paper reparacion y cancer

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[Cancer Biology & Therapy 8:8, 665-670; 15 April 2009]; 2009 Landes Bioscience

Radiotherapy is very effective in local control of canceroustumors, but its curative potential is often limited by intrinsicradioresistance of the tumor cells. Since DNA repair pathwaysremove radiation-induced DNA lesions and protect cells fromlethality, these pathways represent potential therapeutic targetsto radiosensitize tumors. In order to achieve a therapeutic gain,however, there must be a differential between tumor and normalcells that can be exploited to preferentially target the DNA repairof the tumor, while sparing surrounding normal tissues, and thishas represented a significant challenge to progress. Nevertheless,recent advances in our understanding of DNA repair mechanismsand tumor biology, on both the biochemical and genetic levels,have identified molecular differentials that may increase tumorspecificity. This mechanistic insight suggests new strategies forradiotherapeutic targeting of DNA repair. Some of these strate-gies are reviewed here, including synthetic lethal, replicativestress, cell cycle and hypoxia-based approaches. The exampleof PARP1 inhibitor use in BRCA1 and 2 mutated breast cancertherapy is discussed, and future directions and challenges areexplored.

BackgroundRadiotherapy is very effective in achieving local tumor control

and is often curative. However, intrinsic tumor cell radioresistanceis a significant clinical problem that limits the potential of thetherapy.1,2 Drugs that could specifically sensitize tumors to radia-tion would greatly enhance our ability to deliver curative doses while

limiting radiation damage to surrounding normal tissue,3

but effortsto develop clinically useful tumor radiosensitizers have met withlimited success.

It is well established that nuclear DNA is the target for radiation-induced cell killing,4 and lethality is thought to be directlyproportional to the cellular burden of unrepaired DNA damage athe time of cell division. Mammalian cells eliminate DNA damage bemploying multiple enzymatic repair pathways that act on differenclasses of DNA lesions, yet have considerable overlap in terms their substrate specificities. Together, these DNA repair pathwayprotect against both cell killing and mutagenesis. Thus, individua

with heritable DNA repair defects often display hypersensitivity radiation toxicity or increased risk of cancer, or both.5

The evidence that DNA repair can protect against radiationinduced cell killing is very strong, and comes from the biochemicand genetic level, from a wide variety of cellular, animal and humastudies.6 This overwhelming evidence of the radioprotective effect cellular DNA repair suggests the DNA repair proteins may be excelent druggable targets for radiosensitizing tumor cells.

Most human DNA repair takes place as part of one of five majobiochemical pathways, although subpathways and pathway variatioare also known to exist. These pathways include: nucleotide excisirepair (NER), mismatch repair (MMR), base excision repair (BERnon-homologous end joining (NHEJ) and homologous recombination (HR). Although all may participate to some extent in repairinthe tremendously varied lesions produced by ionizing radiation, thlatter three (i.e., BER, NHEJ and HR) probably are responsible foremoving the majority of the damage. In particular, the high yieldof single-strand breaks (SSB) and double-strand breaks (DSB

which contribute heavily toward radiation-induced cell lethality, a

primarily repaired by BER and NHEJ, respectively. In replicatincells, HR may also play a significant role in DSB repair. Thus, thethree DNA repair pathways have received the most attention apotential targets for cellular radiosensitization.

Recently, there has been tremendous progress in characterizinthe details of the mechanisms of DNA repair both biochemicalland genetically, and the extent of this knowledge has been thooughly reviewed elsewhere.7,8 Suffice it to say, we now have a level molecular understanding that affords us the opportunity to rationallyhypothesize specific molecular targets at both the protein and thgene level. Parallel growth in our understanding of tumor biologand genetics now suggests molecular tumor radiosensitizatio

Correspondence to: Timothy J. Jorgensen; Department of Radiation Medicine; TheResearch Building, room E212; Georgetown University Medical Center; 3970Reservoir Road NW; Washington, DC 20057 USA; Email: [email protected]

Submitted: 07/02/08; Accepted: 02/27/09

Previously published online as aCancer Biology & Therapy E-publication:http://www.landesbioscience.com/journals/cbt/article/8304

Review

Enhancing radiosensitivityTargeting the DNA repair pathways

Timothy J. JorgensenDepartment of Radiation Medicine; Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington, DC USA

Abbreviations: NER, nucleotide excision repair; MMR, mismatch repair; BER, base excision repair; NHEJ, non-homologous end joininHR, homologous recombination; SSB, single-strand break; DSB, double-strand break; PARP1, poly(ADP-ribose) polymerase-1; PI3phosphatidylinositol 3-kinase

Key words: DNA repair, radiation biology, radiotherapy, synthetic lethal, poly(ADP-ribose) polymerase, hypoxic, cancer

www.landesbioscience.com Cancer Biology & Therapy 6


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DNA repair targets for tumor radiotherapy

666 Cancer Biology & Therapy 2009; Vol. 8 Issue


strategies that were not evident before, and this hasstimulated new interest in revisiting DNA repair-targeted radiosensitization as a means of enhancingradiotherapy and curing more cancer patients. We

will review here some of these novel strategies, thechallenges they represent, and future directions forthe field.

