Phase II Study of Carfilzomib in Patients With Refractory Renal Cell Carcinoma

Hasanov, Elshad; Tidwell, Rebecca S. Slack; Fernández, Pablo; Park, Lauren; McMichael, C.; Tannir, Nizar M.; Jonasch, Eric

doi:10.1016/j.clgc.2019.07.003

Cited by 8 publications

(3 citation statements)

References 16 publications

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“…Finally, 9 patients received Carfilzomib (0.1%) and 35 patients (0.6%) received Trebabanib. Detailed clinical and pathological prophile of mRCC patients according to second-line therapy was only possible in 18 studies [10][11][12][13]16,17,[22][23][24][25][26][31][32][33][34]36,37]. Table 3 describes the available clinical and pathological features of mRCC patients stratified according the following second-line therapies: axitinib, cabozantinib, nivolumab, everolimus plus levatinib.…”

Section: Second Line Therapymentioning

confidence: 99%

Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review

Longo

Capece

Celentano

et al. 2020

Cancers

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A high percentage of patients with metastatic renal cell carcinoma (mRCC) require a second-line option. We aimed to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. A systematic review was performed in August 2020. We included papers that met the following criteria: original research; English language; human studies; enrolling mRCC patients entering a second-line therapy. Twenty-nine studies enrolling 7650 patients (73.5% male, mean age: 55 to 70 years) were included. Clear cell histology was reported in 74.4% to 100% of cases. Tyrosine kinase inhibitors, immunotherapy, bevacizumab, mTOR inhibitors, and chemotherapy were adopted as first line option in 68.5%, 29.2%, 2.9%, 0.6%, and 0.2% of patients, respectively. Discontinuation of first-line therapy was due to progression and toxicity in 18.4% to 100% and in 17% to 48.8% of patients, respectively. Eastern Cooperative Oncology Group performance status score was 0 or 1 in most cases. Most prevalent prognostic categories according to the International Metastatic RCC Database Consortium and Memorial Sloan–Kettering Cancer Centre score were intermediate and good. About 77.8% of patients harboured ≥2 metastatic sites. In conclusion, patients who enter a second-line therapy are heterogeneous in terms of a clinical-pathological profile. Tailoring of second-line treatment strategies is strongly advocated.

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Section: Second Line Therapymentioning

confidence: 99%

Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review

Longo

Capece

Celentano

et al. 2020

Cancers

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“…Currently, three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, have received regulatory approval and are routinely used ( 26 ). Unfortunately, a phase II study of carfilzomib reported negative safety and efficacy findings that do not favor its use in treating RCC ( 27 ). However, a proof-of-concept study investigating in vivo antitumoral activity of carfilzomib using patient-derived xenografts has indicated that patient-individualized in vitro drug screening and preclinical validation are feasible ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Complexity in radiological morphology predicts worse prognosis and is associated with an increase in proteasome component levels in clear cell renal cell carcinoma

et al. 2022

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BackgroundWe previously reported preoperative radiological morphology (RM) as an independent predictor for pathological upstaging after partial nephrectomy in patients with T1 renal cell carcinoma (RCC).PurposeTo investigate the prognostic importance of RM in all stages and the molecular characteristics underlying the differences between each type of RM in patients with clear cell RCC (ccRCC).Design, setting, and participantsThe Cancer Imaging Archive datasets (TCIA), comprising CT images and RNA-sequencing data, were used (n = 163). Specimens from 63 patients with ccRCC at our institution and their CT images were used. All images were divided into three types according to RM classification.Outcome measurements and statistical analysisRelationships with outcome were analyzed using Cox regression analysis and log-rank test.Results and limitationsThe irregular type was a significant independent predictor of worse disease-free survival (odds ratio: 2.22, p = 0.037) compared to round and lobular types in TCIA datasets. The irregular type showed a significant increase in both mRNA and protein expression of proteasome components, PSMB1 and PSMB3. Moreover, high expression of their coding genes shortened the progression-free survival of the patients with ccRCC who received sunitinib or avelumab plus axitinib therapy. The study limitations include the qualitative classification of RM and the need for novel radiomics and texture analysis techniques.ConclusionsInvestigating RM on pre-treatment CT scans can effectively predict worse prognosis. Increased RM complexity may indirectly predict drug sensitivity via increased expression of PSMB1 and PSMB3 in patients with ccRCC. Specific targeting of the ubiquitin-proteasome system might be a novel treatment strategy for ccRCC with increased RM complexity.Patient summaryThe clinical and morphological characteristics of patients with ccRCC vary greatly according to cancer staging. In this study, we built upon our prior findings of the prognostic importance of RM in T1 RCC and expanded it to encompass all stages of RCC, using a series of patients from a Japanese hospital.

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“…The treatment with this compound showed antitumoral activity not only in RCC tumor cell lines but also in a patient-derived xerograph (PDX) [ 61 ]. Nevertheless, in a phase-II study with mRCC patients it emerged that carfilzomib failed clinical trials since all enrolled patients had disease progression and different side effects [ 62 ]. Taken together, these observations suggest that proteasome inhibitors seem unsuitable for the treatment of metastatic renal carcinoma.…”

Section: Current and New Targeted Therapies For Rcc Treatmentmentioning

confidence: 99%

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

Dell’Atti

Bianchi

Aguiari

2022

Cancers

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Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC.

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Phase II Study of Carfilzomib in Patients With Refractory Renal Cell Carcinoma

Cited by 8 publications

References 16 publications

Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review

Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review

Complexity in radiological morphology predicts worse prognosis and is associated with an increase in proteasome component levels in clear cell renal cell carcinoma

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

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