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Targeted Radionuclide Therapy in Patient-Derived Xenografts Using 177Lu-EB-RGD
Liang Zhao1, Haojun Chen2, Zhide Guo3
1Department of Radiation Oncology, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, China.
Abstract:
Currently, most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced stages with a poor five-year survival rate. Therefore, intensive research aimed at finding novel therapeutic strategies has been ongoing; experimental models that reliably emulate NSCLC disease are greatly needed to predict responses to novel therapeutics. Therefore, we developed patient-derived xenograft (PDX) models of NSCLC, which we then used to evaluate the therapeutic efficacy of 177Lu-EB-RGD, a peptide-based radiopharmaceutical with improved pharmacokinetics that targets integrin αvβ3 In this study, three different groups of NSCLC-PDXs were successfully established, all of which maintained the same IHC and genetic characteristics of the human primary tumor. The two NSCLC-PDX groups with intense and low expression of integrin αvβ3 (denoted as PDXαvβ3+ and PDXαvβ3-) were chosen as the experimental models to evaluate the in vivo biological behavior of 177Lu-EB-RGD. In SPECT imaging and biodistribution studies, 177Lu-EB-RGD showed significantly higher accumulation in PDXαvβ3+ and PDXαvβ3- models than its corresponding monomer 177Lu-RGD. A single dose of 18.5 MBq 177Lu-EB-RGD was enough to completely eradicate the tumors in PDXαvβ3+, with no sign of tumor recurrence during the observation period. Such treatment was also efficacious in PDXαvβ3-: a single dose of 29.6 MBq 177Lu-EB-RGD led to a significant delay in tumor growth as compared with that in the control or 177Lu-RGD group. The preclinical data from the use of this model suggest that 177Lu-EB-RGD may be an effective treatment option for NSCLC and should be further evaluated in human trials.
Insights
New patient-derived xenograft (PDX) models of non-small cell lung cancer (NSCLC) show promise for testing novel therapies. These models demonstrated the effectiveness of 177Lu-EB-RGD, a targeted radiopharmaceutical, in eradicating tumors.
Area of Science:
- Oncology
- Nuclear Medicine
- Translational Research
Background:
- Non-small cell lung cancer (NSCLC) often presents at advanced stages with poor survival rates, necessitating novel therapeutic strategies.
- Effective preclinical models are crucial for evaluating new treatments and predicting clinical responses.
- Targeted radiopharmaceuticals offer a promising avenue for NSCLC treatment, but require robust models for validation.
Purpose of the Study:
- To develop and characterize patient-derived xenograft (PDX) models of NSCLC.
- To evaluate the therapeutic efficacy of the peptide-based radiopharmaceutical 177Lu-EB-RGD in these NSCLC-PDX models.
- To assess the in vivo behavior and targeting of 177Lu-EB-RGD in models with varying integrin αvβ3 expression.
Main Methods:
- Establishment and characterization of three NSCLC-PDX models, confirming preservation of human tumor IHC and genetic profiles.
- Selection of PDX models with high (PDXαvβ3+) and low (PDXαvβ3-) integrin αvβ3 expression for in vivo studies.
- SPECT imaging and biodistribution studies to compare 177Lu-EB-RGD accumulation with its monomeric form (177Lu-RGD).
Main Results:
- 177Lu-EB-RGD demonstrated significantly higher accumulation in both PDXαvβ3+ and PDXαvβ3- models compared to 177Lu-RGD.
- A single dose of 18.5 MBq 177Lu-EB-RGD eradicated tumors in PDXαvβ3+ models with no recurrence.
- In PDXαvβ3- models, a single dose of 29.6 MBq 177Lu-EB-RGD significantly delayed tumor growth compared to controls.
Conclusions:
- NSCLC-PDX models accurately reflect primary tumor characteristics and are suitable for preclinical therapeutic evaluation.
- 177Lu-EB-RGD exhibits potent anti-tumor activity in NSCLC models, effectively targeting integrin αvβ3.
- These preclinical findings support further clinical investigation of 177Lu-EB-RGD as a potential treatment for NSCLC.
