scholarly journals Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 781
Author(s):  
Michele Iuliani ◽  
Sonia Simonetti ◽  
Francesco Pantano ◽  
Giulia Ribelli ◽  
Alberto Di Martino ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Antitumor Effect ◽  
Molecular Profile ◽  
Cell Contact ◽  
Metastatic Rcc

Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients’ survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs. Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a “cell–cell contact” system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment. Results: The Caki-1 cell proliferation increased in the presence of OBs (p < 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 (p < 0.0001) and 786-O (p = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture (p < 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib “indirectly” inhibited Caki-1 cell proliferation (p = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth. Conclusions: Overall, the “direct” effect of cabozantinib on OBs “indirectly” increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.

scholarly journals Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway

2018 ◽  
Vol 47 (1) ◽  
pp. 191-200 ◽  
Author(s):  
Chang-wen Wu ◽  
Yi-guo Wu ◽  
Cheng Cheng ◽  
Zheng-dong Hong ◽  
Zi-min Shi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Western Blotting ◽  
Renal Cell ◽  
Jnk Signaling

Background/Aims: Renal cell carcinoma (RCC) is currently the ninth most common cancer in men. Interleukin (IL)-33 expression has previously been associated with a number of cancers; however, its biological role in RCC is poorly understood. In this study, we sought to elucidate the role of IL-33 in RCC. Methods: Serum IL-33 levels were measured by ELISA. IL-33 expression in clinical RCC samples was examined by immunocytochemistry. The proliferation and apoptosis rate of RCC were determined by CCK8 and flow cytometry. Mcl1 and Bcl-2 expression were measured by quantitative real-time PCR and western blotting. JNK expression were measured by western blotting and flow cytometry. The in vivo role of IL-33 in RCC tumorigenesis was examined by animal models. Results: We found that increased expression of IL-33 in RCC was associated with tumor-lymph node-metastasis (TNM) stage and inversely correlated with prognosis. IL-33 enhances RCC cell growth in vivo and stimulates RCC cell proliferation and prevents chemotherapy-induced tumor apoptosis in vitro. Furthermore, we demonstrated that IL-33 promotes RCC cell proliferation and chemotherapy resistance via its receptor ST2 and the JNK signaling activation in tumor cells. Conclusion: Our findings suggest that targeting IL-33/ST2 and JNK signaling may have potential value in the treatment of RCC.

Phase II Trial of Bortezomib for Patients With Advanced Renal Cell Carcinoma

2004 ◽  
Vol 22 (18) ◽  
pp. 3720-3725 ◽  
Author(s):  
G. Varuni Kondagunta ◽  
Beverly Drucker ◽  
Lawrence Schwartz ◽  
Jennifer Bacik ◽  
Stephanie Marion ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Partial Response ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Sensory Neuropathy ◽  
Molecular Profile ◽  
Weekly Schedule ◽  
Best Response ◽  
Grade 3 ◽  
Metastatic Rcc

Purpose To assess the efficacy and toxicity of bortezomib (Velcade; Milennium Pharmaceuticals Inc, Cambridge, MA; formerly PS-341) in patients with metastatic renal cell carcinoma (RCC). Patients and Methods Thirty-seven patients with metastatic RCC were treated with bortezomib. The first 25 patients enrolled onto the trial were treated with a dose of 1.5 mg/m2. The dose was decreased to 1.3 mg/m2 for the subsequent 12 patients, because more than 50% of the patients treated at the higher dose required dose reductions. Bortezomib was given by intravenous administration on a twice-weekly schedule for 2 weeks followed by 1 week without treatment until progression or unacceptable toxicity occurred. Twenty-three patients (62%) previously had undergone nephrectomy, and 19 patients (51%) had previously been treated with cytokine therapy. Results Of the 37 assessable patients, the best response was a partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients (38%; 95% CI, 23% to 55%). The four patients with partial response experienced response durations of 8, 8+, 15+, and 20+ months. Grade 2 or 3 sensory neuropathy was present in 10 patients (53%) overall. One patient in the 1.5 mg/m2 group had grade 3 sensory neuropathy; no grade 3 sensory neuropathy was seen in the 1.3 mg/m2 group. Conclusion The results of this trial suggest that bortezomib has an antitumor effect in individual patients with metastatic RCC. The small proportion of patients who achieved a partial response does not support routine use in metastatic RCC. Efforts to identify the molecular profile associated with clinical response or combination therapy with interferon alfa or other novel agents, may be considered.

