Targeting CXCR4 and Redox Metabolism for Alpha Particle Therapy of Pulmonary Neuroendocrine Tumors and Carcinomas

Summary / Abstract Atypical carcinoids of the lung and neuroendocrine carcinomas (NECs) are currently incurable with most patients succumbing to disease within five years. A subset of pulmonary neuroendocrine tumors (NETs) and NECs (including small cell lung cancer [SCLC]) initially respond to chemotherapy or to radioligand therapy (RLT) targeting somatostatin receptor type 2 (SSTR2). However, resistance to therapy invariably develops and many of these tumors lack or lose SSTR2 expression such that metastases, progression, and mortality occurs in most cases. This creates a critical need for new therapeutic strategies. Our exciting preliminary data show these lung tumors highly express the G protein coupled receptor, C-X-C chemokine receptor 4 (CXCR4), and can be effectively suppressed using 212Pb-pentixather (212Pb-pent) in preclinical models. Other data using 203Pb-pent show this theragnostic pair (203Pb/212Pb) can be used in preclinical models to calculate radiation doses to tumor and normal target organs (kidney, liver, bone marrow) to maximize tumor dosing with acceptable bone marrow toxicity. Importantly, the high linear energy transfer (LET) unique to alpha particles from 212Pb-pent generate dense ionization tracts in the cytoplasm that damage metabolic structures such as mitochondria, leading to metabolic generation of hydroperoxides. The presence of hydroperoxides can selectively enhance tumor cell kill when combined with inhibition of hydroperoxide metabolism using an FDA approved, thioredoxin reductase inhibitor (Auranofin; Aur) while causing minimal normal tissue injury. The overall hypothesis is targeting CXCR4 with 212Pb-pent in atypical carcinoids and lung NECs combined with inhibition of hydroperoxide detoxification will enhance the responses to 212Pb-pent alpha particle radiation therapy. Our hypothesis is tested in 3 Aims. Aim 1 and Aim 2: Determine if inhibiting hydroperoxide metabolism with Aur induces selective enhancement of 212Pb-pent alpha particle therapeutic efficacy in vitro and in vivo preclinical models of lung NETs and NECs by hydroperoxide mediated oxidative stress with tolerable bone marrow and kidney toxicities. Aim 3: Conduct a Phase 1 trial of alpha emitter dosimetry guided PRRT with 212Pb-pent in patients with atypical lung NETs and pulmonary NECs including SCLC. SIGNIFICANCE: Successful completion of Aims 1 and 2 will result in a high impact biochemical-based paradigm shift in the treatment of lung NETs and NECs. CXCR4 will be targeted with high LET 212Pb-pent and the anti-tumor effects enhanced by exploiting cancer cell-specific hydroperoxide-mediated metabolic oxidative stress. Aim 3 will optimize safety, clinical imaging, and dosimetry for evaluation of CXCR4 receptors for targeting of atypical carcinoids and NECs with 212Pb-pent in anticipation of future Phase 2 clinical trials. Overall, these studies will provide mechanistic and clinical information that will have a lasting impact on the development of 212Pb-pent for improving outcomes in currently incurable neuroendocrine lung cancers. Project Number: 1R01CA298628-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Douglas Spitz (+1 co-PI) | Institution: UNIVERSITY OF IOWA, IOWA CITY, IA | Award Amount: $628,280 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CTH-E (82)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296576