Table 1.
Targeting replication stress as radiation sensitizer.
| Targeted Marker | Mechanism | Drug | Phase | Details (Including NCT Number) | Status |
|---|---|---|---|---|---|
| Inducing exorbitant RS | |||||
| CDC6 | Decreased CDC6 expression in tumor cells effectively inhibits tumor cell growth and promotes apoptosis by preventing G1/S and S/G2 transition. | – | – | – | – |
| TOPK | TOPK sensitizes cancer cells to radiotherapy, owing to the preservation of irradiation-induced damage and reduced tolerance to RS. | – | – | – | – |
| CDC20 | Reduced CDC20 expression disrupts the APC-CDC20 interaction and shows great effect on suppressing tumor proliferating and metastasis. | TAME | – | – | – |
| pro-TAME | – | – | – | ||
| Apcin | – | – | – | ||
| Mcl-1 | Mcl-1 blocks radiation-induced apoptosis and inhibits clonogenic cell death. | BAY1143572 (Atuveciclib) | Phase I | Phase I Dose Escalation of BAY1143572 in Subjects With Acute Leukemia (NCT02345382) | Completed |
| Phase I | Open Label Phase I Dose Escalation Study With BAY1143572 in Patients With Advanced Cancer (NCT01938638) | Completed | |||
| UMI77 | – | – | – | ||
| Targeting RS response | |||||
| PARP | Inhibition of PARP forces PARP to trap onto DNA thus preventing replication restart, causing RS-induced DNA damage. | Rucaparib (AG014699) | Phase I | A Study of Rucaparib Administered With Radiation in Patients With Triple Negative Breast Cancer With an Incomplete Response Following Chemotherapy (NCT03542175) | Recruiting |
| Niraparib (MK-4827, Zejula) | Phase I/II | A Safety Study Adding Niraparib and Dostarlimab to Radiation Therapy for Rectal Cancers (NCT04926324) | Not yet recruiting | ||
| Phase II | The Efficacy and Safety of Radiotherapy Plus Niraparib and Toripalimab in Patients With Recurrent Small Cell Lung Cancer (NCT05162196) | Not yet recruiting | |||
| Phase I/II | Study of Niraparib With Radiotherapy for Treatment of Metastatic Invasive Carcinoma of the Cervix (NCT03644342) | Recruiting | |||
| Phase II | Radiation, Immunotherapy and PARP Inhibitor in Triple Negative Breast Cancer (NCT04837209) | Recruiting | |||
| Phase II | Niraparib With Standard Combination Radiation Therapy and Androgen Deprivation Therapy in Treating Patients With High Risk Prostate Cancer (NCT04037254) | Recruiting | |||
| Phase II | Androgen Ablation Therapy With or Without Niraparib After Radiation Therapy for the Treatment of High-Risk Localized or Locally Advanced Prostate Cancer (NCT04947254) | Recruiting | |||
| Phase II | Niraparib Combined With Radiotherapy in rGBM (NCT04715620) | Recruiting | |||
| Phase II | Niraparib + Dostarlimab + RT in Pancreatic Cancer (NCT04409002) | Active, not recruiting | |||
| Phase I/II | A Multi-Center Trial of Androgen Suppression With Abiraterone Acetate, Leuprolide, PARP Inhibition and Stereotactic Body Radiotherapy in Prostate Cancer (NCT04194554) | Recruiting | |||
| Talazoparib (BMN673, Talzenna) | Phase I |
Talazoparib and Radiation Therapy in Treating Patients With Locally Recurrent Gynecologic Cancers (NCT03968406) |
Recruiting | ||
| Phase II | A Study to Evaluate TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 Negative Patients With PD-L1+ Metastatic Triple Negative Breast Cancer (NCT04690855) | Recruiting | |||
| Phase I | Talazoparib and Thoracic RT for ES-SCLC (NCT04170946) | Recruiting | |||
| Olaparib (AZD2281, KU0059436) | Phase I | Olaparib & Radiation Therapy for Patients Triple Negative Breast Cancer (TNBC) (NCT03109080) | Active, not recruiting | ||
| Phase I/II | Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients (NCT03212742) | Recruiting | |||
| Phase II | Focal Radiation With Pulsed Systemic Therapy of Abiraterone, Androgen Deprivation Therapy (ADT), Lynparza Towards Castration Sensitive Oligometastatic Prostate Cancer (FAALCON) (NCT04748042) | Recruiting | |||
