Fire A., Xu S., Montgomery M.K., Kostas S.A., Driver S.E., Mello C.C. A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. subsequently identified the serum levels of co-expressed hub miRNAs as potential diagnostic and prognostic biomarkers for pancreatic cancer [88]. Matsukura et al. On the basis of preclinical research progress, the current clinical trials involving oligonucleotide therapeutics for patients with pancreatic cancer listed on the U.S. website are summarized in Table 1. Aptamers have been reported to act as players of various roles, such as oncosuppressors, biomarkers, cargo, and detectors for pancreatic cancer, as shown in Table 3. The siRNA-based therapeutic strategy enables selective silencing of targeting gene expression. Yoon S., Huang K.W., Reebye V., Spalding D., Przytycka T.M., Wang Y., Swiderski P., Li L., Armstrong B., Reccia I., et al. Kohn D.B., Bauer G., Rice C.R., Rothschild J.C., Carbonaro D.A., Valdez P., Hao Q., Zhou C., Bahner I., Kearns K., et al. Kratschmer C., Levy M. Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers. Biswas S. MicroRNAs as Therapeutic Agents: The Future of the Battle against Cancer. The https:// ensures that you are connecting to the Enter the username or e-mail you used in your profile. Programmed cell-death 1 ligand 1 (PD-L1) is a protein of the B7/CD28 family that controls T-cell activation, and MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody, may be a promising therapeutic approach for the treatment of cancer [30]. #ots #oligotherapeutics #oligonucleotide #ots22 #arizona #phoenix #biotech #science #abstract #award, Submissions for Awards and Short Talk Abstracts are due this Tuesday, July 19th! antisense oligonucleotides rna readcube altmetric therapeutics interference beyond blocking oligonucleotide muscular dystrophy duchenne Specifically, chondroitin sulfate-E (CS-E), a matrix glycosaminoglycan, was found to be expressed in both the tumor cells and stromal cells surrounding the tumor in pancreatic cancer patient tissues [61,63]. If the efficacy of miR-25 as a diagnostic biomarker of pancreatic cancer is definitively proven in the trial, the clinical meaning for early detection would be significantly impactful. Pharmacol. Kim S.A., Lee Y., Jung D.E., Park K.H., Park J.Y., Gang J., Jeon S.B., Park E.C., Kim Y.G., Lee B., et al. Direct and targeted delivery of effective treatment agents by means of aptamers to pancreatic cancer cells might maximize the therapeutic value and minimize possible adverse events by decreasing uptake into normal biological cells. FOIA Therapeutic oligonucleotides act on different stages of pathological gene expression. MicroRNA history: Discovery, recent applications, and next frontiers. ; supervision, S.K., N.Y., and M.S. The authors also identified the Wnt receptor Frizzled-5 as a common vulnerability that can be exploited therapeutically with antagonistic antibodies [119]. oligonucleotide therapies therapeutics rna Rejiba S., Wack S., Aprahamian M., Hajri A. K-ras oncogene silencing strategy reduces tumor growth and enhances gemcitabine chemotherapy efficacy for pancreatic cancer treatment.

Belvedere R., Saggese P., Pessolano E., Memoli D., Bizzarro V., Rizzo F., Parente L., Weisz A., Petrella A. miR-196a Is Able to Restore the Aggressive Phenotype of Annexin A1 Knock-Out in Pancreatic Cancer Cells by CRISPR/Cas9 Genome Editing. Goetze J.P., Nielsen F.C., Burcharth F., Rehfeld J.F.

Chang H. RNAi-mediated knockdown of target genes: A promising strategy for pancreatic cancer research. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: A multicenter phase II Trial. Taken together, decoy strategies are expected to be translated into various clinical applications, as a new cancer treatment to specifically target any overexpressed oncogenic transcription factor that binds double-stranded DNA. government site.

