Structures already discussed alongside pancreatic neoplasm in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
RCSB Protein Data Bank · entry 6L3A · 3.0 Å · ligand Everolimus (E53). Experimental structure, not a prediction.
In a phase 3 trial of 410 patients with advanced low-grade or intermediate-grade pancreatic neuroendocrine tumours and radiologic progression within the prior 12 months, everolimus 10 mg daily produced a median progression-free survival of 11.0 months versus 4.6 months with placebo (hazard ratio 0.35, 95% CI 0.27 to 0.45). The estimated proportion alive and progression-free at 18 months was 34% with everolimus versus 9% with placebo. Drug-related adverse events were mostly grade 1 or 2; the most common were stomatitis (64% vs 17%), rash (49% vs 10%), diarrhoea (34% vs 10%), fatigue (31% vs 14%), and infections (23% vs 6%). Grade 3 or 4 anaemia occurred in 6% of the everolimus group versus 0% on placebo, and hyperglycaemia in 5% versus 2%. A subgroup analysis of Japanese patients from the same trial (23 on everolimus, 17 on placebo) reported a median progression-free survival of 19.45 months with everolimus versus 2.83 months with placebo (hazard ratio 0.19, 95% CI 0.08 to 0.48). A single case report described a patient with a giant pancreatic neuroendocrine tumour and portal vein thrombus who became resectable after two years of everolimus and remained recurrence-free for 27 months after surgery.
For pancreatic adenocarcinoma, the evidence is less encouraging. A phase 2 study of 19 patients with locally advanced or metastatic pancreatic adenocarcinoma treated with paclitaxel plus the protein kinase C inhibitor bryostatin-1 found no confirmed objective responses; median time to treatment failure was 1.9 months, and 74% of patients discontinued due to progression or death. A retrospective series of 5 patients treated with paclitaxel-containing regimens after gemcitabine failure reported a disease control rate of 60% (3 partial responses, 2 stable disease) and a median overall survival of 10.7 months from the start of salvage therapy. A separate retrospective review of 20 heavily pretreated patients (all had received gemcitabine, 40% had received FOLFIRINOX) given nab-paclitaxel monotherapy reported a median progression-free survival of 3.7 months and overall survival of 5.2 months; 64.7% of 17 evaluable patients had stable disease as best response. A retrospective study of 32 patients receiving first-line nab-paclitaxel plus gemcitabine found that a higher relative dose intensity of nab-paclitaxel was associated with a disease control rate of 81.8% versus 20.0% in the low-dose group, and median overall survival of 12 versus 8 months. In a rat model of pancreatic ischaemia-reperfusion injury, everolimus improved microvascular permeability, functional capillary density, and leukocyte-endothelial cell interaction, but these are preclinical findings.
What remains missing are prospective trials that stratify patients by tumour subtype (neuroendocrine versus adenocarcinoma) and by prior treatment history, and that test everolimus or nab-paclitaxel in defined neoadjuvant or later-line settings with adequate funding and pre-specified endpoints. The bryostatin-1 combination has been ruled out for adenocarcinoma.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2011 · 2860 citations · open access
Everolimus for Advanced Pancreatic Neuroendocrine Tumors
AbstractBACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
https://doi.org/10.1056/nejmoa1009290Japanese Journal of Clinical Oncology · 2012 · 51 citations · open access
Everolimus for Advanced Pancreatic Neuroendocrine Tumours: A Subgroup Analysis Evaluating Japanese Patients in the RADIANT-3 Trial
AbstractOBJECTIVE: Everolimus, an inhibitor of the mammalian target of rapamycin, has recently demonstrated efficacy and safety in a Phase III, double-blind, randomized trial (RADIANT-3) in 410 patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumours. Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival, representing a 65% risk reduction for progression. The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study. METHODS: Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17). The primary endpoint was progression-free survival. Safety was evaluated on the basis of the incidence of adverse drug reactions. RESULTS: Progression-free survival was significantly prolonged with everolimus compared with placebo. The median progression-free survival was 19.45 months (95% confidence interval, 8.31-not available) with everolimus vs 2.83 months (95% confidence interval, 2.46-8.34) with placebo, resulting in an 81% risk reduction in progression (hazard ratio, 0.19; 95% confidence interval, 0.08-0.48; P< 0.001). Adverse drug reactions occurred in all 23 (100%) Japanese patients receiving everolimus and in 13 (77%) patients receiving placebo; most were grade 1/2 in severity. The most common adverse drug reactions in the everolimus group were rash (n = 20; 87%), stomatitis (n = 17; 74%), infections (n = 15; 65%), nail disorders (n = 12; 52%), epistaxis (n = 10; 44%) and pneumonitis (n = 10; 44%). CONCLUSIONS: These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours.
