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Targeting CXCR4 with 212Pb/203Pb-Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer
Keegan A Christensen1, Melissa A Fath1, Jordan T Ewald1,2
1Free Radical and Radiation Biology Program, Department of Radiation Oncology, and Departments of.
Abstract:
Small cell lung cancer (SCLC) has a 6% 5-year overall survival rate. C-X-C chemokine receptor 4 (CXCR4) is an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212Pb/203Pb. The hypothesis that 212Pb/203Pb-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. SPECT-CT imaging and biodistribution studies of tumor-bearing mice injected with 203Pb-pentixather demonstrated CXCR4 expression-dependent uptake and accumulation of radioligand in the kidneys and livers. Dosimetry calculations were performed to estimate 212Pb-pentixather uptake in tumor and normal tissue. 212Pb-Pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. CBCs of mice at 30 days after treatment demonstrated adequate retention of bone marrow function. NSG mice allografted with human hCD34+ bone marrow were treated with 212Pb-pentixather (37-111 kBq/g) to assess damage to human hematopoietic stem cells, demonstrating cytopenias in peripheral blood CBCs at 13-18 days after treatment, resolving by days 28-31. Flow cytometry of bone marrow in these animals at days 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 and reconstitution of the bone marrow with murine CD45+ lineages. 203Pb-Pentixather can be used to image CXCR4-expressing SCLC xenografts. Treatment with high-LET alpha emitter 212Pb-pentixather significantly prolonged overall survival, and recovery of mouse bone marrow from 212Pb-pentixather was significantly greater than that of human bone marrow.
Insights
New theranostic agents using 212Pb/203Pb-pentixather show promise for small cell lung cancer (SCLC) imaging and therapy. This CXCR4-targeted approach effectively delays tumor growth and prolongs survival in preclinical models.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceutical Therapy
Background:
- Small cell lung cancer (SCLC) has a poor prognosis with a 6% 5-year survival rate.
- C-X-C chemokine receptor 4 (CXCR4) is highly expressed in SCLC and is a viable target for theranostic agents.
- Pentixather, labeled with 212Pb/203Pb, offers potential for both imaging and targeted therapy.
Purpose of the Study:
- To evaluate the safety and efficacy of 212Pb/203Pb-pentixather for imaging and therapy of SCLC in xenograft models.
- To assess the diagnostic accuracy of 203Pb-pentixather for visualizing CXCR4 expression in SCLC.
- To determine the therapeutic potential and toxicity profile of 212Pb-pentixather in preclinical SCLC models.
Main Methods:
- SPECT-CT imaging and biodistribution studies using 203Pb-pentixather in SCLC xenograft models.
- Dosimetry calculations to estimate radiation dose to tumors and normal tissues from 212Pb-pentixather.
- Therapeutic efficacy assessment of 212Pb-pentixather treatment on tumor growth and survival, including bone marrow toxicity studies in mice and humanized models.
Main Results:
- 203Pb-pentixather demonstrated CXCR4-dependent uptake in SCLC xenografts, enabling imaging.
- Treatment with 212Pb-pentixather significantly prolonged survival and delayed tumor growth in SCLC xenografts.
- While transient cytopenias were observed in human hematopoietic stem cells, bone marrow function recovered in mice, with greater recovery than in human cells.
Conclusions:
- 203Pb-pentixather is effective for imaging CXCR4-expressing SCLC.
- 212Pb-pentixather shows significant therapeutic potential for SCLC, prolonging survival.
- The theranostic pair 212Pb/203Pb-pentixather presents a promising strategy for SCLC management with manageable toxicity.
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