scholarly journals Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 137
Author(s):  
Eun-Jeong Won ◽  
Hyeji Park ◽  
Tae-Jong Yoon ◽  
Young-Seok Cho
Keyword(s):  
Gene Therapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Target Genes ◽  
Advanced Pancreatic Cancer ◽  
Cancer Therapeutics ◽  
Ductal Adenocarcinoma ◽  
Specific Gene ◽  
Minimal Impact ◽  
Therapeutic Modalities ◽  
Promising Tool

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC.

Predicting Surgical Margins in Patients With Borderline Resectable and Locally Advanced Pancreatic Cancer Undergoing Resection

2021 ◽  
pp. 000313482110111
Author(s):  
Weizheng Ren ◽  
Dimitrios Xourafas ◽  
Stanley W. Ashley ◽  
Thomas E. Clancy
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Univariate Analysis ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Resection Margins ◽  
Borderline Resectable ◽  
Stepwise Selection ◽  
R1 Resection ◽  
Positive Resection Margins

Background Many patients with borderline resectable/locally advanced pancreatic ductal adenocarcinoma (borderline resectable [BR]/locally advanced [LA] pancreatic ductal adenocarcinoma [PDAC]) undergoing resection will have positive resection margins (R1), which is associated with poor prognosis. It might be useful to preoperatively predict the margin (R) status. Methods Data from patients with BR/LA PDAC who underwent a pancreatectomy between 2008 and 2018 at Brigham and Women’s Hospital were retrospectively reviewed. Logistic regression analysis was used to evaluate the association between R status and relevant preoperative factors. Significant predictors of R1 resection on univariate analysis ( P < .1) were entered into a stepwise selection using the Akaike information criterion to define the final model. Results A total of 142 patients with BR/LA PDAC were included in the analysis, 60(42.3%) had R1 resections. In stepwise selection, the following factors were identified as positive predictors of an R1 resection: evidence of lymphadenopathy at diagnosis (OR = 2.06, 95% CI: 0.99-4.36, P = .056), the need for pancreaticoduodenectomy (OR = 3.81, 96% CI: 1.15-15.70, P = .040), extent of portal vein/superior mesenteric vein involvement at restaging (<180°, OR = 3.57, 95% CI: 1.00-17.00, P = .069, ≥180°, OR = 7,32, 95% CI: 1.75-39.87, P = .010), stable CA 19-9 serum levels (less than 50% decrease from diagnosis to restaging, OR = 2.27, 95% CI: 0.84-6.36 P = .107), and no preoperative FOLFIRINOX (OR = 2.17, 95% CI: 0.86-5.64, P = .103). The prognostic nomogram based on this model yielded a probability of achieving an R1 resection ranging from <5% (0 factors) to >70% (all 5 factors). Conclusions Relevant preoperative clinicopathological characteristics accurately predict positive resection margins in patients with BR/LA PDAC before resection. With further development, this model might be used to preoperatively guide surgical decision-making in patients with BR/LA PDAC.

Abstract A17: Challenging pancreatic ductal adenocarcinoma and its stroma by a combination of chemo and gene therapy: A preclinical study

2019 ◽  
Author(s):  
Giulia Grisendi ◽  
Massimiliano Dall'Ora ◽  
Angela D'Esposito ◽  
Giulia Casaria ◽  
Carlotta Spano ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Preclinical Study ◽  
Ductal Adenocarcinoma

scholarly journals Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1825 ◽  
Author(s):  
Alexandros Papalampros ◽  
Michail Vailas ◽  
Konstantinos Ntostoglou ◽  
Maria Lopez Chiloeches ◽  
Stratigoula Sakellariou ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Single Agent ◽  
Poor Response ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Dominant Type ◽  
Therapeutic Modalities ◽  
Senescent Phenotype ◽  
Gene And Protein Expression

Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

scholarly journals Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

2021 ◽  
Vol 4 (6) ◽  
pp. e202000935
Author(s):  
Samantha B Kemp ◽  
Nina G Steele ◽  
Eileen S Carpenter ◽  
Katelyn L Donahue ◽  
Grace G Bushnell ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Gene Expression Signature ◽  
Ductal Adenocarcinoma ◽  
Specific Gene ◽  
Sequencing Analysis ◽  
Tumor Associated Macrophages ◽  
Primary Tumors ◽  
Single Cell Rna Sequencing

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3. Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8. In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients.

scholarly journals mir-218 modulates ARF6 expression and inhibits pancreatic ductal adenocarcinoma invasion

2020 ◽  
Author(s):  
Brenna A. Rheinheimer ◽  
Ronald L Heimark
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Target Genes ◽  
Target Prediction ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Matrix Degradation ◽  
Cancer Migration ◽  
Pancreatic Cancer Cells