scholarly journals SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tong-bing Wang ◽  
Mei Geng ◽  
Hua Jin ◽  
Ai-guo Tang ◽  
Hao Sun ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Regulatory Element ◽  
Severe Combined Immunodeficiency ◽  
Migration And Invasion ◽  
Amino Terminal ◽  
Xenograft Growth

AbstractRenal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo.

TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Lymphatic Invasion ◽  
Cancer Specific Survival ◽  
Candidate Target ◽  
Candidate Target Gene ◽  
And Migration

TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression andits function in renal cell carcinoma (RCC) are still unknown. Here in this study, weinvestigated the clinical significance of TRIM44 and its biological function in RCC.TRIM44 overexpression was significantly associated with clinical M stage, histologictype (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028,respectively). Moreover, TRIM44 overexpression was significantly associated withpoor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function andloss-of-function studies using TRIM44 and siTRIM44 transfection showed thatTRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1and 769P. To further investigate the role of TRIM44 in RCC, we performed integratedmicroarray analysis in Caki1 and 769P cells and explored the data in the Oncominedatabase. Interestingly, FRK was identified as a promising candidate target gene ofTRIM44, which was downregulated in RCC compared with normal renal tissues. Wefound that cell proliferation was inhibited by TRIM44 knockdown and then recoveredby siFRK treatment. Taken together, the present study revealed the associationbetween high expression of TRIM44 and poor prognosis in

scholarly journals Immune-Related Meningoencephalitis following Nivolumab in Metastatic Renal Cell Carcinoma

2021 ◽  
pp. 1051-1058
Author(s):  
Lisa B.E. Shields ◽  
Mohammad S. Alsorogi ◽  
Nataliya Mar ◽  
Arash Rezazadeh Kalebasty
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Rare Complication ◽  
Psoas Muscle ◽  
High Dose ◽  
Lower Extremity Weakness ◽  
Left Psoas Muscle ◽  
Metastatic Rcc

While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.

scholarly journals Downregulation of miR-193a-3p inhibits cell growth and migration in renal cell carcinoma by targeting PTEN

Tumor Biology ◽  
2017 ◽  
Vol 39 (6) ◽  
pp. 101042831771195 ◽  
Author(s):  
Lingqi Liu ◽  
Yanqin Li ◽  
Shuchao Liu ◽  
Qixin Duan ◽  
Liang Chen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cell Growth And Migration ◽  
And Migration

scholarly journals Analysis of various potential prognostic markers and survival data in clear cell renal cell carcinoma

2017 ◽  
Vol 43 (3) ◽  
pp. 440-454 ◽  
Author(s):  
Tastekin Ebru ◽  
Oz Puyan Fulya ◽  
Akdere Hakan ◽  
Yurut-Caloglu Vuslat ◽  
Sut Necdet ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Prognostic Markers ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

scholarly journals Individual approach in choosing second-line targeted therapy for metastatic renal cell carcinoma

2018 ◽  
Vol 14 (2) ◽  
pp. 68-78 ◽  
Author(s):  
B. Ya. Alekseev ◽  
I. M. Shevchuk ◽  
A. D. Kaprin
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Surgical Treatment ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Optimal Dosage ◽  
Second Line ◽  
Newly Diagnosed ◽  
Disease Prognosis ◽  
Metastatic Rcc

Renal cell carcinoma (RCC) is one of the most common genitourinary malignancies worldwide. Approximately 25–30 % of newly diagnosed patients have metastatic RCC (mRCC), whereas in 20–30 % of cases, dissemination occurs after radical surgical treatment. The development of targeted and immunooncological agents in recent years significantly increased survival in patients with mRCC. However, clinicians faced a problem of choosing an optimal therapeutic regimen to achieve maximum effectiveness of the treatment. This article discusses the choice of second-line drugs for mRCC, advantages of axitinib and its optimal dosage, and efficacy of sunitinib depending on the disease prognosis.

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