Anticancer Immunotoxins, Challenges, and Approaches

2020 ◽  
Vol 26 ◽  
Author(s):  
Maryam Dashtiahangar ◽  
Leila Rahbarnia ◽  
Safar Farajnia ◽  
Arash Salmaninejad ◽  
Arezoo Gowhari Shabgah ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Antibody Fragment ◽  
Clinical Use ◽  
Multiple Cancer ◽  
Main Obstacle ◽  
Cancer Types ◽  
Recombinant Immunotoxins ◽  
Cancerous Cells ◽  
High Immunogenicity ◽  
Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

scholarly journals CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists

2019 ◽  
Vol 116 (26) ◽  
pp. 12986-12995 ◽  
Author(s):  
Fang Liu ◽  
Wenyan Jiang ◽  
Yi Sui ◽  
Wei Meng ◽  
Linjun Hou ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Acquired Resistance ◽  
Multiple Cancer ◽  
Bet Inhibitor ◽  
Transcriptional Inhibition ◽  
Effective Inhibition ◽  
Cancer Types ◽  
Almost All

The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.

scholarly journals Therapeutic targeting of SETD2-deficient cancer cells with the small-molecule compound RITA

2021 ◽  
Author(s):  
Kirsten A Lopez ◽  
Sovan Sarkar ◽  
Elena Seraia ◽  
Chiara Toffanin ◽  
Christian Cooper ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Replication Fork Progression ◽  
Stress Markers ◽  
Small Molecule Compound ◽  
Cancer Types ◽  
Novel Therapeutic

The histone methyltransferase SETD2 and its associated histone mark H3 lysine 36 trimethylation (H3K36me3) are frequently lost in certain cancer types, pinpointing SETD2 as an important therapeutic target. Here we show that SETD2-deficient cancer cells are profoundly sensitive to the compound RITA, resulting in significant p53 induction and apoptosis. This is further associated with defects in DNA replication, leading to delays in S-phase progression, increased recruitment of replication stress markers, and reduced replication fork progression. RITA sensitivity is linked to the phenol sulphotransferase SULT1A1, which we find to be highly upregulated in cells that lack SETD2. Depletion of SULT1A1 or addition of the phenol sulphotransferase inhibitor DCNP abolishes these phenotypes and suppresses the sensitivity of SETD2-deficient cancer cells, identifying SULT1A1 activity to be critical in mediating the potent cytotoxicity of RITA against SETD2-deficient cells. These findings define a novel therapeutic strategy for targeting the loss of SETD2 in cancer. Significance: The histone-modifying enzyme SETD2 has emerged as an important tumour suppressor in a number of different cancer types, identifying it as a promising therapeutic target. The concept of synthetic lethality, a genetic interaction in which the simultaneous loss of two genes or pathways that regulate a common essential process renders the cell nonviable, is a useful tool for killing cancer cells that have known mutations. In this study, we conducted a synthetic lethality screen for compounds that specifically target SETD2-deficient cancer cells. The top hit, a compound called RITA, reduces cell viability and induces cell death only in the context of SETD2 loss, thereby highlighting a potential novel therapeutic strategy for treating SETD2-deficient cancers.

Anti-OX40ligand treatment as a novel therapeutic strategy in a murine model of colitis

2001 ◽  
Vol 120 (5) ◽  
pp. A685-A685
Author(s):  
B SINGH ◽  
V MALMSTROM ◽  
F POWRIE
Keyword(s):  
Murine Model ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression

2018 ◽  
Vol 19 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Liwei Lang ◽  
Austin Y. Shull ◽  
Yong Teng
Keyword(s):  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Tumor Development ◽  
Vital Role ◽  
Signaling Cascades ◽  
Cancer Cell Proliferation ◽  
Clinical Use ◽  
Fibroblast Growth ◽  
Apoptosis Resistance ◽  
Downstream Signaling

Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.

scholarly journals Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0214250 ◽  
Author(s):  
Amanda H. Kahn-Kirby ◽  
Akiko Amagata ◽  
Celine I. Maeder ◽  
Janet J. Mei ◽  
Steve Sideris ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

Characterizing the Heterogeneity of Small Extracellular Vesicle Populations in Multiple Cancer Types via an Ultrasensitive Chip

ACS Sensors ◽  
2021 ◽  
Author(s):  
Jing Wang ◽  
Alain Wuethrich ◽  
Richard J. Lobb ◽  
Fiach Antaw ◽  
Abu Ali Ibn Sina ◽  
...  
Keyword(s):  
Extracellular Vesicle ◽  
Multiple Cancer ◽  
Cancer Types

scholarly journals Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1082
Author(s):  
Huitao Liu ◽  
Honglin Luo
Keyword(s):  
Tumor Cells ◽  
Current Knowledge ◽  
Oncolytic Viruses ◽  
Human Enterovirus ◽  
Multiple Cancer ◽  
The Family ◽  
Cancer Types ◽  
Group B ◽  
Type 3 ◽  
Genus Enterovirus

Oncolytic viruses have emerged as a promising strategy for cancer therapy due to their dual ability to selectively infect and lyse tumor cells and to induce systemic anti-tumor immunity. Among various candidate viruses, coxsackievirus group B (CVBs) have attracted increasing attention in recent years. CVBs are a group of small, non-enveloped, single-stranded, positive-sense RNA viruses, belonging to species human Enterovirus B in the genus Enterovirus of the family Picornaviridae. Preclinical studies have demonstrated potent anti-tumor activities for CVBs, particularly type 3, against multiple cancer types, including lung, breast, and colorectal cancer. Various approaches have been proposed or applied to enhance the safety and specificity of CVBs towards tumor cells and to further increase their anti-tumor efficacy. This review summarizes current knowledge and strategies for developing CVBs as oncolytic viruses for cancer virotherapy. The challenges arising from these studies and future prospects are also discussed in this review.

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