A total of nine patients were found to have partial or complete radiologic response following olaparib treatment. Impressive early results were seen in the peritoneal mass of patient 20, which shrank from 53 mm to 18 mm post-treatment. Following up from these results, Study 19 NCT was a placebo-controlled clinical trial of maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum based regimens. In Study 19, eight 50 mg capsules of olaparib were taken twice daily, equivalent to a daily dose of mg and a total of 16 capsules per day.
To reduce capsule burden, a tablet formulation of olaparib was developed, requiring patients to ingest two mg tablets, twice daily, equivalent to a dose of mg and a total of four tablets per day. Investigator-assessed median PFS was significantly longer with olaparib In August , olaparib was granted US Food and Drug Administration FDA approval for maintenance treatment of adult patients with recurrent, epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
In addition to olaparib, two other PARP inhibitors, rucaparib and niraparib, have shown similar activity in patients with BRCA and in patients with high-grade serious ovarian cancer. The average survival time for patients with high-grade serous ovarian cancer is usually around 2—3 years. In Study 19, clinically significant long-term maintenance treatment with olaparib has been observed.
Strategies for increasing the efficacy of DNA damage response targeted therapies. What other evidence do we have that targeting DDR has the potential to increase efficacy and the number of potential cures? In , a study described an outlier response in a patient with metastatic small cell cancer of the ureter, in which the patient achieved a complete response that was durable despite drug therapy discontinuation for nearly 3 years.
The combination of DNA damage and tumour specific DDR deficiencies at multiple points in the cell cycle led were attributed to such an impressive patient response. This is an exemplification of the treatment concept that AstraZeneca is trying to reproduce using DDR inhibitor combinations that are synthetically lethal in tumour cells but not in normal cells with somatic mutations. Thus, the AstraZeneca DDR inhibitor pipeline targets include the key single-strand break and double-strand break pathways as well as the ability of the cell to undergo repair throughout the cell cycle Figure 1. Lastly, the use of DDR inhibitor combinations is not the only approach that could potentially increase therapeutic efficacy, as there is new data emerging regarding links between DDR and the immune response.
In addition, there are interesting links between DDR and ancient antiviral immune response, as retention of DNA in the cytoplasm of the cell can lead to activation of type I interferon genes and the STING-dependent innate immune signalling pathway. In summary, DDR inhibition has the potential to revolutionise the way we treat people with cancer. DNA damage response deficiencies are common across multiple cancers, and targeting them has been clinically validated with a subset of patients experiencing long-term benefit following DDR inhibitor treatment.
To increase therapeutic efficacy, there is potential for DDR inhibitors to be combined with each other as well as other targeted agents to deliver step changes in clinical response. Finally, there is significant scientific rationale and clinical evidence that DDR and immune responses are linked and potentially synergistic. As we better understand the interactions between DNA damage, DDR and the immune response there is potential for increasing clinical efficacy by combining DDR inhibitors with immune-directed therapies.
The potential of DNA damage response inhibitors in combination with radiation treatment. It is usually given concurrently with standard cytotoxic chemotherapy, the specific chemotherapy dependent on the disease site. In the last 20 years there have been major technological advancements in our ability to deliver radiation specifically to tumours. Radiation is given in combination with full systemic doses of chemotherapy, so increasing chemotherapy or radiation doses is not the solution for improving therapy.
Emerging targets in cancer drug resistance
There is a need for tumour cell selective therapies that can be integrated into treatment regimens to improve therapies without increasing toxicity. DDR is a promising target for improving chemoradiation because DNA is the principal target of radiation. DNA damage response is a broad term encompassing a collection of processes in which cells pause in the cell cycle to allow for DNA repair, cells stop DNA replication to prevent replication of a damaged DNA template and cells activate DNA repair pathways.
A common concern regarding the use of DDR inhibitors as therapeutics, is their potential effect on normal cells. During tumourigenesis there is an acquisition of mutations, many of which cause tumour cells to become defective in one or more of the DDR pathways. Strategy 1 — DNA damage response inhibition with standard-of-care.
When combining standard-of-care chemoradiation therapy with DDR inhibitors, DDR inhibitors can be used to sensitise tumour cells to both chemotherapy and radiation. In addition, when DDR inhibitors are given as sensitisers, lower doses of chemotherapy agents can be used than for monotherapy, therefore potentially reducing toxicity. There are currently five on-going clinical trials combining a DDR inhibitor with chemoradiation Table 1. Although this trial is still ongoing, to date the median overall survival data are promising and compare very favourably to historical control data.
Dosage insufficiencies of DNA repair genes might, however, only be unmasked once a cell is challenged with an increased load of DNA damage such as oncogene-induced replicative stress [81, 82]. Synthetic lethal approaches might therefore be applicable not only in cancer cells with deficiencies, but also in those bearing haploinsufficiencies for DDR factors. Evidence from gene targeting studies in mice revealed that, for example, the loss of one allele of ATR or CtIP is sufficient to cause increased chromosomal aberrations, genomic instability and tumour susceptibility [83, 84].
This indicates that heterozygous carriers of DDR defects are more prone to develop tumours once the threshold of endogenous DNA damage is increased as, for example, in precancerous lesions .
However, scientists are just beginning to unravel how haploinsufficiency of DDR genes contributes to carcinogenesis and how these may be exploited for novel synthetic lethal approaches in cancer therapy. To date, DSB-inducing agents have been the core components of conventional cancer therapy, confirming the rationale of inflicting excessive DNA damage in order to kill cancer cells. However, most chemotherapeutic regimens cause severe side effects that limit their therapeutic potential.
