Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside
Abstract
:Simple Summary
Abstract
1. Introduction
2. Antisense Oligonucleotides (ASOs)
2.1. Mechanism of ASO Activity
2.1.1. Inhibition of 5′ Cap Formation
2.1.2. Steric Blocking of Translation
2.1.3. Alteration of Splicing
2.1.4. Activation of RNase H
2.1.5. Inhibition of miRNA Activity (antimiRs)
2.2. Methods of Delivery of ASOs
2.3. Designing ASOs
2.4. Clinical Future of ASOs
2.4.1. Breast Malignancies
2.4.2. Ovarian Malignancies
2.4.3. Hematologic Malignancies
2.4.4. Lung Cancer
2.4.5. Gastrointestinal Cancer
2.4.6. Potential Role of ASO in Immunotherapy and Anti-Angiogenic Therapies
3. Overcoming Challenges for Clinical Application of ASOs
4. Summary and Future Directions
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Correction Statement
Abbreviations
ALSFRS-R | ALS functional rating scale revised |
AML | Acute myeloid leukemia |
ASO | Antisense oligonucleotide |
BCL-2 | B-cell lymphoma 2 |
BCL-XL | B-cell lymphoma-extra-large protein |
cAMP | Adenosine 3′,5′-cyclic monophosphate |
CLN7 | Neuronal ceroid lipofuscinosis 7 (CLN7) gene |
c-Myb | Avian myeloblastosis viral oncogene homolog |
CSF | Cerebrospinal fluid |
DMD | Duchenne muscular dystrophy |
DOPC | 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine |
eIF-4α | Eukaryotic initiation factor 4 alpha |
ERK | Extracellular signal-regulated kinase |
FOXP3 | Transcription factor forkhead box protein 3 |
Grb2 | Growth factor receptor-bound protein 2 |
HER | Human epidermal growth factor receptor |
Hsp27 | Heat shock protein 27 |
IFN-γ | Interferon gamma |
IGF-1 | Insulin-like growth factor 1 |
IGF-1R | Insulin-like growth factor 1 receptor |
IL-12 | Interleukin 12 |
IL-6 | Interleukin 6 |
Kb | Kilobase |
KRAS | Kirsten rat sarcoma |
LNA | Locked nucleic acid |
MAPK | Mitogen-activated protein kinase |
Mcl-1 | Myeloid cell leukemia-1 |
miRNA | MicroRNA |
MOE | 2′-O-methoxyethyl group |
ncRNA | Non-coding RNA |
NfL | Neurofilament Light Chain |
Notch-1 | Neurogenic locus notch homolog protein 1 |
NCI | The National Cancer Institute |
NHGRI | The National Human Genome Research Institute |
OMe | 2′-O-methyl group |
P53 | Tumor protein |
PCH3 | Phosphomethyl group |
PDCD4 | Programmed cell death protein 4 |
PI3K | Phospho-inositide-3-kinase |
PKA | Protein kinase A |
PKC | Protein kinase C |
PNH2 | Phosphoamine group |
PS | Phosphorothioate group |
PTEN | Phosphatase and tensin homolog |
Raf-1 | Rapidly accelerated fibrosarcoma |
RAS | Rat sarcoma |
RISC | RNA-induced silencing complex |
SMA | Spinal muscular atrophy |
STAT3 | Signal transducer and activator of transcription 3 |
TCGA | Cancer Genome Atlas Research Network |
TGF-β2 | Transforming growth factor beta 2 |
TLR9 | Toll-like receptor 9 |
TNF-α | Tumor necrosis factor alpha |
TRPM-2 | Transient receptor potential melastatin 2 |
VEGF | Vascular endothelial growth factor |
XIAP | X-linked Inhibitor of Apoptosis Protein |
