Targeting galectin-3 to overcome drug resistance in metastatic prostate cancer therapy

Project Summanry Abstract Although abirateroneZytigaand enzalutamideXtandirepresent significant advances in the treatment of metastatic castration resistant prostate cancermCRPCall eventually acquire drug resistance over time and become lethalThereforenew research strategy and intervention are urgently needed to develop effective therapy for CRPCWe have shown that galectinGala beta galactoside binding lectinis involved in tumor progression and metastasis in prostate cancerTo target Galwe developed a very potentpicomolar affinityand specific GalantagonistTFDwhich not only blocks metastasisbut also promotes anti tumor immune response in our transgenic mouse model of metastatic prostate cancerHoxbMYC Ptenlox lox BMPC transgenic miceMoreoverGalcontributes to drug resistanceUnlike PCand DULNCaP prostate cancer cells do not constitutively express GalTo explore the mechanisms of drug resistancewe created abiraterone resistant LNCaPAbi LNCaPand enzalutamide resistant LNCaPEnza LNCaPcellsInterestinglyAbi LNCaP and Enza LNCaP cells inducively express Galand become sensitive to Abi and Enza in the presence of TFDBased on the compelling preliminary data we hypothesize that specificontargetinhibition of Galwith TFDwill suppress not only tumor growth and metastasisbut also overcome drug resistance by impeding Galmediated signaling and by promoting anti tumor immune responseTo test this hypothesiswe will first produce recombinant TFDfrom engineered CHO cellsWe will then define the mechanism sof Galmediated drug resistance and sensitize drug resistant cells with TFDThis includes epigenetic modification of Galpromoter and various signaling mechanisms such as androgen receptorARAR variantP glycoproteinPD LTo establish effective dose range of TFDfor in vivo experimentswe will determine TFDs maximum tolerated doseMTDin NSG miceWe will then examine TFDs ability to prevent tumor growth in a patient mCRPC tumor tissue derived xenograftPDXin humanized NSG micehuNSGmodel alone and in conjunction with AbiAfter drug treatmenttumor growth will be measuredHistochemical analyses of the tumors will be performed with various gene markers including Galand ARThis studyfor the first timewill explore the therapeutic utility of a natural carbohydrate compound to overcome drug resistance in mCRPC therapyTFDis anticipated to be a significant advancement in the arsenal against mCRPCexerting amulti prongedattack on tumorswhich is expected to result in longer survival of mCRPC patients with improved quality of life Project Narrative Galectinis involved in prostate cancer progressionmetastasisand drug resistanceThe objective of this project is to use a galectinantagonist from a natural source to prevent metastasis and drug resistanceand to elicit anti tumor immune response