IssuesThe clinical goal of the radiation sensitizer strategy

is to specifically radiosensitize tumor cells withoutradiosensitizing the surrounding normal tissue.Ironically, tumors have traditionally been thought tohave intrinsic deficiencies in DNA repair capabilities.9 In fact, the putative superior DNA repair capacity ofnormal tissues relative to tumor cells has been thoughtto partially explain the therapeutic benefit from frac-tionating radiation therapy doses, since the normaltissue was purported to be more efficient in repairingits DNA than the tumor was during the fractionation

intervals. Thus, fractionation maximized the DNArepair potential of normal tissue and enabled a highertotal therapeutic dose to be delivered to the tumor

while limiting normal tissue complications. [In addi-tion to DNA repair, reoxygenation, reassortment andrepopulation, are also thought to contribute to theeffectiveness fractionated radiotherapy therapy (i.e.,the Four Rs of radiobiology)].6

Recent genetic evidence from cancer prone syndromes seems tosupport the contention that tumors are defective in DNA repairrelative to the normal tissues (e.g., defect in MMR in humannonpolyposis colon cancer10 and DSB repair in familial breastcancers11). Yet, the relevance of these findings to sporadic colon andbreast cancers, as well as cancers in other tissues, is not yet clear.

Paradoxically, the notion that tumors are intrinsically DNArepair deficient relative to their surrounding tissues, suggests thatdrugs designed to inhibit DNA repair may preferentially target theDNA repair proficient normal cells, and actually decrease the thera-peutic ratio for radiotherapy. Another conceptual problem has beenthe known lesion cross-specificity between repair pathways, whichaffords multiple enzymatic avenues for repair of any particular classof lesion, and builds a certain level of pathway redundancy that

would seem difficult to target with a single inhibitory agent.12Despite earlier difficulties, recent developments in our under-

standing of the molecular biology of tumors have, nevertheless,exposed the details of human DNA repair and revealed moleculardifferentials between tumor and normal cells.13,14 In addition, thereare now better research tools for probing the mechanistic aspects ofDNA repair, which have also suggested new DNA repair targets.Together, these findings lend themselves to novel radiotherapeuticstrategies, which are currently being explored.

New Strategies We now know that tumors are not globally defective in DNA

repair, but rather have defects in specific repair pathways.11,14 Someof these pathways are thought to be important for the repair of radia-tion damage and some are not. For example, the MMR pathway is

not thought to be an important pathway for radiation-inducedlesions, while the NHEJ pathway is critical to radiation resistance.

It has also become clear that a defect in a particular repair pathwamakes a tumor cell more dependent on its alternative pathways forepair of any specific type of lesion. This loss of repair redundanmakes the tumor vulnerable to strategies that target the alternativpathway and leave no other options for repair of the lesion (Fig. 1This model of pathway-based vulnerability, where lethality is jointdependent upon independent defects in two pathways with commonfunctionality, is known as synthetic lethality and has been widestudied in yeast and other genetic models.15 The reliance of tumocells on an alternative pathway represents a differential betweetumor and normal cells that provides a synthetically lethal targethat might be exploited for therapeutic gain.16 It also opens thepossibility that a single agent could eliminate a tumor cells abilito repair an entire class of DNA lesions. (See case study of BRCAand 2 below).

In addition, we now understand that tumors driven by oncogene

are under replicative stress.17

This replicative stress introduces DNAstrand breaks and other lesions at replication forks that elevate thsteady state levels of DNA damage in tumor cells, and make themmore dependent than normal cells upon the repair pathways tharepair replication stress lesions.18 Radiation-induced strand breakare within the same class of lesions as those produced by replicatistress. Thus, inhibiting the relevant repair pathways concurrent witirradiation may preferentially saturate repair in tumor cells relative normal cells, since the tumor cells are starting from a higher intrinsbaseline of damage (Fig. 2).

