The conference will provide an overview of current and emerging basic, translational and clinical studies of dna damage response in cancer biology and cancer therapy. Tumours with specific dna repair defects could be completely dependent on backup dna. In addition, alterations in dna repair pathways thatarise during tumour development can make some cancer cells reliant on a reducedset of dna repair pathways for survival. We highlight how such ddr enzymes represent rational targets for the discovery of novel therapeutics fig.
Cincinnati childrens research foundation, 3333 burnet ave. Participation of the atrchk1 pathway in replicative stress. Dna repair in cancer a special issue published by hindawi. Yang department of radiation oncology, uab comprehensive cancer center, birmingham, al 35249, usa. Targets bulky lesions of dna adjacent ts fusing due to uv or g with large hydrocarbons covalently bonded due to carcinogen scans for large distortion in helix, when found it cuts out the distorted dna excinuclease and removes dna using helicase to unwind so it can be removed and the whole fragment is replaced uses helicase. New opportunities are arising through the new classes of agents targeting drugs in the dna repair cell cycle pathways. These include events that lead to cellcycle arrest, regulation of. Switching off dna repairhow colorectal cancer evades. Explore the concept of synthetic lethality for cancer treatment. The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. Targeted cancer therapies are sometimes called molecularly targeted drugs, molecularly targeted therapies. Fanconi anemia proteins, dna interstrand crosslink repair. Fusion conferences deadline for abstractsproposals.
This has led to targeting dna repair pathways and proteins to develop anti cancer agents that will increase sensitivity to traditional chemotherapeutics. The application of biomarkers to assess tumor response to therapy based on targeting dna repair pathways can potentially improve. The impact of dna repair pathways in cancer biology and therapy anatoly nikolaev and eddy s. Dna repair mechanisms in cancer development and therapy. Although hr and nhej can substitute for each other under certain circumstances, it is remarkable that, in a process as crucial as dna repair, there is not more redundancy.
The clinical development of parp inhibitors in patients with germline. Cancerspecific defects in dna repair pathways as targets for. Cancer cells often harbor a reduced repertoire of dnarepair and. Dna repair in cancer therapy provides the reader with a primerlevel introduction to the six major dna repair pathways, their interrelationships, their connectivity and regulation by other cellular operational systems, as well as their impact in shaping the development of effective cancer therapies. Efficient dna repair is an important mechanism by which cancer cells exert therapeutic resistance. Using synthetic dna interstrand crosslinks to elucidate. Pdf disruptions in dna repair pathways predispose cells to accumulating dna damage. Targeting chromosomal architectural hmgb proteins could be. Because the efficacy of cancer chemotherapy and radiotherapy relies on generation of dna damage that will be recognized and repaired by intrinsic dna repair pathways, aberrant expression of a particular dna damage response protein should be a biomarker of resistance or favorable response to therapies that induce the corresponding types of dna. Although selective inhibition of dna repair pathways can be used to enhance current. Abstract dna repair pathways can enable tumour cells to survive dna damage that is induced by. This has led to targeting dna repair pathways and proteins to develop anticancer agents that will increase sensitivity to traditional chemotherapeutics. However, despite surgical removal of the tumor and initial high response rates to firstline chemotherapy, around 80% of women will. Dna repair pathways as targets for cancer therapy request pdf.
The initial, standardofcare, adjuvant chemotherapy in epithelial ovarian cancer is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane. The observation that a variety of tumours frequently present deregulated expression of dna repair genes e. Regulation of genomic stability ionizing radiation a dnadamaging agent activates p53mediated cellcycle checkpoints and dna repair. The majority of anticancer therapeutics radiation and chemotherapy function as genotoxins, eliciting genomic dna damage in an attempt to induce cell death in the tumor. Germline aberrations in critical dnarepair and dna damageresponse ddr genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective ddrdna repair. This dichotomy might explain why only isolated dna repair pathways are inactivated in cancer cells.
This result in reduced dna repair capacity and increased genetic instability of tumour cells. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules molecular targets that are involved in the growth, progression, and spread of cancer. Epigenetic targeting of dna repair in lung cancer pnas. Biomarkers to assess the targeting of dna repair pathways to. Mar 22, 2019 dna repair in cancer a special issue published by hindawi. Hrd appears to be a reliable target in ovarian cancer, though validated predictive biomarkers beyond brca mutation are needed. Oct 03, 2001 2 even if a cancer cell cannot be discriminated from a normal cell on its dna repair capabilities, can dna repair be modulated as a therapeutic strategy. These include events that lead to cellcycle arrest, regulation of dna replication, and the repair or bypass of dna damage. These two features make dna repair a promising target for novel cancer treatments. Homologous recombination genes are particularly attractive targets for precision cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing. Its effectiveness relies mainly on its ability to cause lethal damage to the dna of cancer cells. New opportunities are arising through the new classes of agents targeting drugs in the dna repaircell cycle pathways. However, tumors rely on residual dna repair capacities to survive the damage induced by genotoxic stress. Dna repair pathways maintain the integrity of the genome, reducing the onset of cancer, disease, and aging.
