Candidate Gene and MicroRNA Biomarkers of Metastatic Renal Cell Carcinoma (MRCC) Response to Sunitinib

Backgrounds: The incidence of renal cancer is relatively insidious, and some patients have been metastatic renal cancer at the initial visit. Sunitinib is the first-line systemic therapy for patients with metastatic renal cell carcinoma, however, there is scant analysis of its effect on genes and microRNAs.Methods: In this study, 8 differentially expressed microRNAs and 112 differentially expressed genes were designated by analyzing mRNA and microRNA data sets and weighted correlation network analysis (WGCNA).Results: NIPSNAP1 gene showed the most co-expression with other genes. Through the intersection of the microRNA target gene with our differentially expressed genes, we got 26 genes. KEGG and GO analysis showed that these genes were predominantly concentrated in Pathways in cancer, Sphingolipid metabolism and Glycosaminoglycan degradation. After we set the 26 genes and gene of WGCNA do intersection, received six genes, respectively is NIPSNAP1, SDC4, TBC1D9, NEU1, STK40 and PLAUR. Conclusion: Through subsequent cell, molecular and flow cytometry experiments, we found the PLAUR would play a crucial role in renal cell carcinoma (RCC) resistant to sunitinib, which will be available for new ideas to forecast sunitinib resistance and reverse sunitinib resistance.

Il-2 in combination with immune checkpoints inhibitors as a promising approach for cancer immunotherapy: A literature review

Relevance: Interleukin-2 (IL-2) alone has been shown to induce tumor regression and approved to treat metastatic renal cancer and melanoma. Checkpoint inhibitors realize their therapeutic effect through stimulation of immune system effectors; one of such mechanisms is the enhancement of IL-2 production by T-helpers. The purpose of the study was to determine the effectiveness of IL-2 administration as a component of combined immunotherapy with immune checkpoint inhibitors and to suggest the mechanisms by which IL-2 can reduce the frequency and severity of side effects during checkpoint inhibitor therapy without reducing their effectiveness. Methods: The literature search was performed in the PubMed, SCOPUS, and Web of Science databases by the keywords in article titles: “immunotherapy,” “checkpoint inhibitors,” “interleukin-2,” and “combination therapy” for the period 2011-2021. A total of 248 relevant articles were found. The review’s inclusion criteria were: clinical cases; data of clinical research methods; data on humans/body fluids from humans; literature reviews and meta-analyses. The selected 24 articles met the search criteria and were included in the review. Results: The combined action of IL-2 and сheckpoint inhibitors increases the proliferative and killer activity of the antitumor immunity effectors compared to the action of the same drugs in mono-mode at a level exceeding the summation effect. Conclusion: The combination of IL-2 and сheckpoint inhibitors can increase the effectiveness of anticancer treatment and is a promising area of immunotherapy

Nitrogen partitioning between branched-chain amino acids and urea cycle enzymes sustains renal cancer progression

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we combined multi-omics datasets of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) and generated a computational tool to explore the metabolic landscape during cancer progression. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism is required to maintain the aspartate pool in cancer cells across all tumor stages. We also provide evidence that metastatic renal cancer cells reactivate argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, to enable invasion in vitro and metastasis in vivo. Overall, our study provides the first comprehensive elucidation of the molecular mechanisms responsible for metabolic flexibility in ccRCC, paving the way to the development of therapeutic strategies based on the specific metabolism that characterizes each tumor stage.

Does sunitinib still have a place in the current recommendations for the systemic treatment of advanced renal cell carcinoma?

Renal cancer is a common malignancy. The frequency of renal cell carcinoma (RCC) in the structure of oncological diseases is steadily increasing. Despite the migration of the stage towards an increase in the frequency of primary detection of localized forms of the disease, renal cancer belongs to the aggressive and unpredictable malignant neoplasms. One third of patients already have distant metastases at the time of diagnosis. Surgery is the only radical method of treatment of renal cancer. However, despite the successes of surgery in the treatment of RCC, according to various data, more than 30% of radically operated patients show dissemination of the tumor process during follow-up. Radiation therapy and chemotherapy are ineffective in treating metastatic RCC (mRCC). The results of nonspecific immunotherapy in the treatment of metastatic renal cancer were also unsatisfactory. Progress in the study of molecular biology has led to the discovery of a new group of anti-tumor drugs related to angiogenesis inhibitors. The use of targeted therapies has increased the efficacy of drug therapy in the treatment of mRCC several times over the use of cytokine immunotherapy. One of the first such drugs registered in 2007 for the treatment of mRCC was sunitinib, which in a number of clinical trials has demonstrated the greatest efficacy and acceptable toxicity. Along with new drug regimens, the multikinase inhibitor sunitinib remains the drug of choice for first-line therapy of inoperable locally advanced and disseminated clear cell and non-small cell RCC in patients with favorable prognosis. The literature review presents a critical analysis of the data related to sunitinib research in kidney cancer and changes in the position of monotherapy with this drug in advanced forms of the disease.