Tumors may also be more vulnerable to DNA repair targetestrategies because they are already compromised by a decreased rep

Figure 1. Synthetic lethal strategy for specifically radiosensitizing tumor cells by targeting Drepair pathways. An ionizing radiation-induced lesion that can potentially be removed either of two DNA repair pathways will not be killed by a DNA repair inhibitor that targets one of the pathways. But a tumor cell with a mutated gene in one of the pathways will be hily sensitive to killing by an inhibitor that targets the only remaining functional pathway. Tthe high rate of DNA repair gene mutagenesis in tumors may afford a differential betwetumor and normal cells that could be exploited to preferentially radiosensitize tumors.


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time. In normal cells, radiation-induced DNAdamage initiates a transient cell cycle arrest, whicprovides time for DNA repair to take place beforthe cell replicates its DNA or begins cell divisioMany tumor cells are defective in cell cycle checpoints, which contributes to their tumorigenesisbut also decreases their window of opportunitfor DNA repair. Normal cells may have hours oadditional time to complete DNA repair beforetheir cycling resumes. Thus, targeting DNA repaiin checkpoint-deficient tumors may preferentiallradiosensitize tumor cells because they premturely replicate their DNA and divide beforDNA repair can be completed (Fig. 3). Howeverthe issue is complicated because some of thproteins that promote cell cycle checkpoints (e.gTP53) also promote apoptosis (i.e., programmedcell death). Thus, an enhancement in radiation-induced killing by failure of cell cycle arrest mbe offset by reduced apoptotic cell death.19 Thenet effect is probably tumor tissue specific, anrelated to the importance of apoptosis to tumorregression. This likely explains the failure demonstrate a clearly enhanced radiotherapeutiresponse for TP53 mutated compared to TP53

wild-type tumors.20-26 Nevertheless, it may bpossible to therapeutically uncouple cell cycarrest and apoptosis by targeting downstreamcell cycle arrest proteins, such as p21,27,28 andleaving upstream apoptotic pathways intact.29,30

For tumors with inherent deficiencies in DNA repair, targetingcell cycle arrest may enhance cell killing and improve tumor radiresponse, while targeting DNA repair may improve radiotherapeut

responses for tumors with cell cycle arrest deficiencies.Lastly, hypoxia is another tumor/normal differential thoughto affect the radiotherapeutic ratio. Tumors tend to outgrow theirblood supplies and develop areas of very low oxygen content (i.hypoxic regions). The resulting tumor hypoxia preferentially protectumor cells from radiation-induced DNA damage, because oxygeis a potent radiation sensitizer that fixates DNA damage and greatincreases the number and complexity of DNA lesions produced bradiation. This oxygen enhancement of DNA damage can be as higas three-fold. However, this hypoxic radioprotection may be partialoffset by the downregulation of genes involved in HR repair, one othe two major double-strand break repair pathways, for reasons thaare still unclear.31-36 Thus, therapeutically targeting the other doubl

strand-break repair pathway (i.e., NHEJ) may decrease the radioresistance of hypoxic cells in the tumor and increase the therapeutgain (Fig. 4). It has further been shown that chronic hypoxia caalter the biological state of tumor cells, including the transcriptioand translation of various proteins involved in cell survival.31 Thesegene expression differences between hypoxic and oxic tumor tissmay provide a means to differentially target hypoxic tumor celfor radiotherapeutic gain. This approach, to sensitize hypoxic ovoxic regions within the tumor based on a biochemical differentiais similar to the somatic lethal approach of sensitizing tumor ovenormal tissue based on a genetic differential, as described above.

Figure 2. Post-irradiation cell cycle arrest allows time for DNA repair to occur prior to cell replica-tion. The duration of cell cycle arrest in tumor cells is often shorter than for normal cells due todeficiencies in cell cycle checkpoints. For normal DNA repair rates (minus inhibitor) the durationof the arrest may be sufficiently long enough to allow nearly complete repair in both tumor andnormal tissues. But when DNA repair rates are slowed (plus inhibitor) the shorter duration ofarrest for the tumor cells may be insufficient for repair to finish, resulting in higher radiosensitiv-ity relative to normal cells whose arrest is long enough to complete repair even under slowerDNA repair rates.