| Phase II | Radiation Therapy With or Without Olaparib in Treating Patients With Inflammatory Breast Cancer (NCT03598257) | Recruiting | |||
| Phase I | Study of Olaparib With Radiation Therapy and Cetuximab in Advanced Head and Neck Cancer With Heavy Smoking History (NCT01758731) | Completed | |||
| Phase I | Olaparib and Radiotherapy in Inoperable Breast Cancer (NCT02227082) | Completed | |||
| Phase I | Olaparib and Radiotherapy in Head and Neck Cancer (NCT02229656) | Active, not recruiting | |||
| Phase II | A Study of Radiation Therapy With Pembrolizumab and Olaparib in Women Who Have Triple-Negative Breast Cancer (NCT04683679) | Recruiting | |||
| Phase I | A Study of Olaparib and Low Dose Radiotherapy for Small Cell Lung Cancer (NCT03532880) | Recruiting | |||
| Phase I | Radiotherapy & Olaparib in COmbination for Carcinoma of the Oesophagus (NCT01460888) | Unknown | |||
| Phase I | A Study of Olaparib With Concomitant Radiotherapy in Locally Advanced/Unresectable Soft-tissue Sarcoma (NCT02787642) | Recruiting | |||
| Phase I/II | Olaparib and Durvalumab With Carboplatin, Etoposide, and/or Radiation Therapy for the Treatment of Extensive-Stage Small Cell Lung Cancer, PRIO Trial (NCT04728230) | Recruiting | |||
| Phase I | Radiotherapy and Durvalumab/Durvalumab Combo (Tremelimumab/Olaparid) for Small Cell Lung Cancer (NCT03923270) | Recruiting | |||
| Phase I | Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC (NCT01562210) | Completed | |||
| Phase I | A Study to Investigate Biomarker Effects of Pre-Surgical Treatment With DNA Damage Repair (DDR) Agents in Patients With Head and Neck Squamous Cell Carcinoma (HNSCC) (NCT03022409) | Completed | |||
| Phase I | A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (NCT04550104) | Recruiting | |||
| Phase I/II | Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET) (NCT04086485) | Not yet recruiting | |||
| Phase I | Phase I Study of Olaparib With Cisplatin Based Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck (NCT01491139) | Withdrawn | |||
| Phase II/III | Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (NCT05255653) | Not yet recruiting | |||
| Veliparib (ABT-888, NSC 737664) | Phase I | A Phase I Study of ABT-888 in Combination With Conventional Whole Brain Radiation Therapy (WBRT) in Cancer Patients With Brain Metastases (NCT00649207) | Completed | ||
| Phase I | A Clinical Study Conducted in Multiple Centers Evaluating Escalating Doses of Veliparib in Combination With Capecitabine and Radiation in Patients With Locally Advanced Rectal Cancer (NCT01589419) | Completed | |||
| Phase I | Veliparib in Combination With Gemcitabine and Intensity Modulated Radiation Therapy in Patients With Pancreatic Cancer (NCT01908478) | Completed | |||
| Phase I/II | Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas ( NCT01514201) | Completed | |||
| Phase II | Comparison of Veliparib and Whole Brain Radiation Therapy (WBRT) Versus Placebo and WBRT in Adults With Brain Metastases From Non-Small Cell Lung Cancer | Completed | |||
| Phase I | Veliparib and Radiation Therapy in Treating Patients With Advanced Solid Malignancies With Peritoneal Carcinomatosis, Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer (NCT01264432) | Completed | |||
| Phase I | Veliparib With Radiation Therapy in Patients With Inflammatory or Loco-regionally Recurrent Breast Cancer (NCT01477489) | Completed | |||
| Phase I | Pre-Operative Radiation and Veliparib for Breast Cancer (NCT01618357) | Recruiting | |||
| Phase II | Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations (NCT03581292) | Active, not recruiting | |||
| Phase I | ABT-888, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma Multiforme (NCT00770471) | Completed | |||
