Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug

CONCLUSION: SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer.PMID:34857016 | DOI:10.1186/s13046-021-02153-9
Source: Cell Research - Category: Cytology Authors: Source Type: research

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ooreman Advances in the treatment of pancreatic ductal adenocarcinoma (PDAC) using neoadjuvant chemoradiotherapy, chemotherapy, and immunotherapy have had minimal impact on the overall survival of patients. A general lack of immunogenic features and a complex tumor microenvironment (TME) are likely culprits for therapy refractoriness in PDAC. Induced pluripotent stem cells (iPSCs) should be explored as a means to advance the treatment options for PDAC, by providing representative in vitro models of pancreatic cancer development. In addition, iPSCs could be used for tailor-made cellular immunotherapies or as a source of...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
ariou Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogrammin...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Patrizia Diana The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different pre...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.
Source: Theranostics - Category: Molecular Biology Authors: Tags: Research Paper Source Type: research
Abstract Desmoplasia is a major barrier to chemotherapy in several cancers, particularly pancreatic ductal adenocarcinoma and breast cancer. Tumors comprise cellular and noncellular components and chemoresistant cancer stem cells (CSCs) with established signaling pathways. In this review, we discuss drugs, such as pentoxifylline, aspirin, and metformin, that have been repurposed and investigated for their antidesmoplastic activity in combination with antitumor drugs. We also highlight less explored new small-molecule drugs, and gene and peptide-based therapeutics for the treatment of desmoplasia and to target CSCs...
Source: Drug Discovery Today - Category: Drugs & Pharmacology Authors: Tags: Drug Discov Today Source Type: research
ConclusionPharmacological inhibition of FAK in pancreatic cancer could be a  novel therapeutic strategy as our results show a radiosensitization effect of VS-4718 in vitro in a multicellular 2D- and in a 3D-model of pancreatic cancer.
Source: Strahlentherapie und Onkologie - Category: Cancer & Oncology Source Type: research
In this study, we delivered gemcitabine monophosphate using lipid calcium phosphate nanoparticles, to desmoplastic pancreatic tumors. Monophosphorylation is a critical, rate-limiting step following cellular uptake of gemcitabine and precursor of the pharmacologically active gemcitabine triphosphate. Our drug delivery strategy enabled us to achieve robust tumor regression with a low parenteral dose in a clinically relevant, KRAS mutant, syngeneic orthotopic allograft, lentivirus-transfected KPC cell line-derived model of pancreatic cancer. Treatment with gemcitabine monophosphate significantly increased apoptosis of cancer ...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research
ConclusionsHerein, the expression profiles, oncogenic roles, regulators and inhibitors of DNMT1 in PDACs are presented and discussed. DNMT1 is overexpressed in PDAC cases compared with non-cancerous pancreatic ducts, and its expression gradually increases from pre-neoplastic lesions to PDACs. DNMT1 plays oncogenic roles in suppressing PDAC cell differentiation and in promoting their proliferation, migration and invasion, as well as in induction of the self-renewal capacity of PDAC cancer stem cells. These effects are achieved via promoter hypermethylation of tumor suppressor genes, including cyclin-dependent kinase inhibit...
Source: Cellular Oncology - Category: Cancer & Oncology Source Type: research
Targeting the IκB Kinase Enhancer and Its Feedback Circuit in Pancreatic Cancer. Transl Oncol. 2020 Jan 28;13(2):481-489 Authors: Challa S, Husain K, Kim R, Coppola D, Batra SK, Cheng JQ, Malafa MP Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an overall median 5-year survival rate of 8%. This poor prognosis is because of the development of resistance to chemotherapy and radiation therapy and lack of effective targeted therapies. IκB kinase enhancer (IKBKE) overexpression was previously implicated in chemoresistance. Because IKBKE is frequently elevated in PDAC ...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research
Publication date: Available online 28 November 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Yu Zhou, Wenxi Zhou, Xinli Chen, Qingbing Wang, Chao Li, Qinjun Chen, Yu Zhang, Yifei Lu, Xiaoyi Ding, Chen JiangAbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix (ECM). Based on the theory that bone marrow mesenchymal stem cells (BM-MSCs) can influence the...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research
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