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ASO | Drug Name (Company) | Structure | Target | FDA Approval Year | EMA Approval Year | FDA/EMA Approved Use | Reference |
---|---|---|---|---|---|---|---|
Fomivirsen | Vitravene (Isis Pharmaceuticals, Novartis, Carlsbad, CA, USA) | 21-mer | UL123 mRNA | 1998 (withdrawn in 2001 due to reduced incidence of AIDS-related CMVR) | 1999 (withdrawn in 2002 due to reduced incidence of AIDS-related CMVR) | Cytomegalovirus (CMV) retinitis in AIDS patients | [8] |
Mipomirsen | Kynamro (Genzyme, Isis Pharmaceuticals, Carlsbad, CA, USA) | 20-mer | apoB-100 mRNA | 2013 | Not approved (possible liver damage, risk of cardiovascular events) | Familial hypercholesterolemia | [9,10,11] |
Nusinersen | Spiranza (Biogen Inc. Cambridge, MA, USA) | 18-mer | 7th exon SMN2 | 2016 | 2017 | Spinal Muscular Atrophy (SMA) in pediatric and adult patients | [12,13,14] |
Eteplirsen | Exondys 51 (Sarepta Therapeutics, Cambridge, MA, USA) | 30-mer | 51st exon of the DMD gene | 2016 | Not approved (not satisfactionary effect of the drug compared to placebo) | Duchenne Muscular Dystrophy (DMD) | [15,16] |
Inotersen | Tegsedi (Ionis Pharmaceuticals, Akcea Therapeutics, Carlsbad, CA, USA) | 20-mer | TTR mRNA | 2018 | 2014 (approved as orphan drug) | Adult Patients with Hereditary Transthyretin Amyloidosis | [17,18] |
Goldodirsen | Vyondys 53 (Sarepta Therapeutics, Cambridge, MA, USA) | 25-mer | 53rd exon of dystrophin pre-mRNA | 2019 | - | Duchenne Muscular Dystrophy (DMD) | [19] |
Milasen | Milasen (TriLink, Brammer Bio, Cambridge, MA, USA) | 22-mer | 6th exon of MFSD8 | 2019 (personalized medicine for single patient) | - | Spinal Muscular Atrophy (SMA) | [20,21,22] |
Volanesorsen | Waylivra (Ionis Pharmaceuticals, Akcea Therapeutics, Carlsbad, CA, USA) | 20-mer | apoC-III mRNA | Not approved (safety issues—thrombocytopenia) | 2019 | Familial Chylomicronemia Syndrome or Hypertriglyceridaemia | [23,24,25] |
Viltolarsen | Viltepso (NS Pharma, Inc., Nippon Shinyaku, Kyoto City, Kyoto Prefecture, Japan) | 21-mer | 53rd exon of DMD gene | 2020 | 2022 (decision of approval of investigation plan) | Duchenne Muscular Dystrophy (DMD) | [26,27,28] |
Casimersen | Amondys 45 (Sarepta Therapeutics, Cambridge, MA, USA) | 22-mer | 45th exon of DMD gene | 2021 | - | Duchenne Muscular Dystrophy (DMD) | [29] |
Eplontersen | Wainua (Ionis Pharmaceuticals and AstraZeneca, Carlsbad, CA, USA) | 20-mer linked with N-acetyl galactosamine | TTR pre-mRNA | 2023 | 2023 (approved as orphan drug) | Polyneuropathy of Hereditary Transthyretin Amyloidosis (ATTR) | [30,31] |
Tofersen | Qalsody (Biogen, Cambridge, MA, USA) | 20-mer | SOD1 | 2023 | 2024 (positive opinion) | Amyotrophic Lateral Sclerosis (ALS) | [32,33] |
ASO Generation | Modification | Resistance to Nucleases | Half-Life | Charge | References |
---|---|---|---|---|---|
Not modified | Not applicable | + | ~1 h | Negative | [59,60] |
