Pancreatic cancer, treatment options, and GI-4000

Hartley, Marion L.; Bade, Najeebah A.; Prins, Petra; Ampie, Leonel; Marshall, John L.

doi:10.1080/21645515.2015.1011017

Cited by 19 publications

(10 citation statements)

References 53 publications

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“…However, up until now, no clinical benefit has been obtained using a vaccination strategy, 30 , 31 although new protocols have been designed with new vaccination peptides, which are currently being clinically evaluated. 32 …”

Section: Discussionmentioning

confidence: 99%

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

Bournet¹,

Muscari²,

Buscail³

et al. 2016

Clinical and Translational Gastroenterology

144

110

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Objectives:There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.Methods:The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan–Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.Results:A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7–12.3) and the wild-type (9 months; 95% CI: 8.7–12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4–9.7) compared with the other patients (OS: 9 months; 95% CI: 10–13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).Conclusions:The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.

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Section: Discussionmentioning

confidence: 99%

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

Bournet¹,

Muscari²,

Buscail³

et al. 2016

Clinical and Translational Gastroenterology

144

110

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“…Pancreatic cancer is a highly aggressive condition with one of the poorest prognosis of all cancers (Ansari et al, 2016). It is mainly treated by surgery with adjuvant 5fluorouracil (5-FU) -a pyrimidine analog that inhibits thymidylate synthase, and/or gemcitabine (Hartley et al, 2015). The Panc03.27 cell line was used as a model to study the effect of TPCS 2a -PDT and PCI after induction of 5-FU-resistance (Paper III).…”

Section: Cell Linesmentioning

confidence: 99%

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Olsen

Weyergang

Edwards

et al. 2017

Biochemical Pharmacology

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Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS-PDT-resistance was neither found to correspond with lower TPCS-accumulation nor reduced generation of reactive oxygen species (ROS). Cross-resistance to chemotherapy (doxorubicin) or radiotherapy was not observed. TPCS-PDT-resistant cells acquired a higher proliferation capacity and an enhanced expression of EGFR and ERK1/2. p38 MAPK was found to be a death-signalling pathway in the MA11 cells post TPCS-PDT, contrasting the MA11/TR cells in which PDT generated a sustained phosphorylation of p38 that had lost its death-mediated signalling, and an abrogated activation of its downstream effector MAPKAPK2. No difference in apoptosis, necrosis or autophagy responses was found between the treated cell lines. Development of TPCS-PDT resistance in the MDA-MB-231 cell line was also established, however, p38 MAPK did not play a role in the PDT-resistance. MCF-7 cells did not develop TPCS-PDT-resistance. Photochemical internalisation (PCI) of 1 pM of EGF-saporin induced equal strong cytotoxicity in both MA11 and MA11/TR cells. In conclusion, loss of p38 MAPK-inducing death signalling is the main mechanism of resistance to TPCS-PDT in the MA11/TR cell line. This work provides mechanistic knowledge of intrinsic and acquired PDT-resistance which is dependent on choice of photosensitizer, and suggests PCI as a rational therapeutic intervention for the elimination of PDT-resistant cells.

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“…For example, a recombinant yeast-CEA vaccine has been used in vitro to expand murine and human T cells directed against the CEA protein, as well as in vivo for vaccination of mice bearing CEA-expressing tumors, resulting in antitumor activity Boehm, Higgins, Franzusoff, Schlom, & Hodge, 2010;Cereda et al, 2011;Remondo et al, 2009;Wansley et al, 2008). In clinical studies, heat-killed yeast vaccines have been used in multicenter trials in patients with Hepatitis C, lung, and pancreatic carcinomas, and in patients with metastatic CEA-expressing carcinomas (Bilusic et al, 2014;Chaft et al, 2014;Hartley, Bade, Prins, Ampie, & Marshall, 2014). All of these studies demonstrated that yeast-based vaccines (a) can be injected repeatedly without inducing neutralizing responses, (b) possess excellent safety and tolerability profiles, and (c) are able to induce measurable tumor-specific immune responses.…”

Section: Yeast-based Brachyury Vaccinementioning

confidence: 97%

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Palena

Hamilton

2015

Advances in Cancer Research

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As a manifestation of their inherent plasticity, carcinoma cells undergo profound phenotypic changes during progression towards metastasis. One such phenotypic modulation is the epithelial-mesenchymal transition (EMT), an embryonically relevant process that can be reinstated by tumor cells, resulting in the acquisition of metastatic propensity, stem-like cell properties and resistance to a variety of anti-cancer therapies, including chemotherapy, radiation and some small molecule targeted therapies. Targeting of the EMT is emerging as a novel intervention against tumor progression. This review focuses on the potential use of cancer vaccine strategies targeting tumor cells that exhibit mesenchymal-like features, with an emphasis on the current status of development of vaccine platforms directed against the T-box transcription factor brachyury, a novel cancer target involved in tumor EMT, stemness and resistance to therapies. Also presented is a summary of potential mechanisms of resistance to immune-mediated attack driven by EMT and the development of novel combinatorial strategies based on the use of agents that alleviate tumor EMT for an optimized targeting of plastic tumor cells that are responsible for tumor recurrence and the establishment of therapeutic refractoriness.

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Pancreatic cancer, treatment options, and GI-4000

Cited by 19 publications

References 53 publications

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

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