| Phase I/II | Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery (NCT01386385) | Active, not recruiting | |||
| Phase I/II | A Study Evaluating the Efficacy and Tolerability of Veliparib in Combination With Paclitaxel/Carboplatin-Based Chemoradiotherapy Followed by Veliparib and Paclitaxel/Carboplatin Consolidation in Adults With Stage III Non-Small Cell Lung Cancer (NSCLC) ( NCT02412371) | Terminated | |||
| RPA | Overexpression of RPA significantly increases the radiation resistance in multiple cancer types. | – | – | – | – |
| TopBP1 | TopBP1 is known to form phase-separated nuclear condensates that amplify ATR activity to CHK1 and slow down replication forks. | – | – | – | – |
| ATR-CHK1 | Inhibition of ATR-related signaling pathways increases cell apoptosis and effectively improves tumor radiosensitivity. | AZD6738 (Ceralasertib) | Phase I | Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours (NCT02223923) | Unknown |
| Phase I | A Study to Investigate Biomarker Effects of Pre-Surgical Treatment With DNA Damage Repair (DDR) Agents in Patients With Head and Neck Squamous Cell Carcinoma (HNSCC) (NCT03022409) | Completed | |||
| VE-821 | – | – | – | ||
| SAR-020106 | – | – | – | ||
| BAY1895344 (Elimusertib) | Phase I | First-in-human Study of ATR Inhibitor BAY1895344 in Patients With Advanced Solid Tumors and Lymphomas (NCT03188965) | Active, not recruiting | ||
| Phase I | Testing the Addition of an Anti-cancer Drug, BAY1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer (NCT04576091) | Recruiting | |||
| RAD51 | Inhibition of RAD51 induces RS to promote apoptosis. | Berberine | – | – | – |
| Valproate | Phase II | Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma (NCT00879437) | Completed | ||
| Phase I/II | Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer (NCT01898104) | Recruiting | |||
| Phase II | Valproic Acid With Temozolomide and Radiation Therapy to Treat Brain Tumors (NCT00302159) | Completed | |||
| Phase I | Phase I Study of Temozolomide, Valproic Acid and Radiation Therapy in Patients With Brain Metastases (NCT00437957) | Terminated | |||
| Phase I/II | Valproic Acid With Chemoradiotherapy for Non-Small-Cell Lung Cancer (NCT01203735) | Unknown | |||
| BLM | The high expression of BLM is a poor prognostic biomarker for multiple cancers. Though there’s no data published about the links between BLM inhibitor and radiation sensitivity till now, it’s a promising target worth further research. | ML216 (CID-49852229) | – | – | – |
| WEE1 | Inhibition of WEE1 impairs RS response activated by ATR, and thus increasing tumor cell radiosensitivity. | AZD1775 (Adavosertib, MK-1775) | Phase I | Adavosertib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma (NCT01849146) | Active, not recruiting |
| Phase I | Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers (NCT04460937) | Suspended | |||
| Phase I | Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas (NCT01922076) | Active, not recruiting | |||
| Phase I | Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers (NCT03345784) | Active, not recruiting | |||
| Phase I | Dose-escalating AZD1775 + Concurrent Radiation + Cisplatin for Intermediate/High Risk HNSCC (NCT02585973) | Completed | |||
| Phase I/II | Dose Escalation Trial of AZD1775 and Gemcitabine (+Radiation) for Unresectable Adenocarcinoma of the Pancreas (NCT02037230) | Completed | |||
| Phase I | WEE1 Inhibitor With Cisplatin and Radiotherapy: A Trial in Head and Neck Cancer (NCT03028766) | Completed | |||
| Targeting RS induced DDR | |||||
| p53 | Activation of p53 activates cell cycle block and apoptosis. | – | – | – | – |
| MRE11 | Low MRE11 expression reduces phosphorylated DNA-PKcs expression, further increases tumor radiosensitivity. | Mirin | – | – | – |