AbstractBackgroundPancreatic ductal adenocarcinoma is an extremely malignant disease with the majority of patients having metastatic disease upon diagnosis. Recently, it was shown the SLIT2 plays a regulatory role in melanoma invasion through the control of invadopodia. Therefore, we sought to determine the mechanism behind miR-218 inhibition of pancreatic cancer invasion.Methodsmir-218 target genes were discovered using three miRNA target prediction websites. Modulation of mir-218 target ARF6 was determined by transfection with antagomirs and mimics to mir-218. Pancreatic cancer migration and invasion were measured using Boyden chamber assays. Invasion was further measured using matrix degradation assays.ResultsWe found that mir-218 modulates ARF6 RNA and protein expression in pancreatic cancer. mir-218 did not inhibit pancreatic cancer cell migration, but did inhibit invasion. mir-218 did not affect the formation of invadopodia in pancreatic cancer cells, but did inhibit the total area of matrix degradation caused by functional invadopodia.ConclusionsThis work suggests that miR-218 is a suppressor of pancreatic ductal adenocarcinoma invasion through a pathway that regulates invadopodia maturation.

scholarly journals A Network-Based Approach for Identification of Subtype-Specific Master Regulators in Pancreatic Ductal Adenocarcinoma

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Yuchen Zhang ◽  
Lina Zhu ◽  
Xin Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Network Inference ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Mechanism ◽  
Expression Profiles ◽  
Strong Association ◽  
Predictive Biomarkers ◽  
Integrative Analysis ◽  
Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the predominant subtype of pancreatic cancer, has been reported with equal mortality and incidence for decades. The lethality of PDAC is largely due to its late presentation, when surgical resection is no longer an option. Similar to other major malignancies, it is now clear that PDAC is not a single disease, posing a great challenge to precise selection of patients for optimized adjuvant therapy. A representative study found that PDAC comprises four distinct molecular subtypes: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). However, little is known about the molecular mechanisms underlying specific PDAC subtypes, hampering the design of novel targeted agents. In this study we performed network inference that integrates miRNA expression and gene expression profiles to dissect the miRNA regulatory mechanism specific to the most aggressive squamous subtype of PDAC. Master regulatory analysis revealed that the particular subtype of PDAC is predominantly influenced by miR-29c and miR-192. Further integrative analysis found miR-29c target genes LOXL2, ADAM12 and SERPINH1, which all showed strong association with prognosis. Furthermore, we have preliminarily revealed that the PDAC cell lines with high expression of these miRNA target genes showed significantly lower sensitivities to multiple anti-tumor drugs. Together, our integrative analysis elucidated the squamous subtype-specific regulatory mechanism, and identified master regulatory miRNAs and their downstream genes, which are potential prognostic and predictive biomarkers.

scholarly journals Clinical Benefits of Conversion Surgery for Unresectable Pancreatic Ductal Adenocarcinoma: A Single-Institution, Retrospective Analysis

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1057
Author(s):  
Yuko Mataki ◽  
Hiroshi Kurahara ◽  
Tetsuya Idichi ◽  
Kiyonori Tanoue ◽  
Yuto Hozaka ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Multidisciplinary Treatment ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Conversion Surgery ◽  
Clinical Benefits ◽  
Resectable Cancer

Background: Unresectable pancreatic ductal adenocarcinoma (UR-PDAC) has a poor prognosis. Conversion surgery is considered a promising strategy for improving the prognosis of UR-PDAC. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PDAC. Methods: We retrospectively evaluated patients with PDAC who were referred to our department for possible surgical resection between January 2006 and December 2019. Conversion surgery was performed only in patients with UR-PDAC who could expect R0 resection. We analyzed the prognostic factors for overall survival among patients who underwent conversion surgery. Results: Overall, 638 patients with advanced pancreatic cancer were enrolled in this study. According to resectability, resectable cancer (R) was present in 180 patients, borderline resectable cancer (BR) was present in 60 patients, unresectable locally advanced cancer (UR-LA) was present in 252 patients, and unresectable cancer with distant metastasis (UR-M) was present in 146 patients. Conversion surgery was performed in 20 of the 398 UR cases (5.1%). The median period between the initial therapy and conversion surgery was 15.5 months. According to the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation, the treatment response was CR in one patient, PR in 13, SD in five, and PD in one. Downstaging was pathologically determined in all cases. According to the Evans grading system, grade I was observed in four patients (20%), grade IIb was observed in seven (35%), III was observed in seven (35%), and IV was observed in two (10%). We compared the overall survival period from initial treatment among patients undergoing conversion surgery; the median overall survival durations in the conversion surgery, R, BR, UR-LA, and UR-M groups were 73.7, 32.7, 22.7, 15.7, and 8.8 months, respectively. Multivariate analysis revealed that the presence or absence of chemoradiotherapy (CRT) and the RECIST partial response (PR)/complete response (CR) for the main tumor were statistically significant prognostic factors for overall survival among patients undergoing conversion surgery (p = 0.004 and 0.03, respectively). Conclusion: In UR-PDAC, it is important to perform multidisciplinary treatment, including CRT with conversion surgery.

