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Updated: Dec 21, 2025
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Molecular targeting of renal cell carcinoma by an oral combination
Andre R Jordan1,2, Jiaojiao Wang1, Travis J Yates2,3
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA.
Abstract:
The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.
Insights
Targeting UDP-glucuronosyltransferase-1A9 (A9) with 4-methylumbelliferone (MU) improved sorafenib (SF) efficacy in metastatic renal cell carcinoma (mRCC) models. This combination inhibited tumor growth and metastasis with low toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Metastatic renal cell carcinoma (mRCC) has a poor 5-year survival rate (<12%) due to treatment resistance.
- Sorafenib (SF), a modestly effective drug for mRCC, is inactivated by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation.
- Elevated A9 levels in renal cell carcinoma (RCC) specimens correlate with metastasis and reduced overall survival, suggesting a mechanism for SF treatment failure.
Purpose of the Study:
- To investigate if targeting A9 can overcome SF resistance in mRCC.
- To evaluate the efficacy of combining low-dose SF with 4-methylumbelliferone (MU), an A9 downregulator, in preclinical mRCC models.
Main Methods:
- Assessed A9 expression in clinical RCC cohorts and TCGA dataset.
- Utilized RCC cell lines, patient-derived tumor explants, and co-cultures to test SF and MU combination therapy.
- Investigated the role of A9 in mediating resistance to the combination treatment.
Main Results:
- Elevated A9 levels were observed in RCC specimens and predicted poor outcomes.
- The combination of low-dose SF and MU effectively inhibited RCC cell growth, motility, invasion, and downregulated an invasive signature.
- A9 overexpression conferred resistance to the SF-MU combination, while A9 downregulation sensitized cells to SF monotherapy.
- The combination therapy demonstrated significant inhibition of kidney tumor growth, angiogenesis, and distant metastasis in preclinical models with no detectable toxicity.
Conclusions:
- Targeting A9 with MU in combination with low-dose SF represents a promising therapeutic strategy for mRCC.
- This approach could overcome SF resistance and improve treatment outcomes for mRCC patients with minimal toxicity.
- Targeting specific drug-inactivating mechanisms offers a viable strategy to enhance the efficacy of existing therapies.
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