Sunitinib In Renal Cell Carcinoma Research Articles

Reversing Sunitinib Resistance Facilitated by ITGA1 Through the PI3K/Akt/Bcl-2 Pathway Using Nano Co-Delivery System in Renal Cell Carcinoma

For genitourinary cancers, renal cell carcinoma (RCC) is the third leading cause of death, while target drug resistance has always been a difficult problem. Integrin alpha 1 (ITGA1) is a member of the integrin family, which is significant for the pathogenesis, development, and drug resistance of various malignant tumors. However, it remains unclear for the ITGA1 functions in renal cell carcinoma sunitinib resistance. In this study, we found that the ITGA1 gene facilitates renal cell carcinoma sunitinib resistance through the PI3K/Akt/Bcl-2 signaling pathway. Based on this, we developed a co-delivery system designated as Su/Si-PEAL NPs for the synergistic delivery of ITGA1 small interfering RNA (siRNA) and sunitinib using monomethoxy polyethylene glycol-polylactic acid/glycolic acid-poly-L-lysine triblock copolymer (mPEG-PLGA-PLL, PEAL) as the backbone material. Furthermore, the results of a series of functional experiments confirmed that this codelivery system was capable of downregulating the expression of ITGA1 and enhancing the sensitivity of 786-O-R cells to sunitinib. This co-delivery system could be an efficient approach for reversing sunitinib resistance in renal cell carcinoma.

P13 - Analysis of extracellular vesicles in drug resistance towards Sunitinib in renal cell carcinoma

P13 - Analysis of extracellular vesicles in drug resistance towards Sunitinib in renal cell carcinoma

Emerging role of LINC00461 in cancer

LINC00461 is located in the intergenic region between the protein-coding genes MEF2C and TMEM161B. LINC00461 upregulation was associated with the risk of 13 tumors and was strongly associated with clinicopathologic features and poor prognosis in 11 tumors. LINC00461 is involved in resistance to four anticancer drugs, including sunitinib for renal cell carcinoma, cisplatin for head and neck squamous cell carcinoma and rectal cancer, temozolomide for glioma, and docetaxel for breast cancer. LINC00461 can sponge 18 miRNAs to form a complex ceRNA network that regulates the expression of a large number of downstream genes. LINC00461 is involved in the MAPK/ERK signaling pathway and PI3K/AKT signaling pathway, thereby promoting tumorigenesis. Notably, knockdown of LINC00461 in exosomes antagonizes tumor cell proliferation in multiple myeloma. This article summarizes the diagnostic, prognostic, and therapeutic value of LINC00461 in various tumors, and systematically describes the ceRNA network and signaling pathways associated with LINC00461, providing potential directions for future LINC00461 research.

In-vitro Evaluation of Isatin Derivatives as Potent Anti-Breast Cancer Agents against MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 Breast Cancers Cell Lines: A Review.

Breast cancer (BC) is one of the most frequent malignancies and the most common reasons for impermanence in women. The backbone of therapy for BC is principally chemotherapy, but its non-specific nature to differentiate between normal cells and cancer cells and severe side effects are the main barriers in its use. So, there is an intense requirement to enlarge more efficacious, more specific and safer anti-BC agents. Isatin (IST) is an endogenous molecule that is a principal class of heterocyclic compounds and exhibits a wide range of therapeutic activities which can be used as a starting material for the synthesis of several drug molecules. Many kinds of literature were reported previously on different pharmacological activities of IST derivatives and particularly on anticancer activity but this review mainly focuses on anti-BC activities of IST derivatives through MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 cell lines. Herein we mentioned; a total of 33 IST derivatives (compound 24- 56) which show good anti-BC activity. IST-derived compounds are also available in the market and are used for various cancer types like sunitinib for renal cell carcinoma (RCC) and Nintedanib for the cryptogenic fibrosing alveolitis treatment, but when evaluated for BC, they did not prove to be much successful. This review mainly highlights anti-BC activities of various IST analogues using MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 cell lines, displaying the potent compound of the series and structure-activity relationships of compounds with molecular docking also. So, this study mainly shows the importance of IST as a major source for drug design and development of newer anti-BC drugs.

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. EudraCtNo: 2005-004502-82.

ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).