Dna repair provides a forum for the comprehensive coverage of dna repair and cellular responses to dna damage. Saves academic, medical, and pharma researchers time in quickly accessing the very latest details on dna repair and cancer therapy, as opposed to searching through thousands of journal articles provides a common language for cancer researchers, oncologists, and radiation oncologists to discuss their understanding of new molecular pathways. Inhibition of dna repair in tumors may be an effective approach to enhance the efficacy of dna damagebased therapy of cancer. We have identified protein kinase ck2 as a promising therapeutic target for combination therapy, because ck2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including dna repair, epidermal growth factor receptor signaling, pi3kaktmtor signaling, hsp90 machinery activity, hypoxia. Dna repair pathways can enable tumour cells to survive dna damage that is inducedby chemotherapeutic treatments. In addition, they are frequently mutated in cancers. Sensitizing cancer cells to dna damaging agents by targeting dna repair pathways is an emerging concept that is receiving much deserved attention. Such properties of cancer cells can provide biomarkers or targets for sensitization. Dna repair pathways that protect the genome from ros reactive oxygen speciesinduced lesions are attractive anti cancer targets, as their inhibition may render combinatorial sensitization of tumor cells to both dna damage and oxidative stresses, known as nononcogenic addictions of cancer. Increased dna repair capacity in cancer cells that may remove therapyinduced dna lesions before they become toxic is a major mechanism for development of resistance to therapy.
Dna repair pathways that protect the genome from ros reactive oxygen speciesinduced lesions are attractive anticancer targets, as their inhibition may render. Helleday t1, petermann e, lundin c, hodgson b, sharma ra. Interestingly, prognostic outcomes of many cancer types have been linked with the expression levels of several of these architectural proteins. Therefore, rt efficacy might be enhanced by using drugs that can disrupt cancer cells dna repair. Mirnas targeting double strand dna repair pathways lurk in. Also the better understanding of dna repair systems will allow therapies that specifically target selected repair pathways. Many cancer chemotherapeutic agents form dna interstrand crosslinks icls, extremely cytotoxic lesions that form covalent bonds between two opposing dna strands, blocking dna replication and transcription. Fanconi anemia proteins, dna interstrand crosslink repair pathways, and cancer therapy authors. Base excision repair inhibitors in development and clinical use. Mar 21, 2014 because the efficacy of cancer chemotherapy and radiotherapy relies on generation of dna damage that will be recognized and repaired by intrinsic dna repair pathways, aberrant expression of a particular dna damage response protein should be a biomarker of resistance or favorable response to therapies that induce the corresponding types of dna. Nov 05, 2019 novel strategies that modulate dna damage repair pathways in response to cytotoxic chemotherapy and radiation in lung cancer may provide a path forward. Pdf targeting dna damage response in cancer therapy.
Apr 15, 2009 since dna repair pathways remove radiation induced dna lesions and protect cells from lethality, these pathways represent potential therapeutic. Frontiers altering dna repair to improve radiation therapy. Synthetic lethality between repair pathways has provided a paradigm for. Dna damage and repair pdf free pdf epub medical books. Identify novel targets in dna repair and checkpoint pathways. The journal publishes original observations on genetic, cellular, biochemical, structural and molecular aspects of dna repair, mutagenesis, cell cycle regulation, apoptosis and other biological responses in cells exposed to genomic.
Colorectal cancer cells downregulate dna repair pathways mmr and hr and upregulate errorprone dna polymerases in response to targeted therapies, thereby promoting adaptive mutability and. Experts on dna repair proteins from all areas of cancer biology research take readers from bench research to new therapeutic approaches. However, dna damage not only comprises a root cause for cancer development. Targeted cancer therapies fact sheet national cancer institute. Common and rare fragile sites cfs and rfs, respectively are particularly vulnerable to instability, and there is an inverse correlation between fragile site fs expression and dsb repair protein levels.
Dna damage response ddr is an intricate and interconnected network consisting of signaling pathways, enzymes, factors, and molecules to sense and transduce dna damage and to activate dna repair pathways to repair dna lesions or induce programmed cell death. Defects in dna repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. Assess the therapeutic potential of new anticancer modalities. The impact of dna repair pathways in cancer biology and. Dna repair and resistance to cancer therapy intechopen. Assess the therapeutic potential of new anti cancer modalities. The critical role played by dna repair in the maintenance of genome stability is highlighted by. The main target of cancer therapy is the elimination of tumor cells by their. Molecular targets and clinical applications second edition provides a comprehensive and timely reference that focuses on the translational and clinical use of dna repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. Learn mechanisms of therapeutic resistance and ways to improve cancer therapy. Aug 21, 2010 many cancer chemotherapeutic agents form dna interstrand crosslinks icls, extremely cytotoxic lesions that form covalent bonds between two opposing dna strands, blocking dna replication and transcription.
