Pancreatic Cancer: Targeted Therapy Holds the Promise.
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ABSTRACT:
SUBMITTER: Zhou Z
PROVIDER: S-EPMC8693262 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Liposome is a conventional drug delivery system which has been widely used in the pharmacy field. However, its applications are greatly restricted in clinical practice by the disadvantages of cholesterol and nonselective distribution. Herein, a novel platform for anti-tumor drug delivery was developed by incorporating an amphiphilic stachydrine-octadecane conjugate (SS) as the mitochondria-targeting molecule onto the triptolide-liposome surfaces (SS-TP LPs). The polyethylene glycol (PEG) and the suitable particle size (about 133 nm) of liposomes facilitated their stabilities, the long half-life in blood and the escape from the rapid elimination. The SS-TP LPs were internalized and accumulated into the mitochondria of cancer cells in a time-dependent manner, followed by triggering permeabilization of the mitochondrial outer membrane by inhibiting Bcl-2, and then further caused greater cancer cell death via releasing cytochrome C and initiating a cascade of caspase 3 reactions. In the Pan02 tumor-bearing mice, the SS-TP LPs showed significant efficacy in inhibiting tumor growth and reducing tumor size but synchronously exhibited specific mitochondria-targeting and much lower subacute toxicity compared with the free TP and TP LPs. Our study suggests that SS-TP LPs can be a promising anticancer drug delivery system for mitochondria-targeted therapy in pancreatic cancer.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
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Project description:IntroductionIGF2BP3 (IMP3) is a mRNA binding protein that regulates IGF2 translation and function during embryogenesis. Because IGF2BP3 is undetectable in adult human tissues except the testis, and increased IGF2BP3 expression has been noted in several cancers, it is considered a cancer testis (CT) protein. IGF2BP3 mRNA expression in colorectal cancers (CRC) has not been well studied. This study's aim was to quantitatively assess IGF2BP3 mRNA expression in CRC and, thus, determine if IGF2BP3 has potential as a vaccine target.MethodData were collected prospectively from CRC patients in an IRB-approved tissue and data bank. Total RNA was isolated and purified from tumor and normal colonic tissue samples and cDNA synthesized. IGF2BP3 expression was analyzed by quantitative PCR (QPCR). Expression levels of IGF2BP3 in tumors and testis were determined and compared. Tumors with levels greater than 0.1% or more of the testis levels were considered positive. Analysis of IGF2BP3 protein expression by immunohistochemistry (IHC) in tumor and normal tissues was also performed.ResultsA total of 84 paired tumor and normal tissue specimens were assessed from patients with Stage 2 and 3 CRC; 43% of tumors had IGF2BP3 mRNA expression levels greater than 0.1 % of that of testis and were considered positive. The median tumor expression level was higher in women (p=0.042). No correlation was found between IGF2BP3 mRNA expression and tumor stage or lymph node involvement. IHC was carried out on paired tumor and normal tissue sections from 46 patients; IGF2BP3 staining was noted in 50% of the tumor sections and in 5% of the normal tissue sections.DiscussionIGF2BP3 mRNA was over expressed in 43% of the tumors whereas the protein was noted in 50% of samples. No correlation between mRNA expression and disease severity was noted. This protein holds promise as a vaccine target, however, a larger study that assesses a more diverse population of patients (Stage 1-4) as well as a study of preoperative serum samples for auto-antibodies to IGF2BP3 are needed to pursue this concept.
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Project description:Vaccines for Pseudomonas aeruginosa have been of longstanding interest to immunologists, bacteriologists, and clinicians, due to the widespread prevalence of hospital-acquired infection. As P. aeruginosa becomes increasingly antibiotic resistant, there is a dire need for novel treatments and preventive vaccines. Despite intense efforts, there currently remains no vaccine on the market to combat this dangerous pathogen. This article summarizes current and past vaccines under development that target various constituents of P. aeruginosa. Targeting lipopolysaccharides and O-antigens have shown some promise in preventing infection. Recombinant flagella and pili that target TLR5 have been utilized to combat P. aeruginosa by blocking its motility and adhesion. The type 3 secretion system components, such as needle-like structure PcrV or exotoxin PopB, are also potential vaccine targets. Outer membrane proteins including OprF and OprI are newer representatives of vaccine candidates. Live attenuated vaccines are a focal point in this review, and are also considered for novel vaccines. In addition, phage therapy is revived as an effective option for treating refractory infections after failure with antibiotic treatment. Many of the aforementioned vaccines act on a single target, thus lacking a broad range of protection. Recent studies have shown that mixtures of vaccines and combination approaches may significantly augment immunogenicity, thereby increasing their preventive and therapeutic potential.
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Project description:In recent years, there has been a major paradigm shift in the management of non-small cell lung cancer (NSCLC). NSCLC should now be further sub-classified by histology and driver mutation if one is known or present. Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). Whilst empirical chemotherapy with a platinum-doublet remains the gold standard for advanced NSCLC without a known driver mutation, targeted therapy is pushing the boundary to significantly improve patient outcomes and quality of life. In this review, we will examine the major subtypes of oncogenic drivers behind NSCLC as well as the development of targeted agents available to treat them both now and in the foreseeable future.
| S-EPMC4367711 | biostudies-literature
Project description:SignificanceReal-time histology can close a variety of gaps in tissue diagnostics. Currently, gross pathology analysis of excised tissue is dependent upon visual inspection and palpation to identify regions of interest for histopathological processing. Such analysis is limited by the variable correlation between macroscopic and microscopic findings. The current standard of care is costly, burdensome, and inefficient.AimWe are the first to address this gap by introducing optical coherence tomography (OCT) to be integrated in real-time during the pathology grossing process.ApproachThis is achieved by our high-resolution, ultrahigh-speed, large field-of-view OCT device designed for this clinical application.ResultsWe demonstrate the feasibility of imaging tissue sections from multiple human organs (breast, prostate, lung, and pancreas) in a clinical gross pathology setting without interrupting standard workflows.ConclusionsOCT-based real-time histology evaluation holds promise for addressing a gap that has been present for >100 years.
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