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Therapeutic efficacy of sacituzumab govitecan in recurrent refractory germ cell tumors
Natália Udvorková1, Viktória Blahová2, Pavlína Malchárková2
1Translational Research Unit, 2nd Oncology Clinic of the Medical Faculty, Comenius University, and the National Cancer Institute, Bratislava, Slovakia; Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Purpose:
Recurrent refractory testicular germ cell tumors (rrTGCT) represent very rare disease with limited therapeutic options. Antibody-drug conjugate Sacituzumab govitecan (ADC-SG) targeting TROP2 protein (TACSTD2 gene) demonstrated anti-tumor activity in solid tumors. Our study aimed to investigate efficacy of ADC-SG in rrTGCT.
Experimental Design:
TROP2 expression in tumor samples (n = 71) and cell line-derived xenografts (CDXs) by immunohistochemistry (IHC); and TACSTD 2 expression by qRT-PCR was determined. Cytotoxicity was evaluated in adherent and spheroid conditions. We generated CDXs, TGCT cell-derived metastatic model, and TGCT patient-derived xenografts (PDXs, n = 4) to test ADC-SG cytotoxic activity in vivo. Clinical efficacy of the ADC-SG was evaluated in a rrTGCT patient with progressive disease.
Results:
TROP2 expression was confirmed in 98.6 % of TGCTs with significantly higher expression in tumor compared to normal testis, and in non-seminoma versus seminoma (p = 0.00007). TROP2 expression is ubiquitous in GCTs without any significant correlation to overall or disease-free survival, tumor grade or tumor stage. TROP2 was significantly increased in cisplatin (CPT) resistant CDXs. ADC-SG exhibited cytotoxicity at nanomolar concentrations in vitro. ADC-SG treatment significantly increased survival in a metastatic model derived from TGCT cells and decreased PDXs' volume (n = 4). Our case study demonstrated tumor regression accompanied by decrease in serum markers, reduction in lesion size, and improved ECOG performance status in the rrTGCT patient with progressive disease treated with ADC-SG.
Conclusion:
Our preclinical work on CDX and PDX together with proof-of-concept clinical case provide rationale for further studies. Refractory relapsing TGCTs represent another clinical entity for treatment with ADC-SG.
Insights
Sacituzumab govitecan (ADC-SG), a TROP2-targeting antibody-drug conjugate, shows promise for recurrent refractory testicular germ cell tumors (rrTGCT). Preclinical models and a patient case demonstrate ADC-SG
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Recurrent refractory testicular germ cell tumors (rrTGCT) have limited treatment options.
- Antibody-drug conjugate Sacituzumab govitecan (ADC-SG) targets TROP2 (TACSTD2), showing efficacy in other solid tumors.
Purpose of the Study:
- To investigate the efficacy of ADC-SG in rrTGCT.
- To evaluate TROP2 expression in TGCT and ADC-SG's preclinical and clinical activity.
Main Methods:
- TROP2 expression assessed by IHC and qRT-PCR in TGCT samples (n=71) and cell line-derived xenografts (CDXs).
- In vitro cytotoxicity of ADC-SG evaluated.
- In vivo efficacy tested using CDXs, a metastatic TGCT model, and patient-derived xenografts (PDXs, n=4).
- Clinical efficacy assessed in one rrTGCT patient.
Main Results:
- TROP2 was highly expressed in 98.6% of TGCTs, higher in non-seminoma vs. seminoma and tumors vs. normal testis.
- ADC-SG demonstrated in vitro cytotoxicity and significantly improved survival in metastatic models and reduced PDX volume.
- The patient case showed tumor regression, decreased serum markers, reduced lesion size, and improved performance status.
Conclusions:
- Preclinical data and a clinical case support ADC-SG as a potential treatment for rrTGCT.
- Further studies are warranted to establish ADC-SG's role in refractory relapsing TGCTs.
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