300 Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO2peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO2peak were 65 yrs, 30.5 kg/m2, and 19.2 ml kg−1 min−1. We observed no difference in the primary endpoint of VO2peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]

MP18-18 P53 IS INVOLVED IN RESISTANCE TO SUNITINIB IN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (MP18)1 Apr 2020MP18-18 P53 IS INVOLVED IN RESISTANCE TO SUNITINIB IN RENAL CELL CARCINOMA Yohei Sekino*, Xiangrui Han, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Taniyama Daiki, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, and Akio Matsubara Yohei Sekino*Yohei Sekino* More articles by this author , Xiangrui HanXiangrui Han More articles by this author , Keisuke GotoKeisuke Goto More articles by this author , Shogo InoueShogo Inoue More articles by this author , Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Jun TeishimaJun Teishima More articles by this author , Taniyama DaikiTaniyama Daiki More articles by this author , Naoya SakamotoNaoya Sakamoto More articles by this author , Kazuhiro SentaniKazuhiro Sentani More articles by this author , Naohide OueNaohide Oue More articles by this author , Wataru YasuiWataru Yasui More articles by this author , and Akio MatsubaraAkio Matsubara More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000843.018AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although approximately 70% of the patients show initial response with sunitinib in renal cell carcinoma (RCC), eventually sunitinib resistance occurred. Therefore there is an urgent need to clarify the mechanisms of sunitinib resistance. The tumor protein p53 is involved in chemo-resistance in several cancer. The aim of this study is to examine the expression and functional role of P53 on sunitinib resistance and a possible role of combination with MDM2 inhibitor: nutlin3 and sunitinib in RCC. METHODS: We established sunitinib resistance RCC cell lines. We analyzed the expression of P53 in sunitinib resistance cell lines and examined the effect of P53 knockout on sunitinib resistance. We also investigated the effect of combination with sunitinib and nutlin3. Expression of P53 in 49 RCC tissues treated with sunitinib was determined by immunohistochemisty. RESULTS: We established sunitinib resistance cells in Caki-1 and ACHN cells by culturing cells with increasing concentrations of sunitinib. Western blotting showed that the expression of P53 was decreased in sunitinib resistant cells compared with that in parental cells. Then, we generated the P53 knockout cells in Caki-1 and ACHN cells by CRISPR-cas9 system. Knockout of P53 promoted sunitinib resistance. Mdm2 is an important negative regulator of the p53. Therefore we examined the effect of combination therapy with sunitinib and nutlin3. Sunitinib alone had little effect on cell viability in the sunitinib resistant cell lines. However, the combination of sunitinib and nutlin3 significantly reduced cell viability in the sunitinib resistant cells. Western blotting revealed that the expression of P53 was induced by combination therapy with suniitnib and nutlin3 compared to nutlin3 treatment alone in sunitinib resistant cells. Additionally, we investigated the expression of P53 in 52 ccRCC cases treated with sunitinib treatment. A Kaplan-Meier analysis showed that the positive cases of P53 were associated with poor prognosis after sunitinib treatment (P = 0.04) (Fig. 1). CONCLUSIONS: The expression of P53 was downregulated in sunitinib resistant RCC cell lines. Knockout of P53 promoted sunitinib resistance. Nutlin3 re-sensitized sunitinib resistant cells to sunitinib treatment. These results suggest that the combination therapy with sunitinib and nutlin3 may be promising in RCC. Source of Funding: I have nothing to disclose © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e242-e242 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yohei Sekino* More articles by this author Xiangrui Han More articles by this author Keisuke Goto More articles by this author Shogo Inoue More articles by this author Tetsutaro Hayashi More articles by this author Jun Teishima More articles by this author Taniyama Daiki More articles by this author Naoya Sakamoto More articles by this author Kazuhiro Sentani More articles by this author Naohide Oue More articles by this author Wataru Yasui More articles by this author Akio Matsubara More articles by this author Expand All Advertisement PDF downloadLoading ...

