Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy

Abstract Abstract 4508 Systemic administration of immunotherapeutics often give rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, may overcome this problem. Our research regarding sorting mechanisms of granule proteins have led to a new therapeutic idea – targeted therapy with hematopoietic cells as carriers. Exogenous proteins are expressed, and the gene product is directed for secretory lysosome or granule storage. These organelles are unique storage compartments in neutrophils for biological active proteins, designated for inflammatory foci. The exogenous proteins, would accordingly, be locally released at the site of inflammation. Our model construct, soluble TNF receptor 1 (sTNFR), can be directed for storage by adding a transmembranous region and a sorting signal. We have earlier shown that this construct, retrovirally expressed in murine hematopoietic progenitor cells, are destined for granule targeting. Furthermore, we have transplanted transduced murine progenitor cells with modified granule content, and found stable expression and inducible release of sTNFR1 in vivo. Our goal is cell linage specific expression in order to selectively express sTNFR1 with a transmembranous region and a signal peptide for granule targeting. To achieve this, lactoferrin, perforin and MPO promoters, including regulatory elements, have been inserted into vectors (we use a retroviral vector with self-inactivating LTRs). The vectors is retrovirally transduced into murine hematopoietic progenitor cells, and the cells are cultured during cytokine driven differentiation and analyzed by FACS and Western blotting. Our results suggest that a concept of using secretory organelles of hematopoietic cells as vehicles for therapeutic agents in vivo may become feasible. It will be possible to test this principle by experiments in animal models of inflammatory and malignant diseases. Likewise, development of this concept may give new information on secretory lysosome function and secretion at inflamed/malignant sites. Disclosures: No relevant conflicts of interest to declare.

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Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy

Oncology Letters ◽

10.3892/ol.2017.6724 ◽

2017 ◽

Vol 14 (4) ◽

pp. 4158-4166 ◽

Cited By ~ 6

Author(s):

Yanxia Gong ◽

Jie Zhang ◽

Xiang Wu ◽

Tao Wang ◽

Jia Zhao ◽

...

Keyword(s):

Targeted Therapy ◽

Oligopeptide Transporter ◽

Specific Expression ◽

Primary Hepatocarcinoma ◽

Novel Strategy

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EPEN-09. PRECLINICAL MODELS REVEAL SUBGROUP-STRATIFIED TARGETED THERAPY OPTIONS FOR CHILDHOOD SUPRATENTORIAL EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noz036.066 ◽

2019 ◽

Vol 21 (Supplement_2) ◽

pp. ii79-ii79

Author(s):

Vladimir Amani ◽

Andrew Donson ◽

Andrea Griesinger ◽

Davis Witt ◽

Jean Mulcahy Levy ◽

...

Keyword(s):

Targeted Therapy ◽

Preclinical Models ◽

Therapy Options ◽

Supratentorial Ependymoma

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Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

Frontiers in Oncology ◽

10.3389/fonc.2021.667730 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shaojie Yang ◽

Liwei Pang ◽

Wanlin Dai ◽

Shuodong Wu ◽

Tengqi Ren ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatocellular Carcinoma ◽

Targeted Therapy ◽

Disease Recurrence ◽

High Morbidity ◽

Specific Expression ◽

Factors Affecting ◽

Forkhead Box ◽

Stress Signals ◽

And Function

Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.

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