| Selenium | Phase II | Capecitabine, Oxaliplatin, Selenomethionine, and Radiation Therapy in Treating Patients Undergoing Surgery For Newly Diagnosed Stage II or III Rectal Adenocarcinoma (NCT00625183) | Terminated | ||
| Phase II | Carboplatin, Paclitaxel, Selenomethionine, and Radiation Therapy in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery (NCT00526890) | Terminated | |||
| Phase II | Selenomethionine in Reducing Mucositis in Patients With Locally Advanced Head and Neck Cancer Who Are Receiving Cisplatin and Radiation Therapy (NCT01682031) | Terminated | |||
| Phase II | Selenomethionine and Finasteride Before Surgery or Radiation Therapy in Treating Patients With Stage I or Stage II Prostate Cancer (NCT00736645) | Completed | |||
| Phase II | Selenomethionine in Treating Patients Undergoing Surgery or Internal Radiation Therapy for Stage I or Stage II Prostate Cancer (NCT00736164) | Withdrawn | |||
| OBP-301 (Telomelysin) | Phase I | A Study of OBP-301 With Radiation Therapy in Patients With Esophageal Cancer (NCT03213054) | Unknown | ||
| ATM-CHK2 | Deficiency of ATM shows radiation sensitizer effect in multiple cancer types. The effect of ATM on radiation sensitivity is more depend on cell cycle regulation rather than DDR pathway. | AZD0156 | – | – | – |
| AZD1390 | Phase I | A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer (NCT03423628) | Recruiting | ||
| Early Phase 1 | AZD1390 in Recurrent Grade IV Glioma Patients (NCT05182905) | Recruiting | |||
| Phase I | A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (NCT04550104) | Recruiting | |||
| Phase I | Sarcomas and DDR-Inhibition; a Combined Modality Study (NCT05116254) | Not yet recruiting | |||
| MDM2 | Inhibition of MDM2 phosphorylation leads to cell apoptosis and cell cycle arrest, thus repressing tumor cell proliferation. | MI-219 | – | – | – |
| APG-115 (Alrizomadlin) | – | – | – | ||
| POLQ | Reduced POLQ expression inhibits DSB repair and tumor cell survival. | Novobiocin | – | – | – |
| BRCA | Mutations in BRCA is synthetic lethal with PARP inhibition. | – | – | – | – |
| PI3K/AKT/mTOR | Inhibition of PI3K/AKT/mTOR signaling pathway leads to cell cycle arrest in the G2/M phase and reduces tumor cell radio-resistance. | Dactolisib (BEZ235, NVP-BEZ235) | – | – | – |
| Apitolisib (GDC-0980, RG7422, GNE 390) | – | – | – | ||
| Torin2 | – | – | – | ||
| Others | |||||
| Ubiquitin and SUMO | SUMO/ubiquitin equilibrium at active DNA replication forks controls CDK1 activation. | – | – | – | – |
| UPR | Activated UPR reduces the oxidative phosphorylation thus impairing cell cycle arrest and DNA repair factors after radiation also enhance radiation induced cell death. | ONC201 (TIC10) | Phase II | Combination Therapy for the Treatment of Diffuse Midline Gliomas (NCT05009992) | Recruiting |
| Phase I | ONC201 and Radiation Therapy Before Surgery for the Treatment of Recurrent Glioblastoma (NCT04854044) | Withdrawn | |||
Data retrieved from: https://clinicaltrials.gov/ct2/home Retrieval data 04/19/2022.
RS, replication stress; DDR, DNA damage response; CDC6, cell division cycle 6 homologue; TOPK, t-lymphoid-activated killer (T-LAK) cell-derived protein kinase; CDC20, cell division cycle protein 20 homologue; TAME, tosyl-L-arginine methyl ester; Mcl-1, myeloid cell leukemia sequence 1; PARP, poly (ADP-ribose) polymerases; RPA, replication protein A; TopBP1, topoisomerase II-binding protein 1; ATR, ataxia telangiectasia and rad3-related; CHK, checkpoint kinase; MRE11, meiotic recombination 11; ATM, ataxia telangiectasia mutated; MDM2, mouse double minute 2; POLQ, DNA polymerase theta; BRCA, breast cancer related protein; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; SUMO, small ubiquitin-like modifier; UPR, unfolded protein response.