Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein

AbstractThe cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

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Correlation between prior therapeutic dendritic cell vaccination and the outcome of patients with metastatic melanoma treated with ipilimumab

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20006 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e20006-e20006 ◽

Cited By ~ 7

Author(s):

L. Pierret ◽

S. Wilgenhof ◽

J. Corthals ◽

T. Roelandt ◽

K. Thielemans ◽

...

Keyword(s):

Dendritic Cell ◽

Metastatic Melanoma ◽

Small Sample Size ◽

Objective Response ◽

Small Sample ◽

Cytotoxic Agents ◽

Dendritic Cell Vaccination ◽

Dc Vaccine ◽

Medical Need ◽

Melanoma Patients

e20006 Background: Ipilimumab (Ipi) is an anti-cytotoxic T lymphocyte associated antigen 4 (CTLA4) IgG1 monoclonal antibody active against metastatic melanoma. Ipi acts by reinforcement of CTL-activation trough B7/CD28 receptor stimulation. A pre- existing anti-tumor CTL repertoire, induced by dendritic cell (DC) vaccination, could influence the therapeutic effect of Ipi. The influence of prior DC-vaccination on the outcome of melanoma patients (pts) treated with Ipi at a single center was analyzed to evaluate this hypothesis. Methods: Data were obtained from the medical files of pts treated at the UZ Brussel with Ipi in protocols CA184–022, -025, and the BMS Ipi medical need program. Ipi (0.3, 3 or 10 mg/kg) was administered iv q3 wks x4 q12 wks thereafter. Results: 20 pts (10M/10F; med age 51y, range 28–72) were identified. Prior therapy: autologous DC-vaccine loaded with melanoma associated antigens (14 pts) ± IFN-a2b (9/14 pts), cytotoxic agents (17 pts). Baseline characteristics: AJCC st IV melanoma (20 pts); baseline LDH > ULN (16 pts). Ipi dose: 0.3 mg/kg (4 pts), 3 mg/kg (2 pts), 10 mg/kg (14 pts). Serial LDH measurements were available for 17 pts; 4 types of LDH-response following Ipi administration were observed: increase (11 pts), decrease (1 pt), fluctuation (4 pts), stable (1 pt). Objective response according to mWHO or irWHO: 3 PR, 1 SD, 16 PD. One pt received 0.3 mg/kg of Ipi (CA184–022) and had SD but no LDH response; at PD she received DC-vaccine and subsequently 10 mg/kg Ipi (medical need program) resulting in a fluctuating LDH-response and regression of an orbita-metastasis. Increasing LDH values following Ipi were less often observed in pts with prior DC-vaccination (5/6 pts (83%) without prior DC-vaccination had increasing LDH-values vs 6/12 pts (50%) with prior vaccination). DC- vaccination also correlated with regression of metastases and disease control (3/15 pts (20%) who were vaccinated had a PR/SD vs 1/6 (17%) PR for those who had not received prior DC-vaccinations). Conclusions: These data represent a small sample size from a single institution; however, our results suggests a potential correlation between prior therapeutic DC vaccination and outcomes in advanced melanoma patients treated with ipilimumab. [Table: see text]

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Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial

Cancer Immunology Immunotherapy ◽

10.1007/s00262-012-1242-4 ◽

2012 ◽

Vol 61 (10) ◽

pp. 1791-1804 ◽

Cited By ~ 77

Author(s):

Eva Ellebaek ◽

Lotte Engell-Noerregaard ◽

Trine Zeeberg Iversen ◽

Thomas Moerch Froesig ◽

Shamaila Munir ◽

...

Keyword(s):

Dendritic Cell ◽

Metastatic Melanoma ◽

Phase Ii ◽

Phase Ii Trial ◽

Interleukin 2 ◽

Dendritic Cell Vaccination ◽

Melanoma Patients ◽

Metronomic Cyclophosphamide

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Transcriptional Repression of Raf Kinase Inhibitory Protein Gene by Metadherin during Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms22063052 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3052

Author(s):

Trang Huyen Lai ◽

Mahmoud Ahmed ◽

Jin Seok Hwang ◽

Sahib Zada ◽

Trang Minh Pham ◽

...