Subsequently, a clinical trial of Atu027 plus gemcitabine, administered intravenously in unresectable pancreatic cancer ({"type":"clinical-trial","attrs":{"text":"NCT01808638","term_id":"NCT01808638"}}NCT01808638), was planned in the NIH records, but the study has published no report as of yet. Alberts S.R., Schroeder M., Erlichman C., Steen P.D., Foster N.R., Moore D.F., Jr., Rowland K.M., Jr., Nair S., Tschetter L.K., Fitch T.R. The transforming growth factor-beta (TGF-) signaling pathway is a key player in tumor progression [19], and TGF-2 plays a pivotal role in the malignancy and progression of pancreatic cancer [20,21]. promote the expansion of ASOs for various clinical applications [7]. The OTS Job Board allows you to, Post/Edit Jobs Review/Filter Resumes Manage Employer Profiles, Search the latest job postings in the field of oligonucleotide therapeutics. Depending on the results of current oligonucleotide therapeutics clinical trials, the safety, efficacy, and proper selection of treatment can be better understood. Signal transducer and activator of transcription (STAT) proteins are a family of cytoplasmic transcription factors that are thought to be candidates for anti-cancer therapeutic options, due to the higher dependency of cancer cells on STAT activity compared with normal cells [26]. Golan T., Khvalevsky E.Z., Hubert A., Gabai R.M., Hen N., Segal A., Domb A., Harari G., David E.B., Raskin S., et al. They also reported the evaluation of AZD9150 in a non-Hodgkins lymphoma population [28]. Thus, this class of therapeutics is close to becoming a breakthrough cancer treatment. The same group reported a different targeted aptamer. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents.

Leenders F., Mopert K., Schmiedeknecht A., Santel A., Czauderna F., Aleku M., Penschuck S., Dames S., Sternberger M., Rohl T., et al. A preclinical study indicated that {"type":"entrez-protein","attrs":{"text":"AEG35156","term_id":"333968351","term_text":"AEG35156"}}AEG35156 enhanced the sensitization of tumor necrosis factor (TNF)-related, apoptosis-inducing, ligand-mediated apoptosis in pancreatic carcinoma cells (Panc1) [33]. A preclinical study on Atu027, a liposomal siRNA molecule that specifically impedes PKN3 expression in a mouse model, highlights the further development of Atu027 as a novel siRNA formulation to block the progression of multiple solid cancers, including pancreatic cancer [43]. person, live in Phoenix, Arizona! A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. McGuigan A., Kelly P., Turkington R.C., Jones C., Coleman H.G., McCain R.S. In agreement with the above evidence, we previously demonstrated that high CHST15 expression, which is responsible for the biosynthesis of sulfated CS-E, may represent a potential predictive marker of OS in patients with pancreatic cancer following surgical resection [64], and that STNM01, a CHST15 siRNA, successfully inhibited pancreatic tumor growth in xenograft experiments using the RNAi strategy, as shown in Figure 2 [4]. Ireson C.R., Kelland L.R. Based on their previous work, PAUF is a novel secretory protein involved in pancreatic cancer progression [95]. If you entered an incorrect email address, you will need to re-register with the correct email address. ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2-Deoxyuridine to Pancreatic Cancer. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. Translational applications of microRNAs in cancer, and therapeutic implications. These demonstrate that LODER-derived siG12D significantly suppresses pancreatic cancer growth, both in vitro and in vivo, and impedes pancreatic tumor growth [50], although all of the past studies with direct KRAS modifications for pancreatic cancer had failed [51]. Singh A., Greninger P., Rhodes D., Koopman L., Violette S., Bardeesy N., Settleman J. Ray et al. J. Exp. Recently, complex cancer cell-tumor stroma interactions have been focusing on their crucial roles in tumor initiation, progression, and metastasis [58]. In particular, circulating microRNA-25 (miR-25) has a high specificity for pancreatic cancer, and can be used as a potential biomarker for its early detection, based on the comparative data of miR-25 with CEA and CA19-9, which are widely accepted and conventional tumor markers of pancreatic cancer [89,90]. Schultz N.A., Dehlendorff C., Jensen B.V., Bjerregaard J.K., Nielsen K.R., Bojesen S.E., Calatayud D., Nielsen S.E., Yilmaz M., Hollander N.H., et al. MicroRNAs and Cancer: A Long Story for Short RNAs. Gurbuz N., Ozpolat B. MicroRNA-based Targeted Therapeutics in Pancreatic Cancer. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes; Hsp27 expression becomes highly upregulated, and is related to higher resistance to gemcitabine in patients with pancreatic cancer [35,36]. produced exosomes derived from normal fibroblast-like mesenchymal cells for the specific delivery of siRNA or shRNA to KRASG12D (iExosomes), a common mutation in pancreatic cancer [56]. Subsequently, their group further improved the chemotherapeutic efficacy for pancreatic cancer by forming hybridized aptamerdrug conjugates that involved pancreatic cancer-specific RNA aptamer P19, conducive to higher selectivity of drug delivery with a less toxic effect [105]. Therefore, the authors designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys), and found that the decoy strategy inhibits KRAS in pancreatic cancer cells and reduces tumor growth in human pancreatic cancer xenograft mice [112]. Mutant KRAS is a druggable target for pancreatic cancer. Vorvis et al. Carbohydrate sulfotransferase 15 (CHST15) is a type-2 transmembrane Golgi protein that transfers sulfate to position 6 of GalNAc (4SO4) residues of CS-A to yield CS-E. Biomed. The authors subsequently reported a lipid-modified strategy based on the use of palmitoyl-oleyl-phosphatidylcholine liposomes, which improved the delivery of the G4-decoy by coupling to the liposomes efficiently, resulting in decreased KRAS transcription levels and metabolic activity of pancreatic cancer cells [113]. Regarding the decoy methods used for pancreatic cancer, only one therapeutic and two delivery methods have been reported.