Outcomes Associated with First-Line anti-PD-1/ PD-L1 agents vs. Sunitinib in Patients with Sarcomatoid Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

Immunotherapy based on anti PD-1/PD-L1 inhibitors has proven to be more effective than sunitinib in the first-line setting of advanced renal cell carcinoma (RCC). RCC patients with sarcomatoid histology (sRCC) have a poor prognosis and limited therapeutic options. We performed a systematic review and a meta-analysis of randomized-controlled trials (RCTs) of first-line anti PD-1/PDL-1 agents vs. sunitinib, presenting efficacy data in the sub-group of sRCC patients. The systematic research was conducted on Google Scholar, Cochrane Library, PubMed and Embase and updated until 31th January, 2020. s from ESMO and ASCO (2010–2019) were also reviewed. Full texts and abstracts reporting about RCTs testing first-line anti-PD-1/ PD-L1 agents vs. sunitinib in RCC were included if sRCC sub-group analyses of either PFS (progression-free survival), OS (overall survival) or radiological response rate were available. Pooled data from 3814 RCC patients in the ITT (intention-to-treat) population and from 512 sRCC patients were included in the quantitative synthesis. In the sRCC sub-group vs. the ITT population, pooled estimates of the PFS-HRs were 0.57 (95%: 0.45–0.74) vs. 0.79 (95% CI: 0.70–0.89), respectively, with a statistically meaningful interaction favoring the sRCC sub-group (pooled ratio of the PFS-HRs = 0.64; 95% CI: 0.50–0.82; p < 0.001). Pooled estimates of the difference in CR-R (complete response-rate) achieved with anti-PD-1/PDL-1 agents vs. sunitinib were + 0.10 (95% CI: 0.04–0.16) vs. + 0.04 (95% CI: 0.00–0.07) in the sRCC vs. the non-sRCC sub groups, with a statistically meaningful difference of + 0.06 (95% CI: 0.02–0.10; p = 0.007) favoring the sRCC sub-group. Sarcomatoid histology may be associated with improved efficacy of anti PD-1/PDL-1 agents vs. sunitinib in terms of PFS and CR-R.

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer.

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.

Effect of the Nrf2-ARE signaling pathway on biological characteristics and sensitivity to sunitinib in renal cell carcinoma.

The aim of the present study was to examine the effects of the nuclear factor erythroid-2 related factor 2-antioxidant-responsive element (Nrf2-ARE) signaling pathway on the biological characteristics and sensitivity to targeted therapy in human renal cell carcinoma (RCC) cells. RCC tissues and adjacent tissues were collected and assessed by immunohistochemistry to determine the expression of Nrf2, NAD(P)H dehydrogenase [quinone] 1 (NQO1) and heme oxygenase-1 (HO-1) to analyze the clinicopathological features of RCC. A series of in vitro experiments were conducted to analyze the biological characteristics of Nrf2-ARE signaling in RCC. The renal cancer cell line, 786-0 was used, and cells was divided into a mock group, negative control group and small hairpin (sh)RNA-Nrf2 group. A Cell Counting Kit-8 assay was performed alongside flow cytometry to detect cell viability, cell cycle stage and apoptosis following treatment with sunitinib. The results demonstrated that Nrf2, NQO1 and HO-1 were significantly upregulated in RCC tissues compared with adjacent tissues and were associated with tumor node metastasis stage, Fuhrman classification and lymph node metastasis. Following shRNA-Nrf2 transfection, the 786-0 cells demonstrated a significant decrease in viability, cell invasion and scratch healing rate, and the mRNA and protein expression levels of Nrf2, NQO1, HO-1 and glutathione transferase were significantly decreased, which enhanced the sensitivity to sunitinib, arrested cells in the G0/G1 phase and increased apoptosis. In conclusion, Nrf2-ARE signaling is important for RCC progression, and its inhibition may increase sensitivity to targeted drugs to provide novel developments for RCC treatment.

PT311 - Overexpression of miR-15b promotes resistance to sunitinib in renal cell carcinoma

PT311 - Overexpression of miR-15b promotes resistance to sunitinib in renal cell carcinoma

Neoadjuvant Sunitinib Decreases Inferior Vena Caval Thrombus Size and Is Associated With Improved Oncologic Outcomes: A Multicenter Comparative Analysis.

We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P= .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P= .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P= .351), and no differences were noted in complications (P= .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio= 3.28; P= .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P= .023) for neoadjuvant sunitinib. Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.

Overexpression of miR-15b Promotes Resistance to Sunitinib in Renal Cell Carcinoma.