https://doi.org/10.1093/jjco/hys123American Journal of Clinical Oncology · 2010 · 41 citations · open access
Phase II Study of Paclitaxel Plus the Protein Kinase C Inhibitor Bryostatin-1 in Advanced Pancreatic Carcinoma
AbstractPURPOSE: To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma. METHODS: Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%. RESULTS: Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%. CONCLUSION: The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.
https://doi.org/10.1097/coc.0b013e3181a31920PubMed · 2013 · 16 citations · open access
Nab-paclitaxel monotherapy in refractory pancreatic adenocarcinoma.
AbstractBACKGROUND: The standard of care in patients with metastatic pancreatic adenocarcinoma is undefined beyond second line of treatment. There have been scant reports of benefit from nab-paclitaxel in patients with refractory pancreatic cancer. MATERIALS AND METHODS: A retrospective review was carried out in patients with pancreatic adenocarcinoma at Siteman Cancer Center, who had received nab-paclitaxel monotherapy after experiencing disease progression on standard treatments. Nab-paclitaxel was given either two out of every three weeks or three out of every four weeks. RESULTS: Twenty patients were identified and included for data analysis. Median age was 63.5 years old. All patients had previously received gemcitabine, while 40% had also received FOLFIRINOX. Median number of prior lines of systemic treatment was 2. Patients were treated for a median of 15 weeks, with a range of 1 to 41.7 weeks. Median dose of nab-paclitaxel was 100 mg/m(2) with range of 75-125 mg/m(2). Best response imaging was available in 17 patients and 11 out of the 17 patients (64.7%) had stable disease. Median progression-free survival (PFS) was 3.7 months and overall survival (OS) were 5.2 months. Most common treatment related toxicities included grade 1 pneumonitis in five patients (25%), grade 3 or 4 neutropenia in three patients (15%), and dehydration resulting in hospitalization in one patient (5%). CONCLUSIONS: Nab-paclitaxel monotherapy had acceptable level of toxicity in a heavily pretreated patient population with pancreatic cancer and appeared to provide a clinical benefit. This agent is worthy of further prospective studies to evaluate extent of benefit after standard therapies have failed.
https://doi.org/10.3978/j.issn.2078-6891.2013.034Pancreas · 2015 · 10 citations
Everolimus Improves Microcirculatory Derangements in Experimental Postischemic Pancreatitis Modulating the Expression of Vascular Endothelial Growth Factor, Interleukin 6, and Toll-Like Receptor 4
AbstractOBJECTIVES: Ischemia/reperfusion injury (IRI) of the pancreas is a serious complication following pancreatic transplantation and hemorrhagic shock. The present study was designed to investigate the influence of the potent mammalian target of rapamycin inhibitor everolimus interfering via microvascular permeability changing key proteins hypoxia-inducible factor (HIF) and vascular endothelial growth factor on pancreatic IRI-induced microvascular disturbances. METHODS: Anesthetized male Sprague-Dawley rats were assigned to 3 groups (n = 7/group): (1) sham, (2) 60-minute ischemia/reperfusion of the pancreas (I/R), and (3) I/R and everolimus (10 mg/kg BW orally). Quantification of the effective microvascular permeability (P), functional capillary density (FCD), and leukocyte-endothelial cell interaction (LEI) was performed using digital and analog intravital epifluorescence microscopy. Serum-amylase, lipase, interleukin 6, and vascular endothelial growth factor concentration were quantified using enzyme-linked immunosorbent assay. RESULTS: Sham compared with I/R (P: [×10 cm/s] 0.068 ± 0.079 vs 1.516 ± 0.314; FCD: [cm/cm] 357 ± 14 vs 258 ± 13; LEI: [cells/mm] 148 ± 25 vs 349 ± 75) demonstrates a significant increase in microcirculatory damage and all previously mentioned serum parameters. Except amylase, I/R + everolimus led to a statistically significant improvement of almost all increased parameters (P: 0.434 ± 0.296, FCD: 347 ± 16, LEI: 178 ± 30). CONCLUSIONS: Everolimus attenuated experimental microvascular and inflammatory IRI of the pancreas. Therefore, these results may warrant further investigation of everolimus as a therapeutic agent following clinical states with pancreatic ischemia/reperfusion.