The event will also be available virtually. Qadir M.I., Faheem A. miRNA: A Diagnostic and Therapeutic Tool for Pancreatic Cancer. Currently, a phase I study of mesenchymal stromal cell-derived iExosomes administered intravenously for metastatic pancreatic cancer patients harboring the KRASG12D mutation has been planned ({"type":"clinical-trial","attrs":{"text":"NCT03608631","term_id":"NCT03608631"}}NCT03608631). Based on these studies, Hong and colleagues are now recruiting study patients to investigate whether AZD9150 administered intravenously in combination with MEDI4736 can control advanced pancreatic, lung, or colorectal cancer in a phase II clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT02983578","term_id":"NCT02983578"}}NCT02983578). Reilley M.J., McCoon P., Cook C., Lyne P., Kurzrock R., Kim Y., Woessner R., Younes A., Nemunaitis J., Fowler N., et al.

Several advanced ASO and RNAi agents have already reached clinical trials; thus, we focus mainly on the clinical trials in this chapter. Schlingensiepen K.H., Schlingensiepen R., Steinbrecher A., Hau P., Bogdahn U., Fischer-Blass B., Jachimczak P. Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. All authors have read and approved the final manuscript. International Journal of Molecular Sciences,, clustered regularly interspaced short palindromic repeats, endoscopic ultrasonography guided fine-needle injection, pancreatic adenocarcinoma upregulated factor, Systematic Evolution of Ligands by Exponential Enrichment, signal transducer and activator of transcription. The authors characterize the aptamer and the target protein, CypB. Accordingly, clinical trials of miRNA for pancreatic cancer will probably continue to grow in number, especially in the field of diagnosis. Increased incorporation of adenosine into adenine nucleotide pools in serum-deprived mammalian cells. identified that the FOXA2 transcription factor is involved in pancreatic cancer pathogenesis, by integrating gene and microRNA profiling analyses together with CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) genome editing technology [117]. Zhang J., Li S., Liu F., Zhou L., Shao N., Zhao X. SELEX aptamer used as a probe to detect circulating tumor cells in peripheral blood of pancreatic cancer patients. Then, aptamers directly inhibit proteins in the process of pathogenesis. Accordingly, silencing KRAS is indicative of the inhibition of pancreatic cancer proliferation [49]. The DNA aptamer binds stemness-enriched cancer cells in pancreatic cancer. CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. A study showed that a pancreatic cancer-specific RNA aptamer can be used for the targeted drug delivery of the nucleoside drug 5-fluoro-2-deoxyuridine to pancreatic cancer cells expressing alkaline phosphatase placental-like 2, a putative biomarker, leading to the inhibition of tumor growth [103]. Eser S., Schnieke A., Schneider G., Saur D. Oncogenic KRAS signalling in pancreatic cancer. The authors declare no conflict of interest. Since then, RNAi has become a major tool in various types of laboratory studies; the first application of an RNAi strategy was successfully assessed using an siRNA directed against the mRNA encoding the N-protein of respiratory syncytial virus (RSV) [10]. They also evaluated drug response using the in vivo CRISPR screening method [120]. Friess H., Yamanaka Y., Buchler M., Ebert M., Beger H.G., Gold L.I., Korc M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. All submissions are due by 11:59 pm MT via the online portal. Cullen B.R., Greene W.C. Regulatory pathways governing HIV-1 replication. Protein kinase N3 (PKN3), a molecule distantly related to protein kinase C, is regulated by the phosphoinositide-3-kinase (PI3K) signal transduction pathway [42]. The possibility of applying oligonucleotide therapeutics in the regulatory mechanisms of the microenvironment of pancreatic cancer has been indicated. Cunningham C.C., Holmlund J.T., Geary R.S., Kwoh T.J., Dorr A., Johnston J.F., Monia B., Nemunaitis J. The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-beta2.

Hence, I ended up working with antisense oligonucleotides by chance. The Zamecnik P.C., Stephenson M.L. devised an aptamer strategy to identify RNA ligands that was reported to detect structural differences between the secretomes of pancreatic cancer cells and noncancerous cells [96]. Melle C., Ernst G., Escher N., Hartmann D., Schimmel B., Bleul A., Thieme H., Kaufmann R., Felix K., Friess H.M., et al. Treatment of Pancreatic Cancer by Aptamer Conjugated C/EBPalpha-saRNA. Decoys, which form a double-stranded DNA (dsDNA) structure, inhibit DNA transcription by blocking the activity of the dsDNA-binding transcription factors. Based on a previous study, which reported that high-mobility group AT-hook 1 (HMGA1) promotes chemoresistance to gemcitabine through an Akt-dependent mechanism in human pancreatic cancer cells [114], Hassan et al.

Knott G.J., Doudna J.A. A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial. Click below for additional information. Hong et al.

Aptamers are single-stranded oligonucleotide ligands that demonstrate a high affinity toward target proteins and inhibit their physiological effect, by forming complexes with proteins based on their unique three-dimensional (3D) folding in the later phase of disease progression [91,92]. The sweet and sour of cancer: Glycans as novel therapeutic targets. focus on myc-associated zinc-finger (MAZ), which is a G4-DNA structure that binds to nuclear proteins to promote the activation of KRAS transcription [112]. Aleku M., Schulz P., Keil O., Santel A., Schaeper U., Dieckhoff B., Janke O., Endruschat J., Durieux B., Roder N., et al.

