360 research outputs found
BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer
Background: Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for
over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP)
inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to
platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA
repair through an increasing number of different mechanisms.
Methods: Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion)
who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through nextgeneration
sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in
the tumour.
Results: Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2
mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2,
which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells.
Conclusions: To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitorbased
therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism
of resistance and how it may impact the choice of therapy for patients with pancreatic cancer
Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients
Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site
Tyrosine 23 Phosphorylation-Dependent Cell-Surface Localization of Annexin A2 Is Required for Invasion and Metastases of Pancreatic Cancer
The aggressiveness of pancreatic ductal adenocarcinoma (PDA) is characterized by
its high metastatic potential and lack of effective therapies, which is the
result of a lack of understanding of the mechanisms involved in promoting PDA
metastases. We identified Annexin A2 (ANXA2), a member of the Annexin family of
calcium-dependent phospholipid binding proteins, as a new molecule that promotes
PDA invasion and metastases. We found ANXA2 to be a PDA-associated antigen
recognized by post-treatment sera of patients who demonstrated prolonged
survival following treatment with a PDA-specific vaccine. Cell surface ANXA2
increases with PDA development and progression. Knockdown of ANXA2 expression by
RNA interference or blocking with anti-ANXA2 antibodies inhibits in
vitro invasion of PDA cells. In addition, post-vaccination patient
sera inhibits in vitro invasion of PDA cells, suggesting that
therapeutic anti-ANXA2 antibodies are induced by the vaccine. Furthermore,
cell-surface localization of ANXA2 is tyrosine 23 phosphorylation-dependent; and
tyrosine 23 phosphorylation is required for PDA invasion. We demonstrated that
tyrosine 23 phosphorylation resulting in surface expression of ANXA2 is required
for TGFβ-induced, Rho-mediated epithelial-mesenchymal transition (EMT),
linking the cellular function of ANXA2 which was previously shown to be
associated with small GTPase-regulated cytoskeletal rearrangements, to the EMT
process in PDA. Finally, using mouse PDA models, we showed that shRNA knock-down
of ANXA2, a mutation at tyrosine 23, or anti-ANXA2 antibodies,
inhibit PDA metastases and prolong mouse survival. Thus, ANXA2 is part of a
novel molecular pathway underlying PDA metastases and a new target for
development of PDA therapeutics
A multi‐institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99090/1/cncr28117.pd
Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma
Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration: ClinicalTrials.gov Identifier: NCT01088815
Vaccination with ENO1 DNA Prolongs Survival of Genetically Engineered Mice with Pancreatic Cancer.
BACKGROUND & AIMS:: Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor, and patients typically present with late-stage disease; rates of 5-year survival after pancreaticoduodenectomy are low. Antibodies against -enolase (ENO1), a glycolytic enzyme, are detected in more than 60% of patients with PDA, and ENO1-specific T cells inhibit the growth of human pancreatic xenograft tumors in mice. We investigated whether an ENO1DNA vaccine elicits anti-tumor immune responses and prolongs survival of mice that spontaneously develop autochthonous, lethal pancreatic carcinomas. METHODS:: We injected and electroporated a plasmid encoding ENO1 (or a control plasmid) into Kras(G12D)/Cre mice (KC) and Kras(G12D)/Trp53 (R172H) /Cre (KPC) mice when they were 4 weeks old (when pancreatic intraepithelial lesions are histologically evident). Anti-tumor humoral and cellular responses were analyzed by histology, immunohistochemistry, ELISAs, flow cytometry, and ELISpot and cytotoxicity assays. Survival was analyzed by Kaplan-Meier analysis. RESULTS:: The ENO1 vaccine induced antibody and a cellular responses and increased survival times by a median 138 days in KC mice and 42 days in KPC mice, compared with mice given the control vector. In histologic analysis, the vaccine appeared to slow tumor progression. The vaccinated mice had increased serum levels of anti-ENO1 immunoglobulin G, which bound the surface of carcinoma cells and induced complement-dependent cytotoxicity. ENO1 vaccination reduced numbers of myeloid-derived suppressor cells and T-regulatory cells, and increased T-helper 1 and 17 responses. CONCLUSIONS:: In a genetic model of pancreatic carcinoma, vaccination with ENO1DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival. This vaccination strategy might be developed as a neo-adjuvant therapy for patients with PD
A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma
A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma
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