Keyword(s):

Cancer Progression ◽

Transcriptional Repression ◽

Cancer Metastasis ◽

Human Cancer ◽

Inhibitory Protein ◽

Human Cancer Cells ◽

Protein Levels ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Phosphatidylethanolamine Binding Protein

Raf kinase inhibitory protein (RKIP), also known as a phosphatidylethanolamine-binding protein 1 (PEBP1), functions as a tumor suppressor and regulates several signaling pathways, including ERK and NF-κκB. RKIP is severely downregulated in human malignant cancers, indicating a functional association with cancer metastasis and poor prognosis. The transcription regulation of RKIP gene in human cancers is not well understood. In this study, we suggested a possible transcription mechanism for the regulation of RKIP in human cancer cells. We found that Metadherin (MTDH) significantly repressed the transcriptional activity of RKIP gene. An analysis of publicly available datasets showed that the knockdown of MTDH in breast and endometrial cancer cell lines induced the expression RKIP. In addition, the results obtained from qRT-PCR and ChIP analyses showed that MTDH considerably inhibited RKIP expression. In addition, the RKIP transcript levels in MTDH-knockdown or MTDH-overexpressing MCF-7 cells were likely correlated to the protein levels, suggesting that MTDH regulates RKIP expression. In conclusion, we suggest that MTDH is a novel factor that controls the RKIP transcription, which is essential for cancer progression.

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Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20215367 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5367

Author(s):

Madokoro ◽

Yoshino ◽

Kato ◽

Sato ◽

Mizuno ◽

...

Keyword(s):

Precursor Protein ◽

Inhibitory Protein ◽

Cholinergic Activity ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Peptide Precursor ◽

Hippocampal Network ◽

Medial Septal Nucleus ◽

Phosphatidylethanolamine Binding Protein ◽

Cholinergic Projection

The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network.

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Dendritic cell vaccination in melanoma patients: Update and subgroup analysis of clinical response to post-vaccine treatment

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9042 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9042-9042

Author(s):

L. Ridolfi ◽

L. Fiammenghi ◽

M. Petrini ◽

A. M. Granato ◽

V. Ancarani ◽

...

Keyword(s):

Dendritic Cell ◽

Clinical Response ◽

Metastatic Melanoma ◽

B Cell Lymphoma ◽

Delayed Type Hypersensitivity ◽

Dendritic Cell Vaccination ◽

Autologous Tumor ◽

Mixed Response ◽

Vaccine Treatment ◽

Melanoma Patients

9042 Background: Dendritic cells (DCs) play a crucial role in the interplay between innate and adaptive immune response towards cancer. The combination of immunotherapies with standard treatments for cancer could represent a further chance for advanced melanoma patients. In the literature, higher response rates than those normally obtained have been reported after second-line chemotherapy in patients with non small cell lung cancer pre-treated with vaccines and in patients with follicular B-cell lymphoma vaccinated with an anti-idiotype vaccine whilst in remission. On the basis of this data, we reviewed and updated the clinical results of our dendritic cell based vaccine clinical trial in stage IV melanoma patients. Methods: From December 2002 to 2007, 24 pre-treated metastatic melanoma patients were vaccinated with mature DCs (mDCs) pulsed with autologous tumor lysate (ATL) and keyhole limpet hemocyanin (KLH) followed by a 5-day treatment with low-dose subcutaneous Interleukin-2. Results: We observed 2 complete response (CR), 2 mixed response (MR), 5 partial response (PR), 4 stable disease (SD) and 11 progressive disease (PD) (overall response (OS) 37.5%; clinical benefit 54.1%). All 13 responders had delayed-type hypersensitivity (DTH) positivity to KLH, of whom 10 also showed positivity to the lysate. Eleven (45.8%) of the 24 patients underwent further lines of treatment (5 chemotherapy [CT], 3 surgery [S], 4 biotherapy, 2 radiotherapy [RT] and 4 biochemotherapy [BioCT]) after stopping vaccination (8 due to progression and 3, in SD, because all of their lysate had been used). Of these 11 patients, 2 obtained CR (1 RT, 1 S), 5 PR (3 BioCT, 2 S) for an OR of 63.6%, 1 SD (BioCT) and 3 showed PD as the best response to subsequent therapies, with a median OS of 30 months (range 16–52). Of the 3 SD patients who were forced to stop vaccine treatment, 1 had CR following RT and 2 progressed. Conclusions: Metastatic melanoma responds poorly to standard therapy, in particular after first-line treatment. Vaccination could enhance clinical response to subsequent third- or fourth-line therapies, thus prolonging overall survival. No significant financial relationships to disclose.

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