Once dna damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. Recent advances in cancer therapy targeting proteins involved. Investigating the nexus between dna repair pathways and. Ck2 inhibitor cx4945 suppresses dna repair response. Targets for cancer therapy 2017 2nd exploring dna repair. Dna repair pathways that protect the genome from ros reactive oxygen speciesinduced lesions are attractive anticancer targets, as their inhibition may render combinatorial sensitization of tumor cells to both dna damage and oxidative stresses, known as nononcogenic addictions of cancer. For example, defects or upregulation of the specific pathways. However, cellular responses triggered by icls can cause resistance in tumor cells, limiting the efficacy of such treatment. Dna repair pathways that protect the genome from ros reactive oxygen speciesinduced lesions are attractive anti cancer targets, as their inhibition may render. Schematic presentation of dna repair pathways is shown in fig. Targets for cancer therapy 2017 is a medical, life science and genetics conference, organized in cancun, mexico.
Pdf targeting dna repair pathways for cancer treatment. Radiation therapy rt is widely used in cancer care strategies. Aneuploidy can arise by dysregulation of a spindle checkpoint or by loss of telomere integrity. Targeting dna repair pathways for cancer treatment. Dna repair pathways can enable tumour cells to survive dna damage that is induced by chemotherapeutic treatments. Accumulation of small mutations as a result of defects in the machinery that is responsible for dna mismatch repair.
The efficacy of dna damagebased cancer therapy can thus be. Request pdf dna repair pathways as targets for cancer therapy dna repair pathways can enable tumour cells to survive dna damage that is induced by chemotherapeutic treatments. When these ddr pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Since dna repair pathways remove radiation induced dna lesions and protect cells from lethality, these pathways represent potential therapeutic. Molecular targets and clinical applications, second edition provides a comprehensive and timely reference that focuses on the translational and clinical use of dna repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. The dna damage response ddr is a collective term for the plethora of different intra and intercellular signaling events and enzyme activities that result from the induction and detection of dna damage. These pathways are diverse and target different types of lesions. Homologous recombination genes are particularly attractive targets for precision cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing cancer cells while leaving normal cells unscathed. Double strand break dsb repair mechanisms guard genome integrity and their deterioration causes genomic instability. Defect in dna damage repair and checkpoint control is the underlying mechanism for tumorigenesis, since it allows the accumulation of multiple genetic alternations, which are essential for the initiation of tumorigenesis. It will be of particular importance to gain a deeper understanding how the various dna repair systems interact with each other in the context of cellular homeostasis and dna metabolism in order to optimize targeted. Highlight recent advances in the field of dna damage repair.
Main targets of drug development are in red see the text for details. Here we discuss recent advances in our understanding of the. Dna repair pathways as targets for cancer therapy nature. Ovarian cancer is one of the most lethal gynecologic malignancies reported throughout the world. Chromatinassociated architectural proteins are part of a fundamental support system for cellular dnadependent processes and can maintainmodulate the efficiency of dna replication, transcription, and dna repair. In order to achieve a therapeutic gain, however, there must be a. Novel strategies that modulate dna damage repair pathways in response to cytotoxic chemotherapy and radiation in lung cancer may provide a path forward. Synthetic lethality between repair pathways has provided a paradigm for many. The potential of inhibitors of dna repair in the future of cancer therapy is starting to become apparent. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of polyadpribose polymerase inhibitors for treating brca12 mutated ovarian cancers. Increased dna repair capacity in cancer cells that may remove therapy induced dna lesions before they become toxic is a major mechanism for development of resistance to therapy. Mgmt, parp1 rapidly lead to the notion that dna repair pathways could be targeted in cancer treatment and lead to personalized therapy 24, 25.
Disruptions in dna repair pathways predispose cells to accumulating dna damage. When errors in dna are detected, dna damage repair ddr genes and their regulators are activated to effect repair. Dna repair pathways as targets for cancer therapy pubmed. For example, defects or upregulation of the specific pathways that recognize or. The impact of dna repair pathways in cancer biology and therapy. Dna repair pathways safeguard the human genome from such mutagens, and thereby suppress the multistep process of carcinogenesis. However, some cancers have shown to be particularly radioresistant partly because of efficient and redundant dna repair capacities. Exploring dna repair pathways as targets for cancer therapy. Dna repair in cancer initiation, progression, and therapya double. Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Targeting dna damage response in cancer therapy hosoya 2014. Dna repair pathways thus modulate the efficacy of cancer therapy.
Upon dsb repair dysfunction, genes residing at these sites are at. Additionally, dna damage and repair biomarkers for prognosis in different types of cancer will be discussed. The disruption of the fa pathway results in defective dna repair, genomic instability, and tumorigenesis, and provides promising targets for breast cancer therapy, by inducing completely different biological characteristics in tumor cells. Cancer, dna repair mechanisms, and resistance to chemotherapy. Small molecule inhibitors of dna repair have been combined with conventional chemotherapy drugs in several phase iii clinical trials. Tumour development is commonly associated with perturbed dna damage response and repair pathways.
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