As summarised in this review, SMIs and synthetic lethal approaches targeting the individual genetic profile of the tumours are under clinical development, with the aim to improve the patients' benefit by increasing the efficacy while lowering the toxicity of cancer treatments. A prerequisite for personalised therapy is the molecular characterisation of tumours with reliable biomarkers to assign patients the appropriate treatment. In order to stratify cancer patients according to their DNA repair status, tumour biopsies can be analysed with immunohistochemistry, fluorescence in-situ hybridisation FISH , gene sequencing, expression profiling and other methods .
Relevant biomarker assays should ideally predict the functionality of DNA repair pathways, rather than just providing information about mutations or expression levels of proteins involved in the DDR. Certainly, such a detailed molecular profiling of cancer versus normal tissue from a given patient is critical to maximise the potential of personalised cancer drugs in terms of both therapeutic success and cost-effectiveness.
Recent in-vitro and in-vivo research has deepened our knowledge about synthetic genetic interactions and put forward alternative ways to treat cancer. Furthermore, by utilising ribonucleic acid RNA interference technologies, screens for synthetic lethal interactions of cancer-specific defects in DNA repair pathways have augmented the discovery of targets for cancer therapy. Recently discovered inhibitors of RPA and RAD51 are promising candidates, which are in preclinical testing in order to be approved for the use in clinical trials soon [48, 50].
These observations highlight the therapeutic potential of miRNA mimics or inhibitors in future approaches for cancer therapy . In summary, as the concept of personalised medicine emerges, tumour-specific defects of DSB repair pathways represent a promising therapeutic target to be exploited for the selective elimination of cancer cells.
Thus, there is an air of optimism for targeted cancer therapy through exploiting the DDR of tumour cells in the clinics.
Acknowledgement: We wish to thank D. We also would like to apologize to all authors whose significant contributions could not be cited due to space limitations. Correspondence: Professor Alessandro A. Hallmarks of cancer: the next generation. Repair and genetic consequences of endogenous DNA base damage in mammalian cells.
Annu Rev Genet. DNA damage, aging, and cancer. N Engl J Med. The DNA-damage response in human biology and disease. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. The DNA damage response and cancer therapy. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. FEBS Lett. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. DNA interstrand crosslinks: natural and drug-induced DNA adducts that induce unique cellular responses. The DNA damage response: making it safe to play with knives.
Mol Cell. Playing the end game: DNA double-strand break repair pathway choice. Double-strand break end resection and repair pathway choice. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Sensing and repairing DNA double-strand breaks. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Targeting Chk1 in pdeficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.
J Clin Invest. Proc Soc Exp Biol Med. Cancer Res. Caffeine inhibits the checkpoint kinase ATM. Curr Biol. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Small molecule inhibitors of the PI3-kinase family. Curr Top Microbiol Immunol. Identification and evaluation of a potent novel ATR inhibitor, NU, in breast and ovarian cancer cell lines. Br J Cancer. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.
J Med Chem. Nat Chem Biol. The novel ATR inhibitor VE increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.
Nat Struct Mol Biol. Purification, physico-chemical properties, structural determination and biological activities. J Antibiot. J Biol Chem. Structural basis for Chk1 inhibition by UCN Mol Cancer Ther. Clin Cancer Res. CDC25 phosphatase inhibitors: an update. Mini Rev Med Chem. Int J Cancer. Bioorg Med Chem Lett. A forward chemical genetic screen reveals an inhibitor of the MreRadNbs1 complex. Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin.
Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening. ACS Chem Biol. RI a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. Inhibition of BRCT BRCA1 -phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option.
Breast Cancer Res Treat. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly ADP-ribose polymerase inhibition. Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly ADP-ribose polymerase inhibitor in a novel drug combination. Mol Pharmacol. Liu, X. ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis.
Barakat, D. Riganti, C. Lin, W. Genes Dev 15 , — Macgregor, S. Genome-wide association study identifies a new melanoma susceptibility locus at 1q Davies, J. Inherited variation in the PARP1 gene and survival from melanoma. Int J Cancer. Murai, J. CAN MCT Reinhold, W. CellMiner: a web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI cell line set.
CAN [pii] Calabrese, C.
Davidson, D. Delaney, C. Clinical cancer … Miknyoczki, S. Molecular cancer … , — Tentori, L. Inhibition of telomerase increases resistance of melanoma cells to temozolomide, but not to temozolomide combined with poly adp-ribose polymerase inhibitor. Molecular pharmacology 63 , — Wang, L. Schreiber, V. Poly ADP-ribose : novel functions for an old molecule. Masson, M. Mol Cell Biol 18 , — El-Khamisy, S.
Nucleic Acids Res 31 , — Satoh, M. Helleday, T. DNA repair as treatment target. Kedar, P. MCR Ikejima, M. The zinc fingers of human poly ADP-ribose polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA. J Biol Chem , — Mortusewicz, O. Altmeyer, M. Molinete, M. EMBO J 12 , — Download references. Correspondence to Panayiotis V. Benos or Hussein Tawbi. Reprints and Permissions. By submitting a comment you agree to abide by our Terms and Community Guidelines.
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Targeting DNA double-strand break signalling and repair: recent advances in cancer therapy
Subjects Cancer Prognostic markers Therapeutics. Introduction Advances in cancer management have improved the overall outlook of patients with metastatic malignancies but chemotherapy remains a mainstay of treatment for most common cancers. Table 1 Characteristics of study population. Full size table. Figure 1. Full size image. Figure 2. Discussion Application of different therapies in well-defined subgroups of patients is an important step towards cancer precision medicine.
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