Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer

Lili, Loukia N.; Matyunina, Lilya V.; Walker, L. DeEtte; Daneker, George W.; McDonald, John F.

doi:10.1097/mpa.0000000000000020

Cited by 31 publications

(23 citation statements)

References 90 publications

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“…High-throughput gene-expression analysis has also found evidence of enrichment in immune response pathways, including JAK-STAT in pancreatic cancer. 112 That genetic aberrations other than oncogenic mutations in JAK2 might mediate STAT-pathway activation in pancreatic cancer is possible. Preclinical studies in pan creatic cancer cell lines suggest that increased expression of the cytokine receptor common gp130 subunit and phosphorylated STAT3 might predict response to JAK2 inhibitors in this disease.…”

Section: Janus Kinase Inhibitorsmentioning

confidence: 99%

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

2015

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Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.

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Section: Janus Kinase Inhibitorsmentioning

confidence: 99%

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

2015

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“…However, additional study is necessary to create personalized gene-targeted therapies for patients with PDAC. 35 Second, with the fact that a part of Gd atoms in nanocarriers were isolated with water molecules (H 2 O) by the plasmid, the nanoparticles have a lower relaxivity rate compared with small molecular contrast medium, and the signal intensity in tumor parenchyma injected with nanoparticles was relatively lower than that of …”

Section: Resultsmentioning

confidence: 99%

Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

Wang¹,

Li²,

An³

et al. 2015

IJN

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Background Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery. Methods The experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC. Results The nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×10 4 ±9.75×10 2 p/s/cm 2 /sr) was significantly ( P <0.05) higher than in those treated with Gd-DTPA (9.56×10 2 ±6.15×10 p/s/cm 2 /sr) and Gd-DP (5.75×10 3 ± 7.45×10 2 p/s/cm 2 /sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging. Conclusion This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

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“…The ddPCR-based assays reported here should enhance the early diagnosis, prognostication, and therapeutic management of common B-cell lymphomas. The field of personalized medicine (39,40 ) demands patient-specific molecular assays to track ctDNA levels in the blood or other biological fluids (26 ). We assert that the single-probe strategy introduced here may enable researchers and clinicians to design cost-effective experiments that demand lower amounts of clinically precious samples and, notably, promote the possibility to investigate clonal evolution in response to therapeutic treatment by tracking multiple mutations in one single assay.…”

Section: Discussionmentioning

confidence: 99%

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma

Alcaide

Bushell

et al. 2016

Clinical Chemistry

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BACKGROUND:A plethora of options to detect mutations in tumor-derived DNA currently exist but each suffers limitations in analytical sensitivity, cost, or scalability. Droplet digital PCR (ddPCR) is an appealing technology for detecting the presence of specific mutations based on a priori knowledge and can be applied to tumor biopsies, including formalin-fixed paraffin embedded (FFPE) tissues. More recently, ddPCR has gained popularity in its utility in quantifying circulating tumor DNA.

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Evidence for the Importance of Personalized Molecular Profiling in Pancreatic Cancer

Abstract: Supplemental digital content is available in the text.

Cited by 31 publications

References 90 publications

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies

Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

Multiplex Droplet Digital PCR Quantification of Recurrent Somatic Mutations in Diffuse Large B-Cell and Follicular Lymphoma

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