I | An oxygen atom in the -P=O position is replaced by sulfur, methyl, or amine group | ++ | ~4–6 h | Negative | [59,60] |
II | Modification of sugar in 2′-position including insertion of methyl or methoxylethyl group | +++ | 22 days | Multiple negative charges | [61] |
III | Sugar modification and phosphate linkages | ++++ | ~20 h | Neutral | [59,60] |
Type of Cancer | Gene or Protein Associated with Cancer | ASO | Recruitment Status and Phase of Clinical Trial | Reference |
---|---|---|---|---|
Solid tumors | Akt-1 | WGI-0301 | Recruiting, phase 1 | [184] |
Lymphomas | Bcl-2 | BP1002 | Recruiting, phase 1 | [185] |
Acute Myeloid Leukemia | Bcl-2 | BP1002 | Recruiting, phase 1 | [186] |
Leukemia | Bcl-2 | G3139 (oblimersen) | Completed, phase 1/2 | [187] |
Renal cancer | Bcl-2 | G3139 (oblimersen) | Completed, phase 2 | [188] |
Lung cancer | Bcl-2 | G3139 (oblimersen) | Completed, phase 1/2 | [189] |
Melanoma | Bcl-2 | G3139 (oblimersen) | Completed, phase 3 | [190] |
Solid tumors | Bcl-2 | G3139 (oblimersen) | Completed, phase 1 | [191] |
Small cell lung cancer | Bcl-2 | G3139 (oblimersen) | Completed, phase 1 | [192] |
Breast cancer | Bcl-2 | G3139 (oblimersen) | Terminated, phase 1/2 | [193] |
Lymphoma | Bcl-2 | G3139 (oblimersen) | Completed, phase 1 | [194] |
Multiple myeloma | Bcl-2 | G3139 (oblimersen) | Completed, phase 3 | [195] |
Melanoma | Bcl-2 | G3139 (oblimersen) | Unknown, not applicable | [196] |
Solid tumors | Bcl-2 | G3139 (oblimersen) | Completed, phase 1 | [197] |
Lung cancer | Bcl-2 | G3139 (oblimersen) | Unknown, phase 2/3 | [198] |
Prostate cancer | Bcl-2 | G3139 (oblimersen) | Completed, phase 2 | [199] |
Leukemia | Bcl-2 | G3139 (oblimersen) | Completed, phase 3 | [200] |
Prostate cancer | Bcl-2 | OGX-011 | Completed, phase 1 | [201] |
Colorectal cancer | Bcl-2 | G3139 (oblimersen) | Completed, phase 1/2 | [202] |
Lymphoma | Bcl-2 | G3139 (oblimersen) | Terminated, phase 2 | [203] |
Solid tumors | Clusterin | OGX-011 (custirsen sodium) | Completed, phase1 | [204] |
Breast cancer | Clusterin | OGX-011 (custirsen sodium) | Completed, phase 2 | [205] |
Prostate cancer | Clusterin | OGX-011 (custirsen sodium) | Terminated, phase 3 | [206] |
Hematologic neoplasms | c-Myb | c-Myb AS ODN | Completed, phase 1 | [207] |
Solid tumors | FOXP3 | AZD8701 | Active, not recruiting, phase 1 | [208] |
Acute myeloid leukemia | Grb2 | BP1001 (Prexigebersen) | Recruiting, phase 2 | [129] |
Lymphomas | Grb2 | BP1001 (Prexigebersen) | Completed, phase 1 | [128] |
Lymphomas | Grb2 | BP1001 (Prexigebersen) | Withdrawn, phase 1/2 | [209] |
Solid tumors | Grb2 | BP1001 (Prexigebersen) | Recruiting, phase 1 | [130] |
Lymphomas | HIF-1α | EZN-2968 | Completed, phase 1 | [210] |
Solid tumors | HIF-1α | EZN-2968 | Completed, phase 1 | [211] |
Bladder cancer | Hsp27 | OGX-427 | Unknown, phase 1 | [212] |
Cancers | Hsp27 | OGX-427 | Completed, phase 1 | [213] |
Prostate cancer | Hsp27 | OGX-427 | Completed, phase 2 | [214] |
