PDAC cell migration was also blocked by PD-1 inhibition. Our work provides a possible mechanism by which prior studies have demonstrated that combined CXCR4 and PD-1 inhibition leads to decreased tumor growth. This is the first report investigating PD-1 and CXCR4 interactions in PDAC cells and our results can serve as the basis for further investigation of combined therapeutic targeting of CXCR4 and PD-1.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods: Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results: Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions: The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.

Background: Despite the increased accessibility and availability of technology in recent years, equality and access to health-related technology remain limited to some demographics. In particular, patients who are older or from rural communities represent a large segment of people who are currently underusing mobile health (mHealth) solutions. System usability continues to hinder mHealth adoption among users with nontraditional digital literacy. Objective: This study aims to investigate if state-of-the-art mobile app interfaces from open-source libraries provide sufficient usability for rural patients with cancer, with minimal design changes and forgoing the co-design process. Methods: We developed Assuage (Network Reconnaissance Lab) as a research platform for any mHealth study. We conducted a pilot study using Assuage to assess the usability of 4 mobile user interfaces (UIs) based on open-source libraries from Apple’s ResearchKit and CareKit. These UIs varied in complexity for reporting distress symptoms. Patients with cancer were recruited at the Markey Cancer Center, and all research procedures were conducted in person. Participants completed the distress assessment using a randomly selected UI in Assuage with little to no assistance. Data were collected on participant age, location, mobile app use, and familiarity with mHealth apps. Participants rated usability with the System Usability Scale (SUS), and usability issues were documented and compared. A one-way ANOVA was used to compare the effect of the UIs on the SUS scores. Results: We recruited 30 current or postsurgery patients with cancer for this pilot study. Most participants were aged >50 years (24/30, 80%), from rural areas (25/30, 83%), had up to a high school education (19/30, 63%), and were unfamiliar with mHealth apps (21/30, 70%). General mobile app use was split, with 43% (14/30) of the patients not regularly using mobile apps. The mean SUS score across the UIs was 75.8 (SD 22.2), with UI 3 and UI 4 achieving an SUS score ≥80, meeting the industry standard for good usability of 80. Critical usability issues were related to data input and navigation with touch devices, such as scale-format questions, vertical scrolling, and traversing multiple screens. Conclusions: The findings from this study show that most patients with cancer (20/30, 67%) who participated in this study rated the different interfaces of Assuage as above-average usability (SUS score >68). This suggests that Apple’s ResearchKit and CareKit libraries can provide usable UIs for older and rural users with minimal interface alterations. When resources are limited, the design stage can be simplified by omitting the co-design process while preserving suitable usability for users with nontraditional technical proficiency. Usability comparable to industry standards can be achieved by considering heuristics for interface and electronic survey design, specifically how to segment and navigate surveys, present important interface elements, and signal gestural interactions.

We recently demonstrated that immune checkpoint PD-1 was endogenously expressed in pancreatic ductal adenocarcinoma (PDAC) cells. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we sought to further characterize PD-1 expression in PDAC. We utilized a phospho-explorer array to identify pathways upregulated by PD-1 signaling. We discovered PD-1-mediated activation of the proto-oncogene MET in PDAC cells, which was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. We then discovered that the PD-1/MET axis in PDAC cells regulated growth, migration, and invasion. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a well-established early oncogenic process in PDAC. We observed that combined targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of cytotoxic immune responses. This is the first report of PDAC-endogenous PD-1 expression regulating MET signaling, which builds upon our growing body of work showing the oncogenic phenotype of PD-1 expression in PDAC cells is distinct from its immunogenic role. These results highlight a paradigm shift that the tumor-specific PD-1 axis is a novel target to effectively kill PDAC cells by antagonizing previously unrecognized PD-1-dependent oncogenic pathways.

Exceptional response to trastuzumab, a monoclonal antibody against human epidermal growth factor receptor-2 (HER2/ERBB2), as manifested by prolonged absence of radiographic evidence of disease (durable complete response, DCR) is uncommon.