https://doi.org/10.1097/mpa.0000000000000428Surgical Case Reports · 2017 · 9 citations · open access
A case of successful conversion from everolimus to surgical resection of a giant pancreatic neuroendocrine tumor
AbstractBACKGROUND: Although pancreatic neuroendocrine tumors generally have a far better prognosis relative to pancreatic cancer, the varied manifestations lead to treatment-related challenges. Everolimus therapy is generally recommended for patients with advanced pancreatic neuroendocrine tumors; however, its efficacy in a neoadjuvant setting remains unclear. Here we present a case of a giant pancreatic neuroendocrine tumor with a portal tumor thrombus that became resectable after everolimus therapy. CASE PRESENTATION: A 62-year-old woman was admitted to our hospital for surgical resection of a giant pancreatic neuroendocrine tumor in the left upper abdomen. Unfortunately, she was ineligible for surgery because the tumor had extended near the hepatic hilus in the portal vein, and she was administered everolimus (10 mg/day). After 2 years of this therapy, the extent of portal vein involvement had decreased, despite the lack of significant changes in the tumor size, and the hepatic hilus became free of disease. She was subsequently referred to us for resection via distal pancreatectomy with portal vein reconstruction because the tumor had begun to grow slowly. Pathological review identified a grade 2 neuroendocrine tumor with no lymph node metastasis. The patient's postoperative course was uneventful, and she has remained recurrence-free for 27 months, despite a lack of additional treatment. CONCLUSIONS: Our experience suggests that everolimus could be useful for neoadjuvant therapy in cases of locally advanced pancreatic neuroendocrine tumor.
https://doi.org/10.1186/s40792-017-0361-8Translational Cancer Research · 2022 · 6 citations · open access
Efficacy of relative dose intensity of nab-paclitaxel for the short-term outcomes, survival, and quality of life in patients with advanced pancreatic cancer: a retrospective study
AbstractBackground: To optimize treatment, choosing the appropriate relative dose intensity (RDI) of nab-paclitaxel is an important way to improve patient tolerance, therapeutic efficacy, and survival. However, few studies have focused on the efficacy of the RDI of nab-paclitaxel in patients with advanced pancreatic cancer, and whether the RDI of nab-paclitaxel could be employed as an index for treatment remains unknown. To explore the relationship between RDI of nab-paclitaxel and chemotherapy efficacy, survival, quality of life (QoL), and adverse effects in patients with advanced pancreatic cancer. Methods: In this retrospective study, a total of 32 patients with advanced pancreatic cancer, ECOG score of 0 to 2 were included from January 2017 to March 2020. The patients were treated with nab-paclitaxel combined with gemcitabine as a first-line treatment and divided into high and low RDI groups. Chemotherapy efficacy, survival, QoL, and adverse effects between two groups were compared. Results: The disease control rate (DCR) was 20.0% in the low RDI group, compared with 81.8% in the high RDI group (P=0.002). A good correlation between nab-paclitaxel RDI and short-term efficacy was observed in all 32 patients (r=0.728, P<0.01). Furthermore, the high RDI group had significantly better median overall survival (mOS: 12 vs. 8 months, P=0.034) and median progression-free survival (mPFS: 5.5 vs. 3 months, P=0.052) compared to that of low RDI patients. Univariate regression analysis showed that longer overall survival was associated with lower ECOG score [hazard ratio (HR): 10.88; 95% confidence interval (CI): 2.54–46.5, P=0.001], tumors located in the body or tail of pancreases (HR: 3.82; 95% CI: 1.4–10.3, P=0.0081), and higher RDI (HR: 0.21; 95% CI: 0.071–0.6, P=0.004). The high RDI group had a significantly better physical function and emotional function improvement compared to the low RDI group (P<0.05). Moreover, high RDI did not increasing the severity and frequency of the adverse events. Conclusions: It is recommended to maintain a sufficient RDI of nab-paclitaxel to ensure that the balance between lerability, therapeutic efficacy, and survival benefits is satisfied in patients with advanced pancreatic cancer.
https://doi.org/10.21037/tcr-22-1604Case Reports in Oncology · 2011 · 4 citations · open access
Paclitaxel-Based Chemotherapy for Advanced Pancreatic Cancer after Gemcitabine-Based Therapy Failure: A Case Series of 5 Patients
AbstractBACKGROUND/OBJECTIVES: Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. RESULTS: The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. CONCLUSION: Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.
https://doi.org/10.1159/000334704Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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