Seite - 63 - in Cancer Nanotheranostics - What Have We Learnd So Far?

MorenoandPêgo AONcancer therapeutics Table2 |On-goingandrecentlycompletedanti-cancerAONclinical trials. DRUG AON(carrier) TARGET INDICATION STATUS DEVELOPER Custirsen (OGX-011) 2′-O-MOE-PSgapmerODN (“naked”) Clusterin (i) castrate resistantprostate cancer; (ii) non-small cell lung cancer I and (ii) Phase III (recruiting) OncoGenex EGFRantisense DNA PhoshorothioateODN (“naked”) EGFR AdvancedHeadandNeck SquamousCellCarcinoma Phase I/II (recruiting) UniversityofTexas Apatorsen (OGX-427) 2′-O-MOE-PSgapmerODN (“naked”) Hsp27 prostatecancer; pancreatic; non-squamousnon-small cell lungcancer; other Phase II (recruiting) OncoGenex ISIS-STAT3Rx (ISIS 481464/AZD9150) cEt-PSgapmerODN (“naked”) STAT3 Lymphoma;hepatocellular carcinoma Phase I/II (recruiting) Astrazeneca (ISISPharmaceuticals) ISIS-ARRx (AZD5312) cEt-PSgapmerODN (“naked”) Androgen Receptor Advancedsolid tumors (prostatecancer indications) Phase I (recruiting) Astrazeneca (ISISPharmaceuticals) Trabedersen (AP 12009) PhoshorothioateODN (“naked”) TGFβ2 (i) PancreaticNeoplasms, Melanoma,Colorectal Neoplasms; (ii)Glioblastoma; AnaplasticAstrocytoma (i) Phase I; (ii) Phase IIb (bothcompleted) IsarnaTherapeutics EZN-2968 LNA-PSgapmerODN (“naked”) HIF-1α Advancedsolid tumors Phase I (completed) EnzonPharmaceuticals (SantarisPharma) LErafAON-ETU DNA-PSmodifiedat5′ and3′ end (lipossome) c-raf AdvancedCancer Phase I (completed) INSYSTherapeutics Inc ODN—oligodeoxynucleotide; cEt—constrainedEthyl. theotherhand, thisunspecificproteinbindingfeaturecanpoten- tially lead to associated toxicities or cellular effects not entirely sequencespecific,suchascomplementactivation, increasedcoag- ulation times and unwanted immune activation (Brown et al., 1994;Krieg andStein, 1995;Henry et al., 1999;Mouet al., 2001; Krieg et al., 2003; Senn et al., 2005). These effects, however, are most often oligonucleotide length and concentration dependent (Webb et al., 2001). Immune activation, on the other hand, is also enhanced by specific nucleotide sequences (CpG motifs) (Barchet et al., 2008), although this can be minimized by dif- ferent types of nucleotide modifications (Henry et al., 2000). Nevertheless, immune activation is an important factor that has previously led to erroneous interpretations of datawhen inhibi- tion of tumor growthwas not primarily driven by the antisense mechanism but by the immunostimulatory properties of CpG sequences found in certain AONs (Badros et al., 2005; Gekeler et al., 2006). Regarding potential PS-derived unspecific cellular effectsthesehavebeenproposedtoaffectthemechanismofaction of an anti-cancer oligonucleotide drug by the down-regulation of several anti-apoptotic proteins and glycolytic enzymes. These were actually seen as important contributors to the apoptotic action(Stessl etal., 2009;Winkleretal., 2010). Another important concern relates to hybridization depen- dent toxicity, deriving fromexaggerated pharmacological action (a consequence also seenwith any other chemical drug), or off- target hybridization. The latter can beminimized by designing the antisense drug taking into account a detailed bioinformatics analysis for identificationof both, geneswithperfectmatches or withpartialcomplementarity(lookingout for1–3mismatchesas themost relevantones) (BennettandSwayze,2010). The above considerations have raised somedifficulties, espe- cially invivo, for theexactpredictionof themechanismofaction ofanantisensedrugandareamongthecausesprobablyhamper- ing amore resolute demonstration of the therapeutic relevance of antisensedrugs towardnotonly cancerbutalsootherdiseases in general. This concern canbedemonstrated by the case of the antisensedrugLY2275796(asecondgenerationAONwithPSand MOEmodifications targeting eIF-4E)where, besides target gene downregulation, housekeeping genes were considerably affected aswell, raising the question towhether the antisense actionwas sequence specific or also mediated by off-target effects (Hong etal., 2011). This scenario only reinforces the need for an in-depth phar- macologic and pharmacokinetic analysis at the preclinical stage ofAONdevelopment. CHALLENGESFORANTISENSETECHNOLOGY—2.DELIVERY The efficient and targeted delivery of nucleic acid therapeutics is seen as, if not the biggest, one of the most important chal- lenges for this class of drugs. Themost commonly used nucleic acidsdrugs (namely,plasmidDNA, siRNAandAONs)have spe- cific features influencing their cellularuptakeanddeliveryvector development. AONs, due to the short chain size have very low charge density, in addition, being single-stranded, they have the www.frontiersin.org October2014 |Volume2 |Article87 | 63