Targeting CXCR4 with 212Pb/203Pb-Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer

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.