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We have previously reported an important role of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, in the support of critical oncogenic pathways required for oncogenesis and the malignant phenotype of pancreatic cancer. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor inhibits the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins. Our studies show that inactivation of p53 by siRNA-knockdown, gene-deletion, HPV-E6-mediated degradation, or expression of the loss-of-function mutant p53 R175H results in increased PR55α protein stability, which is accompanied by reduced protein expression of FBXL20 and decreased ubiquitination of PR55α. Subsequent studies demonstrate that knockdown of FBXL20 by siRNA mimics p53 deficiency, reducing PR55α ubiquitination and increasing PR55α protein stability. Functional tests indicate that ectopic p53 R175H or PR55α expression results in an increase of c-Myc protein stability with concomitant dephosphorylation of c-Myc-T58, which is a PR55α substrate, whose phosphorylation otherwise promotes c-Myc degradation. A significant increase in anchorage-independent proliferation is also observed in normal human pancreatic cells expressing p53 R175H or, to a greater extent, overexpressing PR55α. Consistent with the common loss of p53 function in pancreatic cancer, FBXL20 mRNA expression is significantly lower in pancreatic cancer tissues compared to pancreatic normal tissues and low FBXL20 levels correlate with poor patient survival. Collectively, these studies delineate a novel mechanism by which the p53/FBXL20 axis negatively regulates PR55α protein stability., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Stereotactic body radiation therapy (SBRT) is the standard of care treatment for nonsurgical patients with early-stage non-small cell lung cancer (NSCLC). A recent report has indicated an improvement in overall survival (OS) with adjuvant chemotherapy in patients with tumors ≥ 4 cm treated with SBRT. We present a retrospective study evaluating the impact of histology in patients treated with SBRT and adjuvant chemotherapy., Materials and Methods: Patients (≥18 years) diagnosed with clinical stages I-II NSCLC from 2004 to 2013 were identified using the National Cancer Database (n = 12,055). The Kaplan-Meier method was used to estimate overall survival (OS) distributions and the log-rank test was used to compare distributions by treatment strategy. Clinical stages I and II were subdivided according to the TNM staging and log-rank tests was used to compare survival distributions by treatment strategy within each subgroup. We performed subgroup analysis for the three main NSCLC histologies (i.e., adenocarcinoma, squamous cell carcinoma (SCC), and large cell)., Results: In patients with adenocarcinoma, SCC and, large cell carcinoma; adjuvant chemotherapy was associated with worse OS in tumors < 4 cm (P<.0001, P<.0099, and P=.0082, respectively). In patients with adenocarcinoma and tumor ≥ 4 cm, adjuvant chemotherapy was not associated with improved OS (P=.262); however, in patients with SCC and large cell, adjuvant chemotherapy improved OS (P<.0001, and P=.0129, respectively)., Conclusion: In patients with NSCLC ≥ 4 cm treated with SBRT, adjuvant chemotherapy was associated with improved OS in patients with SCC and large cell histologies., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is increasingly utilized in the neoadjuvant and definitive settings for pancreatic adenocarcinoma. The risk of local and regional recurrence after this treatment remains largely unknown. Because of the lack of elective nodal treatment and high fractional dose, we hypothesized that the incidence of regional out-of-field recurrence would predominate after SBRT., Methods and Materials: Electronic medical records of all patients treated in our department with SBRT for pancreatic adenocarcinoma were retrospectively reviewed. Patients were separated into those who converted or did not convert to surgical resectability. Demographic, treatment, and outcome data were collected and analyzed. Recurrence was assessed based on the Response Evaluation Criteria In Solid Tumors version 1.1. Treatment plans were reviewed to determine the locations of failure with respect to treatment volume. Statistical comparisons were made using Mann-Whitney U testing for continuous variables and χ 2 testing for dichotomous variables., Results: Data on 69 patients was available for analysis. After treatment, 18 patients (26.1%) suffered in-field recurrence and 11 patients (15.9%) recurred regionally out of field. The median time to in-field and out-of-field failures were similar at 120.5 and 108.0 days, respectively (P = .65). Of those who failed out-of-field, 4 of 11 patients (36.4%) were without in-field failure prior to death. In-field failure rates were less in patients who subsequently underwent surgical resection compared with those who did not (2 of 22 patients [9.1%] vs 16 of 47 patients [34.0%]; P = .028), but out-of-field recurrence was unaffected by subsequent surgical resection (3 of 22 patients [13.6%] vs 8 of 47 patients [17.0%]; P = .720). All out-of-field failures occurred in areas that received <2600 cGy., Conclusions: The incidence of out-of-field failure remains acceptable after SBRT for pancreatic adenocarcinoma. Despite the high biological equivalent dose allowed by SBRT, in-field control remains problematic and continues to signal relative radiation resistance that is associated with bulky disease., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)