Figure 3. Replicative stress lesions add to the DNA damage burden of tumorcells. Replicative stress driven by oncogenes or other growth-stimulatingfactors in tumor cells can produce collapsed replication forks and other DNAstructures that constitute additional DNA damage that needs to be repaired.Thus, tumor cells may have higher endogenous levels of DNA damagethan normal cells, and radiation adds further lesions that also need to berepaired. Under proficient DNA repair conditions both tumor and normalcells may be able to accomplish full repair without saturating the DNA repairprocesses. However, if DNA repair is inhibited, the tumor cells additionalburden of lesions may saturate the DNA repair capacity and specificallysensitize the tumor cells relative to the normal.


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Future Directions and ChallengesMuch has been made lately about the very high numbers o

gene mutations that tumor cells can harbor and the fact that thereseems to no single defect that provides a universal molecular Achilheel for targeted treatment.52-54 Yet, as mentioned above, tumorare very often defective in particular DNA repair pathways due tsomatic mutations in their DNA repair genes. These DNA repaigene mutations appear to be early (and possibly initiating) evenin the carcinogenic pathway. In fact, mutation of DNA repair genemay be an early and essential requirement for carcinogenesis, sinit contributes to the genomic instability and hypermutation ratethat speeds the phenotypic progression to an increasingly malignanstate. For this reason, targeting DNA repair for radiation sensitivitmay represent a window that opens early at the very beginning tumorigenesis, when other biochemistry pathways are still intacand begins to close when mutations have accumulated to thpoint that tumor heterogeneity and hypermutation have afforded

to tumor the opportunity to evade any single target treatmentRemarkably, it has been recently shown that tumor mutagenesis caalso produce a BRCA2 revertant with restored resistance to PARPinhibitors.55-57 This means that radiosensitization by DNA repaiinhibition is unlikely to be a panacea for all types of tumors at astages of malignancy, but it may be of extreme value for a definsubset of early stage cancers.

Also, the synthetic lethal approach to radiosensitization requireknowledge of which alternative DNA repair pathways the tumors arelying on for survival. Since this will differ from patient to patieand tumor to tumor, either genotyping of DNA repair genes intumors54 or some type of pathway specific tumor biomarker will b

Case Study in Somatic Lethality TherapyBRCA1 and 2 andDNA Repair

The synthetic lethal concept for cancer therapy was first proposedby Hartwell et al.,37 based largely on yeast genetics. In principle,the approach should be useful for cancer therapy targeting anypair of functionally redundant pathways that have a role in tumorcell viability.16,38 However, at present, the only synthetically lethaltherapy that has progressed to clinical trials is one that targets DNArepair.39,40

It has recently been demonstrated that BRCA1 and BRCA2familial breast cancers are highly sensitive to inhibitors of the enzymepoly(ADP-ribose) polymerase-1 (PARP1).41-45 PARP1 inhibitors

AZD2281 (AstraZeneca) and AG014699 (Pfizer GRD) are currentlyin clinical trials as a monotherapy for women with BRCA1- orBRCA2-mutated breast or ovarian cancer. Although BRCA1 andBRCA2 are believed to have multiple functions, both are thoughtto contribute to HR, and it is the defect in HR that is thought tounderlie the synthetic lethal effect in BRCA1 or 2 mutated tumorcells. This contention is supported by the demonstration that deficien-cies in other genes associated with HR also confer PARP1 inhibitorsensitivity.45 This, in turn, suggests that HR repair of DSB repair iscompromised in BRCA1 and BRCA2-mutated cells, and that PARP1inhibition suppresses NHEJthe only other major DSB repairpathwayleaving toxic DSBs unrepaired. However, PARP1s majorfunction has been ascribed to BER, which is thought to have a role inrepair of SSBs but not DSBs,46 so the alternate DNA repair pathwaytargeted by PARP1 inhibition is not clear. Inhibition of BER wouldnot be expected to produce a synthetic lethal effect. Nevertheless, aPARP1-dependent NHEJ pathway has been described,47 so one sub-type of NHEJ could be the target of PARP1 inhibition.

An alternative explanation for the sensitivity of BRCA1 and 2mutated cells to PARP1 inhibitors is that PARP1 inhibition actually

