The Impact of Modifying Sunitinib Treatment Scheduling on Renal Cancer Tumor Biology and Resistance

With sunitinib treatment of metastatic renal cell carcinoma, most patients end up developing resistance over time. Recent clinical trials have shown that individualizing treatment protocols could delay resistance and result in better outcomes. We developed an in vivo xenograft tumor model and compared tumor growth rate, morphological, and transcriptomic differences between alternative and traditional treatment schedules. Our results show that the alternative treatment regime could delay/postpone cancer progression. Additionally, we identified distinct morphological changes in the tumor with alternative and traditional treatments, likely due to the significantly dysregulated signaling pathways between the protocols. Further investigation of the signaling pathways underlying these morphological changes may lead potential therapeutic targets to be used in a combined treatment with sunitinib, which offers promise in postponing/reversing the resistance of sunitinib.

Denoised VEGFR2 expression relates to sunitinib efficacy in advanced Clear Cell Renal Cell Carcinoma

Short summary: Personalized biomarkers can facilitate decision making upon multiple therapeutic options in ccRCC. VEGFR2 expression denoised with 37 normal and tumor gene expressions relates to sunitinib effect whereas raw VEGFR2 expression does not relate to sunitinib effect. Background: Several studies suggested that molecular analysis of patients with advanced clear cell renal cell carcinoma (ccRCC) could indicate whether a patient is susceptible of benefiting from sunitinib in first line systemic treatment compared to immunotherapies. However, data remain conflicting and no predictive biomarker is validated so far to decipher if sunitinib could still represent a good therapeutic option in first line setting and beyond. Methods: PREDMED denoised the tumor RNA expression of 37 genes including KDR (encoding VEGFR2) estimated by RTqPCR, by normalizing it on the expression of normal kidney tissue and cell types. We investigated the performance of PREDMED VEGFR2-scoring to predict the clinical effect of sunitinib for patients affected by ccRCC. Results: Among the 34 ccRCC patients samples retrospectively retrieved from the UroCCR project (NCT03293563), high VEGFR2 scores were associated with objective clinical responses under sunitinib treatment and low scores with stable disease or progression with a sensitivity of 86%, a specificity of 67% and an AUC of 72.5% (95%CI[50.1, 94.9]; p=0.04). VEGFR2 scores were significantly and positively related to progression-free survival (HR = 0.465; 95%CI[0.221, 0.978]; p=0.0311) and overall survival (HR = 0.400; 95%CI[0.192, 0.834]; p=0.0134) under sunitinib treatment. In our cohort, raw VEGFR2 expression (before PREDMED processing) was not related to the above mentioned outcomes. Conclusion: We describe a gene expression based algorithm that is accurately related to the effect of sunitinib for patients with ccRCC. We further plan a validation of PREDMED for combinatorial strategies involving antiangiogenics and immune-checkpoint blockers.

Sunitinib Treatment for Advanced Paraganglioma: Case Report of a Novel SDHD Gene Mutation Variant and Systematic Review of the Literature

BackgroundParagangliomas (PGLs) are neuroendocrine neoplasms arising from chromaffin cells of sympathetic or parasympathetic paraganglia. Systemic therapies have been used only in metastatic PGLs. Antiangiogenic agents, such as sunitinib, could be a viable therapeutic choice in the subgroup of patients with SDH-positive PGLs. We describe the case of a man with Familial Paraganglioma Syndrome type 1 (FPGL) related to a novel mutation in SDHD gene treated with sunitinib. Furthermore, we performed a systematic review of the literature aimed to address the following question: is sunitinib treatment effective in patients with advanced/progressive/metastatic PGL?MethodsWe performed a data search using MEDLINE, Cochrane Library, and Scopus between April 2019 and September 2020. We included studies reporting data on clinical or biological characteristics, or clinical outcomes of patients with PGLs treated with sunitinib.ResultsThe search leaded to the selection of 25 publications. Data from case reports and case series showed that disease control rate (DCR = stable disease + partial response + complete response) was achieved in 34.7% of cases under sunitinib treatment. In 39% of patients DCR was followed by progressive disease (PD) or tumor relapse, 26.1% patients showed PD. Data from clinical trials showed that DCR was 83%, and the median progression free survival was 13.4 months.DiscussionData from the present literature review suggested that sunitinib could be a viable therapeutic option in advanced/progressive/metastatic inoperable PGLs. However, further trials on the efficacy of sunitinib in FPGL and sporadic PGL are needed.

Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway

Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry

Aim: Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Materials & methods: Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Results: Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5–13.6] months) versus nonusers (6.9 [5.7–8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9–28.3] months) versus nonusers (25.7 [22.7–33.0] months) (p = 0.0212). Conclusion: Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 ( ClinicalTrials.gov )