Circulating Tumor Cell-informed RADioresponse Assessment from heme-axis signatuRes

Objective

Bone metastases are a hallmark of castration-resistant prostate cancer (CRPC) and remain a major therapeutic challenge. Ra-223 is the only approved alpha-emitting radiopharmaceutical that prolongs survival in this setting. Radiographic monitoring is difficult and PSA responses are uncommon, underscoring the need for predictive biomarkers. Despite this clinical need, no blood-based biomarker panel currently exists to stratify patients for Ra-223 or to mechanistically inform radioresponse. CTC-RADAR (Circulating Tumor Cell-informed RADioresponse Assessment from heme-axis signatuRes) addresses this gap by leveraging CTC transcriptomes to define functional biomarkers. Analyses of pre-Ra-223 CTCs compared between responders and non-responders revealed strong enrichment of heme-metabolism programs (NES > 4) in the non-responder group. Within this enrichment, MFRN1 and FECH emerged as leading-edge genes, nominating the MFRN1–FECH axis as a candidate determinant of radioresponse. Building on these findings, CTC-RADAR will (i) define a CTC-based heme signature from responder vs non-responder comparisons, (ii) test the mechanistic role of the MFRN1–FECH axis through genetic and pharmacologic perturbations, and (iii) identify DNA damage–repair liabilities using a focused CRISPR dropout screen in heme-high, non-responder–like models. By integrating patient-derived CTC transcriptomes with functional assays, CTC-RADAR will deliver the first systematic evaluation of radioresponse defined by a CTC-driven heme signature and uncover clinically actionable DDR vulnerabilities with translational relevance for therapy development. In the longer term, prospective clinical studies could be designed to test and validate this signature, paving the way for its integration into patient care.