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Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC).
Hecht, JR, Papadopoulos, KP, Falchook, GS, Patel, MR, Infante, JR, Aljumaily, R, Wong, DJ, Autio, KA, Wainberg, ZA, Bauer, TM, et al
Investigational new drugs. 2021;(1):182-192
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Abstract
Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 μg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).
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Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer.
Kutschat, AP, Johnsen, SA, Hamdan, FH
Cells. 2021;(5)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) displays a particularly poor prognosis and low survival rate, mainly due to late diagnosis and high incidence of chemotherapy resistance. Genomic aberrations, together with changes in the epigenomic profile, elicit a shift in cellular signaling response and a transcriptional reprograming in pancreatic tumors. This endows them with malignant attributes that enable them to not only overcome chemotherapeutic challenges, but to also attain diverse oncogenic properties. In fact, certain genetic amplifications elicit a rewiring of calcium signaling, which can confer ER stress resistance to tumors while also aberrantly activating known drivers of oncogenic programs such as NFAT. While calcium is a well-known second messenger, the transcriptional programs driven by aberrant calcium signaling remain largely undescribed in pancreatic cancer. In this review, we focus on calcium-dependent signaling and its role in epigenetic programs and transcriptional regulation. We also briefly discuss genetic aberration events, exemplifying how genetic alterations can rewire cellular signaling cascades, including calcium-dependent ones.
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New Roles for Vitamin D Superagonists: From COVID to Cancer.
Easty, DJ, Farr, CJ, Hennessy, BT
Frontiers in endocrinology. 2021;:644298
Abstract
Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.
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Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): A post hoc analysis of NAPOLI-1.
Chen, LT, Macarulla, T, Blanc, JF, Mirakhur, B, de Jong, FA, Belanger, B, Bekaii-Saab, T, Siveke, JT
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2021;(1):192-199
Abstract
BACKGROUND Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). METHODS Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. RESULTS Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). CONCLUSION An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.
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Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
Kocher, HM, Basu, B, Froeling, FEM, Sarker, D, Slater, S, Carlin, D, deSouza, NM, De Paepe, KN, Goulart, MR, Hughes, C, et al
Nature communications. 2020;(1):4841
Abstract
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
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Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells.
Galenkamp, KMO, Sosicka, P, Jung, M, Recouvreux, MV, Zhang, Y, Moldenhauer, MR, Brandi, G, Freeze, HH, Commisso, C
Cancer discovery. 2020;(6):822-835
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Abstract
Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. SIGNIFICANCE NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a "proton sink" for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.See related commentary by Ward and DeNicola, p. 768.This article is highlighted in the In This Issue feature, p. 747.
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Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition.
Obón-Santacana, M, Luján-Barroso, L, Freisling, H, Naudin, S, Boutron-Ruault, MC, Mancini, FR, Rebours, V, Kühn, T, Katzke, V, Boeing, H, et al
International journal of cancer. 2020;(1):76-84
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Abstract
Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.
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Personalizing KRAS-Mutant Allele-Specific Therapies.
Falcomatà, C, Schneider, G, Saur, D
Cancer discovery. 2020;(1):23-25
Abstract
KRAS G12R mutations occur almost exclusively in pancreatic ductal adenocarcinoma. The results of a study that reveals specific differences in KRAS downstream signaling and metabolic rewiring of pancreatic cancer cells harboring KRAS G12R mutations promise to improve our possibilities to better stratify patients for individualized therapies.See related article by Hobbs et al., p. 104.
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Upfront molecular profiling of pancreatic cancer patients - An idea whose time has come.
Bhutani, MS, Cazacu, IM, Roy-Chowdhuri, S, Maitra, A, Pishvaian, MJ
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2020;(3):391-393
Abstract
Pancreatic cancer patients have not benefited from survival improvements brought about by personalized medicine in other malignancies. Even though this is the era of precision medicine, unfortunately most clinicians in practice either do not embrace or are unaware of the concept of molecular profiling for pancreatic cancer patients. Improving the grim prognosis of this challenging disease requires a paradigm shift. To exploit all potential therapeutic options in this lethal disease, molecular profiling should be performed ideally at the moment of diagnosis to identify potentially trial-eligible tumoral mutations or support off label use of an agent approved for another indication. This perspective article aims to increase awareness of the importance of upfront molecular profiling for pancreatic cancer patients.
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Early detection of pancreatic cancer.
Pereira, SP, Oldfield, L, Ney, A, Hart, PA, Keane, MG, Pandol, SJ, Li, D, Greenhalf, W, Jeon, CY, Koay, EJ, et al
The lancet. Gastroenterology & hepatology. 2020;(7):698-710
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Abstract
Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.