Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Comparative Genomics for Evolutionary Cell Biology Using AMOEBAE: Understanding the Golgi and Beyond.

Taking an evolutionary approach to cell biology can yield important new information about how the cell works and how it evolved to do so. This is true of the Golgi apparatus, as it is of all systems within the cell. Comparative genomics is one of the crucial first steps to this line of research, but comes with technical challenges that must be overcome for rigor and robustness. We here introduce AMOEBAE, a workflow for mid-range scale comparative genomic analyses. It allows for customization of parameters, queries, and taxonomic sampling of genomic and transcriptomics data. This protocol article covers the rationale for an evolutionary approach to cell biological study (i.e., when would AMOEBAE be useful), how to use AMOEBAE, and discussion of limitations. It also provides an example dataset, which demonstrates that the Golgi protein AP4 Epsilon is present as the sole retained subunit of the AP4 complex in basidiomycete fungi. AMOEBAE can facilitate comparative genomic studies by balancing reproducibility and speed with user-input and interpretation. It is hoped that AMOEBAE or similar tools will encourage cell biologists to incorporate an evolutionary context into their research.

Platelets stimulate programmed death-ligand 1 expression by cancer cells: Inhibition by anti-platelet drugs.

BACKGROUND: Platelets facilitate hematogenous metastasis in part by promoting cancer cell immunoevasion, although our understanding of platelet function in modulating the adaptive immune system in cancer is limited. A major negative regulator of the adaptive response is the immune checkpoint protein Programmed Death Ligand 1 (PD-L1). OBJECTIVES: As platelets secrete factors that may increase PD-L1 expression, we investigated whether they up-regulate cancer cell PD-L1, thus promoting immunoevasion, and whether common anti-platelet drugs inhibit this process. METHODS: Platelets were isolated from human volunteers. A549 lung, PD-L1 null A549, and 786-O renal cancer cells were incubated with and without platelets, and cancer cell PD-L1 expression was measured by qPCR and flow cytometry. Additionally, platelet-cancer cell incubations were performed in the presence of common anti-platelet drugs, and with growth factor neutralizing antibodies. Following incubation with platelets, A549 were co-cultured with T-cells and interleukin-2 (IL-2) levels were measured by flow cytometry as a marker of T-cell activation. RESULTS: Platelets increased PD-L1 mRNA and surface protein expression by A549 and 786-0 cells. Combined neutralization of VEGF and PDGF prevented the platelet-induced up-regulation of PD-L1 by A549, as did the anti-platelet drug eptifibatide. A549 incubated with platelets demonstrated a reduced ability to activate human T-cells, an effect reversed by eptifibatide. CONCLUSIONS: As platelets promote immunoevasion of the adaptive immune response by increasing cancer cell PD-L1 expression and as anti-platelet drugs prevent this immunoevasive response, the investigation of anti-platelet drugs as adjuvant therapy to immune checkpoint inhibitors may be warranted in the treatment of cancer.