In particular, chemically synthesized siRNAs are mainly being used as a new class of therapeutic agents. 8600 Rockville Pike Petrovic N., Ergun S. miRNAs as Potential Treatment Targets and Treatment Options in Cancer. used the genome-wide CRISPR screening approach to quantify gene-specific phenotypic variation in PANC-1 cells in response to gemcitabine, and confirmed that proteasome subunit alpha type-6 is an essential gene in pancreatic cancer cells [121]. Ryan D.P., Hong T.S., Bardeesy N. Pancreatic adenocarcinoma. Szlachta K., Kuscu C., Tufan T., Adair S.J., Shang S., Michaels A.D., Mullen M.G., Fischer N.L., Yang J., Liu L., et al. Identification of Circulating MiR-25 as a Potential Biomarker for Pancreatic Cancer Diagnosis. Subsequently, antisense RNA, small interfering RNA (siRNA), and microRNA (miRNA) act to target mRNAs. performed an open-label phase I/IIa clinical trial, and revealed that the combination of siG12D LODER and gemcitabine was well-tolerated and safe, and had potential value in 15 patients with locally advanced pancreatic cancer, as the median OS was 15.1 months and the 18-month survival rate was 38.5% [54]. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications. All submissions are due July 19, 2022, by 11:59 pm MT via the online portal. Pharmacother. Thus, we summarize several studies that have shown the value of CRISPRs in pancreatic cancer.

Thereafter, a phase II trial of OGX-427 plus gemcitabine and nab-paclitaxel administered intravenously in patients with metastatic pancreatic cancer was conducted, and revealed that the addition of OGX-427 to chemotherapy provided no improvement in the effect of the first-line setting [38]. KRAS: Feeding pancreatic cancer proliferation. A different group revealed the value of AZD9150 in combination with conventional chemotherapy for patients with neuroblastoma [29]. Vannini I., Fanini F., Fabbri M. Emerging roles of microRNAs in cancer. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children. However, I directly liked the idea to tackle viral disease by disturbing different steps of viral RNA processing as this offers a promising and very specific way to inhibit viral replication. J. Physiol. An RNA aptamer that specifically binds pancreatic adenocarcinoma up-regulated factor inhibits migration and growth of pancreatic cancer cells.

Although the mechanisms by which oligonucleotides produce their effects mostly depend on their structure and chemistry (Table 2), the major premise of controlling the expression of targeted gene products is immutable. Xu Z., Wang Y., Zhang L., Huang L. Nanoparticle-delivered transforming growth factor-beta siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. Cell. Based on the MEK signaling pathway, which is the major driver of tumor formation, and being a promising therapeutic approach in pancreatic cancer, Szlachta et al. Schultz et al. The Oligonucleotide Therapeutics Society (OTS) is an open, nonprofit forum to foster research and development of oligonucleotide therapeutics. Deadline to Apply: August 21, 2022 (11:59pm PT) will also be available for a limited time. Collins M.A., Pasca di Magliano M. Kras as a key oncogene and therapeutic target in pancreatic cancer. Chondroitin sulfate (CS)-E is a matrix glycosaminoglycan (GAG), a linear polysaccharide composed of a repeating disaccharide unit containing D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc), whose 4- and 6-positions are sulfated. Therefore, oligonucleotide therapeutics have a high specificity and target molecules that cannot be controlled by conventional drugs, such as mRNA or noncoding RNA, resulting in the development of innovative drugs against cancers and genetic diseases. #ots #oligotherapeutics #oligonucleotide #mentorprogram #otsmember #science #research, We're excited to host the 2022 Oligo Meeting in person, live in Phoenix, Arizona! Incredibly,oligonucleotidetherapeutics have also been used to create an individualized treatment for one single person with a rare, fatal disease. The median survival was 6.6 months, and the response rate was 10.4%. The KRAS mutation is a primary trigger in >90% of cases of pancreatic cancer progression [45,46,47], and contains a nuclear-hypersensitive element (NHE). The most recent study reported the therapeutic effects of an aptamer-based gemcitabine delivery system, APTA-12, on pancreatic cancer cells both in vitro and in vivo [111]. Ors-Kumoglu G., Gulce-Iz S., Biray-Avci C. Therapeutic microRNAs in human cancer. Just register as an employer and start posting your openings. Thus, pancreatic cancer is receiving extensive attention in research on pharmaceutical agents, given the absence of satisfactory treatments for long-term survival and the increasing trend in diseases. National Library of Medicine Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer.
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