produces elevated DSBs, and that it is the increase in DSBs in HRrepair-compromised cells that results in the enhanced lethality. Themechanism is thought to involve PARP1s role in SSB repair, sincepersistent unrepaired SSBs would be converted to lethal DSBs whenstalled replication forks collapse. This alternative mechanism wouldseem to combine synthetic lethality with a unique type of replica-tive stress induced by PARP1 inhibition specifically in HR deficientcells. This notion is supported by the observation that BRCA1 and 2mutated cells are radiosensitive,48,49 suggesting that they are deficientin repairing DSBs produced either through PARP1 inhibition orionizing radiation. More research is needed on the exact mechanismof lethality of BRCA1 and 2 mutated cells by PARP1 inhibitors. Italso begs the question as to whether a stronger somatic lethal effectcould be achieved in BRCA1 or 2 mutated tumors if DNA-PKcs,Ku, or other NHEJ proteins could be directly targeted withdrugs. Wortmannin, a well known inhibitor of phosphatidylinositol3-kinase (PI3K) related protein kinases such as DNA-PKcs, is acell radiosensitizer,50 but its specificity is questionable, it has hightoxicity, and is inherently unstable is cells, making it unsuitable forclinical use. But other PI3K protein kinase inhibitors are currentlyunder development for cancer therapy.51 It also raises the questionof whether such a tumor-targeted chemotherapy could be combined

with localized radiotherapy to enhance the somatic lethal effect onthe tumor cells and produce increased cures.

Figure 4. Hypoxic regions of tumors may have deficiencies in specific Drepair pathways. Tumors often have interior regions with very low oxygtensions. Since oxygen is a potent radiation sensitizer, these hypoxic areare relatively resistant to radiation. Thus, tumor hypoxia presents a challenfor radiotherapy. But recent evidence suggests that hypoxic cells may haaltered metabolisms that include deficiencies in some types of DNA repasuch as homologous recombination (HR). This biochemical differential inbetween oxic and hypoxic regions of tumors suggests that inhibition of nhomologous end joining (NHEJ), the other major repair pathway for DSmay result in preferential toxicity to the hypoxic cells, which could mititheir radio-resistance conferred by low oxygen tensions.


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34. Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, et al. Hypoxia-indudownregulation of BRCA1 expression by E2Fs. Cancer Res 2005; 65:11597-604.

35. Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, et al. Hypoxia downrelates DNA double strand break repair gene expression in prostate cancer cells. Radio

Oncol 2005; 76:168-76. 36. Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, et al. Downregulation

Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell B2004; 24:8504-18.

37. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaes into the discovery of anticancer drugs. Science 1997; 278:1064-8.

38. Chan DA, Giaccia AJ. Targeting cancer cells by synthetic lethality: autophagy and VHLcancer therapeutics. Cell Cycle 2008; 7:2987-90.

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40. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhtors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Onc2008; 26:3785-90.

41. De Soto JA, Wang X, Tominaga Y, Wang RH, Cao L, Qiao W, et al. The inhibit ion antreatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors. InBiol Sci 2006; 2:179-85.

42. De Soto JA, Deng CX. PARP-1 inhibitors: are they the long-sought genetically spec

drugs for BRCA1/2-associated breast cancers? Int J Med Sci 2006; 3:117-23. 43. McCabe N, Lord CJ, Tutt AN, Martin NM, Smith GC, Ashworth A. BRCA2-deficienCAPAN-1 cells are extremely sensitive to the in hibition of Poly (ADP-Ribose) polymeran issue of potency. Cancer Biol Ther 2005; 4:934-6.

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needed to assess the DNA repair competence of individual tumors toidentify which therapeutic targeting strategy to employ.58,59 This areaof research is sadly lagging and needs to be developed much furtherif pathway specific targeting is to reach its full potential. If tumorgenotyping or DNA pathway specific biomarkers were to becomeavailable, however, it would allow us to stratify patients for therapiesto identify the subsets that could benefit from a DNA repair targetedapproach. It may also allow us to revisit earlier DNA damage basedtherapies that had shown marginal or null benefits, and determine

whether those therapies might have specifically benefited patients with tumors harboring specific DNA repair defects.

Lastly, radiotherapy is known to result in a significant incidenceof radiation-induced secondary cancers.60,61 Since DNA repairinhibition can increase both cellular mutagenesis cell lethality 5 itmight be expected that tumor radiosensitization strategies that relyon DNA repair inhibition may increase secondary cancer rates as

well. However, some of the DNA repair pathways that are potentialtherapeutic targets are already error prone62,63 in that the repairmechanism itself is mutagenic (e.g., NHEJ), so it is not clear whatthe net effect of DNA repair inhibition on carcinogenesis would

be. In the final risk-benefit analysis the therapeutic gains may faroutweigh the carcinogenic risks. Nevertheless, the issue of secondarycancer risk needs to be addressed, especially for those individuals

where an inherited mutation of a DNA repair gene is the cause oftheir primary cancer, and who therefore may already be at elevatedrisk for a radiation-induced cancer.64,65 Such patients may warrantincreased monitoring for secondary cancers.

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