Bladder carcinoma | Hsp27 | OGX-427 | Completed, phase 2 | [215] |
Glioblastoma | IGF-1R | IMV-001 | Not yet recruiting, phase 2 | [216] |
Solid tumors | KRAS | AZD4785 | Completed, phase 1 | [217] |
Solid tumors | miRNA-221 | LNA-i-Mir-221 | Completed, phase 1 | [103] |
Acute myeloid leukemia | p53 | Cenersen | Withdrawn, phase 2 | [218] |
Myelodysplastic Syndromes | p53 | Cenersen | Terminated, phase 1 | [219] |
Acute Myelogenous Leukemia | p53 | Cenersen | Completed, phase 2 | [220] |
Chronic or Small Lymphocytic Leukemia | p53 | Cenersen | Terminated, phase 2 | [221] |
Renal carcinoma | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1/2 | [222,223] |
Acute Myeloid Leukemia | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 2 | [224] |
Acute Myeloid Leukemia | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1 | [225] |
Solid tumors | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1/2 | [226] |
Colorectal cancer and solid tumors | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1 | [227] |
Solid tumors | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1 | [228] |
Acute Leukemia | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, phase 1 | [229] |
Prostate cancer | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed phase 2 | [230] |
Breast cancer | R2 subunit of ribonucleotide reductase | GTI-2040 | Completed, Phase 2 | [231] |
Breast cancer | Raf-1 | ISIS 5132 | Completed, phase 2 | [232] |
Ovarian Cancer | Raf-1 | ISIS 5132 | Completed, phase 2 | [146] |
Cancers | Raf-1 | LErafAON-ETU | Completed, phase 1 | [233] |
Cancers | Raf-1 | LErafAON | Completed, phase 1 | [234,235] |
Lymphomas | STAT3 | ISIS 481464 | Completed, phase 1/2 | [236] |
Gastrointestinal cancers | STAT3 | AZD9150 (Danvatirsen) | Terminated (not enough patients), phase 2 | [237] |
Advanced Solid Tumors | STAT3 | AZD9150 (Danvatirsen) | Active nor recruiting, phase 1 | [238] |
Advanced Solid Malignancies | STAT3 | AZD9150 (Danvatirsen) | Completed, phase 1 | [239] |
Diffuse Large B-Cell Lymphoma | STAT3 | AZD9150 (Danvatirsen) | Completed, phase 1 | [240] |
Ovarian Cancer | STAT3 | AZD9150 (Danvatirsen) | Terminated, phase 2 | [241] |
Solid Tumors | STAT3 | AZD9150 (Danvatirsen) | Active not recruiting, phase 1/2 | [242] |
AML/MDS | STAT3 | AZD9150 (Danvatirsen) | Active recruiting, phase 1 | [243] |
NHL DLBCL Non-hodgkin’s Lymphoma | STAT3 | AZD9150 (Danvatirsen) | Completed, phase 1 | [244] |
Muscle Invasive Bladder Cancer | STAT3 | AZD9150 (Danvatirsen) | Active not recruiting, phase 1 | [245] |
Non-Small Cell Lung Cancer | STAT3 | AZD9150 (Danvatirsen) | Active not recruiting, phase 2 | [246] |
Solid tumors | TGF-B2 | TGF-B2 (TASO-001) | Recruiting, phase 1 | [247] |
Solid tumors | TLR9 | SD-101 | Active not recruiting, phase 1 | [248] |
Pancreatic adenocarcinoma | TLR9 | SD-101 | Recruiting, phase 1 | [249] |
Pancreatic adenocarcinoma | TLR9 | SD-101 | Completed, phase 1 | [250] |
Advanced malignancies | TLR9 | SD-101 | Terminated, phase 1 | [251] |