Impact of Body Mass Index on Survival of Metastatic Renal Cancer

Obesity has been established as a risk factor for renal cell carcinoma (RCC). Recently, studies have described obesity as a probable protecting factor in the metastatic stage of RCC. In this study, we assessed the relationship between body mass index (BMI) and overall survival in patients under systemic therapy.The correlation between BMI and overall median survival was studied in 76 patients diagnosed with metastatic RCC under systemic therapy. The groups were divided into overweight and obesity (BMI > 25 kg/m2) and underweight or normal (BMI < 25 kg/m2). Statistical analysis was performed using the Cox regression model adjusted by gender.A total of 76 patients were studied: 16 women (21%) and 60 men (79%). The median BMI was 27.96 kg/m2; 24 patients (31.6%) had low BMI and 52 (68.4%) had high BMI. Median overall survival in the group with BMI > 25 kg/m2 was 17 months (95% confidence interval [CI]: 13–34 months), while in the group with BMI ≤ 25 kg/m2, it was 14 months (95% CI: 8–20 months). When adjusted by gender, the group with BMI > 25 kg/m2 presented a hazards ratio of 0.54 (95% CI: 0.30–0.96), P = 0.044 (Log Rank).A high BMI significantly acts as a protecting factor. We observed an increased overall survival of overweight and obese patients within the context of metastatic RCC under systemic treatment. These data confirm the findings published in other studies that suggest the role of lipid metabolism in this type of tumors.

Metastatic renal cancer: real-world evidence from a large Italian claims database

Purpose: To assess the healthcare resources’ consumption and integrated costs of patients with renal cancer and new metastasis (mRCC), in the perspective of the Italian National Health System (NHS). Methods: From the ReS database, through the administrative data record linkage, adults with a primary/secondary hospital (ordinary/daily admissions) diagnosis (ICD9-CM code) of renal cancer and lymph node and/or distant metastases in the same hospital discharge (index date) were selected in 2015. Metastases were defined new if they were absent in the 2 previous years. Patients were described in terms of gender, age (mean ± SD) and comorbidities of interest. The 2-year survival and annual pharmacological treatments, hospitalization, outpatient specialist services and costs were analysed. Results: Out of >6 million adults in the 2015 ReS database, 133 (2.1 × 100,000) were hospitalized with a diagnosis of RCC and metastasis. Patients with new metastases were 63.2% (1.4 × 100,000; 73.8% males; mean age 68 ± 13). Hypertension was the most common comorbidity (70.2% of mRCC patients). The 2-year survival of mRCC patients was 26.2%. During 1-year follow-up, at least a drug was prescribed to 88.1% of mRCC patients (on average € 12,095/patient), 91.7% were hospitalized (€ 8,897/patient) and 82.1% entrusted the outpatient specialist care (€ 1,075/patient). The mean overall expenditure for the NHS was € 22,067 per capita. Conclusions: This study shows the mRCC burden on the Italian real clinical practice and its economic impact in the perspective of the NHS. Real-world analyses prove to be useful to concretely estimate the overall healthcare responsibility on patients affected by mRCC.

Overall Survival in Metastatic Renal Cancer in the Central Region of Morocco: A Real Life Experience Over One Decade

Background: Available treatments for metastatic RCC (mRCC) are usually non-curative. In the last decade, novel targeted therapies have significantly improved mRCC outcome. The objective in this study was to describe outcomes in patients with mRCC in Morocco.Methods: 100 patients with mRCC were recruited between January 2008 and December 2018 in the Hassan II University Hospital of Fez. Data were retrospectively collected. Kaplan-Meier survival analysis was used to determine overall survival (OS) and progression free survival (PFS).Results: Mean age of the patients was 58.6 years(±12). Sixty seven percent of patients were male. Clear cell carcinoma was the most common histological subtype (78%). According to the IMDC scoring, 72% of patients were in the intermediate and 18% in the poor risk groups. Seventy patients received targeted therapy. Overall response rate (according to RECIST criteria version 1.0) was 38.6%. The median PFS was 7.0 months (95% CI, 4.6 to 9.4). The median OS was 11.6 months (95% CI, 7.9 to 15.3). In the multivariate analysis, cancer specific mortality was impacted by treatment with VEGFR inhibitors (HR: 0.2; 95% CI, 0.1 to 0.4; p =0.001) and IMDC score (intermediate risk group HR: 3.5 (95% CI, 1.4 to 9.1; p =0.009); and poor risk group HR: 5.5 (95% CI, 1.9 to 16.1; p =0.002)).Conclusion: This is the first report from clinical practice in an African country of OS data in mRCC. The study showed high mortality rates. However, outcomes of VEGFR inhibitors are consistent with studies investigating these treatments.