Background African American and Hispanic/Latino breast cancer patients are underrepresented in experimentalmodelsofbreastcancer,aswellasinclinicaltrialsinvestigatingnewtherapeutics.Thisoversight contributes to poor clinical outcomes observed for these minority ethnic groups across all types of breast cancer. This has generated a critical unmet need to identify experimental models that better represent these ethnicsubsetsinordertodesignclinicaltrialsthatareaimedtoservethesepopulations. Objective/HypothesisTheobjectiveofthisstudyistocharacterizethegenome,transcriptomeandkinomeof 100breastcancerPDXlines,>70%ofwhicharederivedfrompatientsofAfricanAmericanorHispanic/Latino ethnicity. By understanding fundamental cancer pathways specific to these minority groups this study will delineateefficacyofpre-existing,CTEP-approvedtherapiesinminorityethnicities.
SpecificAims Aim1:Systematicallycharacterizeestrogenreceptor(ER)signalingandresponsetoendocrine treatmentinPDXlinesderivedfromAAandHispanicbreastcancerpatients.
Aim2 :CharacterizeDNArepairprofilesofER+andtriplenegativePDXlinesacrossethnicgroups.
Aim3 :Generate-omics?basednetworkprofilesspecificforHispanic,AAandCAPDXs. StudyDesignInAim1,globalERsignalingpathwayswillbecharacterizedacross30PDXsderivedfromAA and Hispanic breast cancer patients by generating and analyzing whole exome sequence and RNA-seq data from PDX tumors grown in the absence of estrogen. Growth response to estrogen deprivation and/or fulvestranttreatmentofPDXsfromtheseminoritypopulationswillalsobetested.
In Aim2, differencesinDNA repair defects, beyond BRCA1/2 mutations, will be characterized across 28 ER+ and 72 triple negative PDX lines derived from CA, AA and Hispanic breast cancer patients, with more than 70% of the lines being from minoritypopulations.BasedondifferencesinDNArepairdefects,useofCDK4/6inhibitorsorPARPinhibitors in PDXs from AA/Hispanic patients will be tested in vivo.
In Aim 3, an unbiased 10-KiP assay will be used to characterizeactivekinomesof>100PDXlinesusing10pharmacologicalkinaseinhibitorscovalentlylinkedto sepharose beads. The top three pharmacological hypotheses generated by this assay will be tested in three ER+andthreetriplenegativePDXlineseachfromAAandHispanicpatientsinvivo. ImpactTheresultsofthisstudywillgeneratestrongandcomprehensivepreclinicalrationaletodesignclinical trials directed at finding better therapeutic solutions for minority populations, a long-awaited development in breastcancer.Moreover,thecharacterizationof>70PDXlinesderivedfromminoritypopulationsattheDNA, RNA and protein level will lay a foundation from which underlying molecular differences in breast cancer biologyandoutcomesbasedonraceandethnicitycanbebetterstudied.
| Matsunuma, Ryoichi; Chan, Doug W; Kim, Beom-Jun et al. (2018) DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer. Proc Natl Acad Sci U S A 115:E11978-E11987 |
