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Avapritinib efficacy in primary hepatic neuroendocrine carcinoma with elevated PDGFRA expression: Insights from a PDX
Yang Zhou1, Xiang-Lin Song2, Luo-Bin Guo3
1Biobank, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
Background & Aims:
Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research.
Methods:
We employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks.
Results:
Pathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA.
Conclusion:
Our findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.
Insights
Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is aggressive. Targeting PDGFRA with Avapritinib significantly reduced tumor growth in a preclinical model, suggesting a new therapeutic avenue for this rare cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare, aggressive malignancy with high recurrence rates.
- Current treatment is limited to surgical resection, with limited understanding of targeted therapies.
- The efficacy of tyrosine kinase inhibitors (TKIs) for PHNEC is largely unexplored.
Purpose of the Study:
- To investigate potential therapeutic targets in PHNEC.
- To evaluate the efficacy of a PDGFRA-targeting drug in a preclinical PHNEC model.
Main Methods:
- Immunohistochemical staining was used to diagnose PHNEC and assess tyrosine kinase receptor expression.
- A patient-derived xenograft (PDX) model of PHNEC was established.
- PDX mice were treated with Avapritinib, a PDGFRA inhibitor, and tumor growth was monitored.
Main Results:
- PHNEC diagnosis was confirmed, with significant overexpression of PDGFRA identified.
- Avapritinib treatment resulted in a 73.9% reduction in tumor growth in the PDX model.
- Avapritinib decreased PDGFRA and Ki-67 expression, indicating inhibition of tumor cell proliferation.
Conclusions:
- PDGFRA is a potential therapeutic target for PHNEC.
- Avapritinib demonstrates efficacy in reducing PHNEC tumor growth in a preclinical setting.
- Targeting PDGFRA may offer a novel therapeutic strategy for patients with PHNEC.