Liver tumors | TLR9 | SD-101 | Recruiting, phase 1/2 | [252] |
Low Grade B cell Non Hodgkin Lymphomas | TLR9 | SD-101 | Active not recruiting, phase 1 | [253] |
Follicular lymphoma | TLR9 | SD-101 | Active recruiting, phase 1/2 | [254] |
Uveal Melanoma with metastasis in liver | TLR9 | SD-101 | Recruiting, phase 1 | [255] |
Renal carcinoma | TLR9 | IMO-2055 (EMD 1201081) | Completed, phase 2 | [256] |
Colorectal cancer | TLR9 | IMO-2055 (EMD 1201081) | Terminated, phase 1 | [257] |
Non-Small Cell Lung Cancer | TLR9 | IMO-2055 (EMD 1201081) | Completed, phase 1 | [258] |
Squamous Cell Carcinoma of the Head and Neck Cancer | TLR9 | IMO-2055 (EMD 1201081) | Completed, phase 2 | [259] |
Squamous Cell Carcinoma of the Head and Neck | TLR9 | IMO-2055 (EMD 1201081) | Terminated, phase 1 | [260] |
Mesothelioma | VEGF | VEGF-AS | Withdrawn, phase 1/2 | [183] |
Pancreatic carcinoma | XIAP | AEG35156 | Terminated, phase 1/2 | [261] |
Breast cancer | XIAP | AEG35156 | Terminated, phase 1/2 | [262] |
Solid tumors | XIAP | AEG35156 | Completed, phase 1 | [263] |
Solid tumors | XIAP | AEG35156 | Completed, phase 1 | [264] |
Advanced cancers | XIAP | AEG35156 | Terminated, phase 1 | [265] |
Leukemia | XIAP | AEG35156 | Terminated, phase 2 | [266] |
Leukemia | XIAP | AEG35156 | Terminated, phase 1/2 | [267] |
Leukemia | XIAP | AEG35156 | Completed, phase 1/2 | [268] |
Hepatocellular Carcinoma | XIAP | AEG35156 | Completed, phase 1/2 | [269] |
Non-Small-Cell Lung | XIAP | AEG35156 | Terminate, phase 1/2 | [270] |
Malignant Pleural Mesothelioma | TGF-β | OT-101 (Trabedersen) | Not yet recruiting, phase 2 | [271] |
Pancreatic cancer | TGF-β | OT-101 (Trabedersen) | Not yet recruiting, phase 2/3 | [272] |
Lung Non-Small Cell Carcinoma | TGF-β | OT-101 (Trabedersen) | Withdrawn, phase 2 | [273] |
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Share and Cite
Çakan, E.; Lara, O.D.; Szymanowska, A.; Bayraktar, E.; Chavez-Reyes, A.; Lopez-Berestein, G.; Amero, P.; Rodriguez-Aguayo, C. Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside. Cancers 2024, 16, 2940. https://doi.org/10.3390/cancers16172940
Çakan E, Lara OD, Szymanowska A, Bayraktar E, Chavez-Reyes A, Lopez-Berestein G, Amero P, Rodriguez-Aguayo C. Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside. Cancers. 2024; 16(17):2940. https://doi.org/10.3390/cancers16172940
Chicago/Turabian StyleÇakan, Elif, Olivia D. Lara, Anna Szymanowska, Emine Bayraktar, Arturo Chavez-Reyes, Gabriel Lopez-Berestein, Paola Amero, and Cristian Rodriguez-Aguayo. 2024. "Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside" Cancers 16, no. 17: 2940. https://doi.org/10.3390/cancers16172940
APA StyleÇakan, E., Lara, O. D., Szymanowska, A., Bayraktar, E., Chavez-Reyes, A., Lopez-Berestein, G., Amero, P., & Rodriguez-Aguayo, C. (2024). Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside. Cancers, 16(17), 2940. https://doi.org/10.3390/cancers16172940