Investigation Of Novel Theranostic Approaches For Radioiodine-refractory Thyroid Cancers

BackgroundAlthough most patients with differentiated thyroid cancer（DTC）may have favorable outcome and prognosis after receiving comprehensive treatments including surgery,radioiodine treatment and thyroid stimulating hormone（TSH）suppression therapy,patients with radioiodine refractory-differentiated thyroid cancer（RR-DTC）or anaplastic thyroid cancer（ATC）are refractory to radioiodine treatment and therefore have an unsatisfying prognosis.Although clinical application of molecularly targeted therapies,for instance,BRAF^V600Especific inhibitor vemurafenib,is changing the therapeutic landscape of certain RR-DTCs and ATCs,adverse effects and drug resistance inevitably occur,leading to termination of the single-agent treatment.In this setting,novel effective theranostic approaches are urgently needed for patients with RR-DTC or ATC.MethodsIn this study,we will investigate the underlying mechanisms accounting for vemurafenib resistance in treating DTCs,and further explore novel strategies that can be adapted to overcome vemurafenib resistance or enhance the therapeutic efficacy of vemurafenib in treating DTCs.To achieve this,various methods like Western blot and flow cytometry will be used,followed by in vivo validatation of the therapeutic efficacies of the novel formulae in mouse models bearing human thyroid cancer exnografts.Furthermore,in identifying molecular markers suitable for imaging ATC,flow cytometry will be used to screen potential markers highly expressed on the surface of ATC cells.Based on a HER2-specific monoclonal antibody（m Ab）pertuzumab,we are going to design HER2-specific molecular imaging probes by chemical engineering.By using fluorescent imaging and positron emission tomography（PET）imaging,the diagnostic efficacies of the developed probes in detecting subcutaneous and orthotopic ATCs will be interrogated.ResultsOur results indicate that increased mitochondrial metabolism,increased activity of autophagy,and formation of RAF dimers（that is,BRAF/CRAF dimers or CRAF/BRAF dimers）are underlying mechanisms for vemurafenib resistance.A next-generation pan-RAF inhibitor,LY3009120,or a combinational treatment formula comprising vemurafenib and obatoclax,are quite effective in overcoming vemurafenib-induced drug resistance and in suppressing the growth of DTCs.Meanwhile,we successfully developed two HER2-targeting molecular imaging probes,that is,one near infrared fluorescent imaging probe IRDye 800CW-pertuzumab and another PET imaging probe ⁸⁹Zr-Df-pertuzumab.Multimodal imaging with these two tracers are capable of detecting ATCs by visualizing HER2 expression on the surface of tumor cells.ConclusionOur results demonstrate that single administration of a novel pan-RAF inhibitor LY3009120 or synergistic use of vemurafenib and obatoclax can readily overcome vemurafenib-induced drug resistance and suppress the growth of DTC.Moreover,multimodal molecular imaging with IRDye 800CW-pertuzumab and ⁸⁹Zr-Df-pertuzumab is very effective in selecting HER2-postive ATCs.With further clinical translation and application,these therapeutic and diagnostic approaches may help refine the clinical management of RR-DTCs and ATCs in the foreseeable future.