scholarly journals Dynamic Perfusion CT – A Promising Tool to Diagnose Pancreatic Ductal Adenocarcinoma

HPB ◽  
2021 ◽  
Vol 23 ◽  
pp. S883-S884
Author(s):  
I. Zaborienė ◽  
K. Žvinienė ◽  
S. Lukoševičius ◽  
P. Ignatavičius ◽  
A. Gulbinas ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Perfusion Ct ◽  
Ductal Adenocarcinoma ◽  
Promising Tool

Outcomes with FOLFIRINOX for locally advanced pancreatic cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 256-256
Author(s):  
Brian A. Boone ◽  
Jennifer Steve ◽  
Alyssa M. Krasinskas ◽  
Amer H. Zureikat ◽  
Barry C. Lembersky ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Response Rates ◽  
Biologically Active ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Borderline Resectable

256 Background: Trials examining the use of FOLFIRINOX in metastatic pancreatic ductal adenocarcinoma demonstrate significantly higher response rates compared to gemcitabine-based regimens. These high response rates may be particularly important for patients with locally advanced pancreatic ductal adenocarcinoma (LAPD), in which there is currently limited experience with FOLFIRINOX. We examined the outcomes of patients with LAPD treated with neoadjuvant FOLFIRINOX at our high volume clinic. Methods: Retrospective review of a prospectively maintained pancreatic cancer database was used to identify patients who were recommended neoadjuvant treatment with FOLFIRINOX. Clinical outcomes were reviewed. Resectability was determined using SSO criteria. Results: Between 2/2011 and 9/2012 FOLFIRINOX was recommended for 25 patients with LAPD, 13 (52%) unresectable (UR) and 12 (48%) borderline resectable (BR). Median age was 59. 4 patients (16%) either refused treatment or were lost to follow up. 21 patients (84%) were treated with a median of 4.7 cycles (Range: 2-8). 5 patients (24%) required dose reductions secondary to toxicity. 2 patients (9%) were unable to tolerate treatment and 3 patients (14%) had disease progression on treatment. Of the remaining 16 patients, 13 patients (62%) displayed a radiologic response allowing for surgical exploration, 4 (31%) of which were initially unresectable. 6 of these patients (29%) received additional chemotherapy and/or radiation therapy prior to surgery. Peritoneal metastases were discovered at surgery in 2 (8%) patients. Of the patients who were BR, 7/8 (88%) had a R0 resection. Of the 10 UR patients, 3 (33%) underwent surgical resection, with 2 (20%) R0 resections. Overall R0 resection rate was 43%. A total of 4 patients (19%) demonstrated a major pathologic response (2 complete responses and 2 near complete responses) and 8 other patients (73%) had some pathological response. Conclusions: FOLFIRINOX alone or as part of multimodality approach is a biologically active regimen in LAPD with encouraging R0 resection rates, especially in BR LAPD. Further research is needed to determine the utility of additional chemoradiotherapy with FOLFIRINOX and to identify predictors of response in UR patients.

scholarly journals Combination of gemcitabine, nab-paclitaxel, and S-1(GAS) as the first-line treatment for patients with locally advanced or advanced pancreatic ductal adenocarcinoma: study protocol for an open-label, single-arm phase I study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chen Chang ◽  
Xiaofen Li ◽  
Dan Cao
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Chinese Patients ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Systemic Treatments

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is still a highly fatal malignancy among the most common cancers. More powerful treatments are expecting to bring hope for patients. Biweekly gemcitabine/nab-paclitaxel/S-1 (GAS) was proved safe and effective for patients with locally advanced pancreatic cancer in Japan. The objective of this study is to evaluate the feasibility and toxicity of GAS (repeated every 3 weeks) in the treatment of locally advanced or advanced pancreatic cancer and determine the recommended dose of S-1 in this combination. Methods This is an open-label, single-arm, and single-center phase I trial. Patients who have been diagnosed with locally advanced or advanced PDAC pathologically without previous systemic treatments will be enrolled and be treated with GAS chemotherapy every 3 weeks (nab-paclitaxel 125 mg/m 2, ivgtt, day1, 8; gemcitabine 1000 mg/m2, day1, 8; different doses of S-1 within a dose escalation scheme) until the presence of disease progression (PD), intolerable adverse events (AEs), or requirement of patients and researchers. The primary endpoints are maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints include safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Discussion This trial will adjust the administration of GAS to make it more effective for Chinese patients, while exploring the toxicity and feasibility of this adjustment. Trial registration ChiCTR, (ChiCTR1900027833). Registered 30 November 2019.

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