Aim: Sunitinib remains the frontline treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Drug resistance is inevitable and related mechanism warrant insightful elaboration.Methods: In silico data mining of GEO and TCGA datasets was performed to identify potential target micro-RNA. In vitro and in vivo studies were performed to validate findings.Results: Reproduction of GEO datasets revealed miR-15b significantly upregulated in sunitinib- resistant ccRCC. Five out of seven ccRCC cell lines demonstrated significantly overexpressed miR-15b after sunitinib treatment. Vector-mediated overexpression of miR-15b significantly induced resistance to sunitinib in ccRCC cells. Overexpression of miR-15b significantly induced less population in G1 phase of cell cycle and less apoptosis in cells treated sunitinib. Expression of genes negatively correlated with miR-15b in TCGA ccRCC (KIRC) dataset were cross-referenced with predicted targets of miR-15b and CCNC was selected as potential target for resistance mediation. Overexpression of miR-15b suppressed CCNC expression and protein (Cyclin C) levels. Cyclin C-associated proteins CDK19 and CDK8 were also suppressed following miR-15b overexpression. Silencing of CCNC mimicked overexpression of miR-25 inducing cell cycle progression passing G1 phase and less apoptosis in ccRCC cells treated by sunitinib. Overexpression of miR-15b also counteracted suppression of migration and colony formation by sunitinib in ccRCC cell lines. In vivo mouse xenograft models showed recovered tumor growth with miR-15b expression in mice treated with sunitinib.Conclusion: We here show miR-15b as a possible culprit for sunitinib resistance in ccRCC. Targeting miR-15b could potentially overcome drug resistance and related mechanism warrants further investigation.

A systematic review of non-standard dosing of oral anticancer therapies

BackgroundThe use of oral systemic anticancer therapies (SACT) has increased and led to improved cancer survival outcomes, particularly with the introduction of small molecule targeted agents and immunomodulators. Oral targeted SACT are, however, associated with toxicities, which might result in reduced quality of life and non-adherence. To reduce treatment-related toxicity, the practice of non-standard dosing is increasing; however guidance to govern this practice is limited. A systematic review was conducted to identify evidence of, and outcomes from, non-standard dosing of oral SACT in oncology and malignant haematology.MethodsA comprehensive search of 78 oral SACT was conducted in the following databases: MEDLINE®, EMBASE®, Cochrane Library©, and Cumulative Index to Nursing and Allied Health Literature (CINAHL©). Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings. Due to diversity of study designs and heterogeneity of reported outcomes, studies were categorised and evidence was synthesised in three main themes: dose interruption; dose reduction; and other dosing strategies.ResultsThirty-four studies were eligible for inclusion: four clinical trials, fifteen cohort studies and fifteen case reports. Evidence for non-standard dosing was reported for eleven oral SACT. Dose interruptions were the most commonly reported strategy (14 studies); nine studies reported dose reductions; and eleven reported other dosing strategies. Eight retrospective cohort studies reported dose interruption of sunitinib in renal cell carcinoma and showed either similar or improved responses and survival outcomes, and fewer or equivalent high grade toxicities, compared to the standard schedule. Four cohort studies retrospectively evaluated dose reductions of imatinib, gefitinib or erlotinib, for chronic myeloid leukaemia and non-small cell lung cancer, respectively. Other dosing strategies included alternate-day dosing. The quality of the evidence was limited by the small sample size in many studies, retrospective study designs, and lack of reported toxicity and/or QoL outcomes.ConclusionsThis review identified limited evidence to support current non-standard dosing strategies, but some of findings, e.g. dose interruption of sunitinib, warrant further investigation in large-scale prospective clinical trials.

An Attempt to Quantitate "Value" In Medical Oncologic Therapy.

ObjectiveWe wanted to examine the incremental cost-effective ratio (ICER) for a variety of Food and Drug Administration (FDA) approved oncology drugs in the adjuvant or curative setting to determine the value provided.DesignWe examined the annualized incremental drug costs of a variety of FDA approved chemotherapeutic drugs used in an adjuvant or curative setting based on National Comprehensive Cancer Network (NCCN) category 1 practice guidelines for melanoma, Her2/neu over-expressive breast cancer, renal cell carcinoma, stage IIIA non-small cell lung cancer, myeloma, B cell lymphoma, and Hodgkin lymphoma. The studies we examined were randomized clinical trials on which the NCCN guidelines are based; we solely examined the incremental cost-effectiveness of the trial drug as we assumed that the costs of the health care provided were equivalent between the two treatment arms. We used a formula to determine the incremental cost-effectiveness ratio (ICER). The ICER compares a new intervention (C new) with its alternate (C alt) divided by the quality-adjusted life-years (QALY) that results from the new intervention (QALY new) versus the alternate (QALY alt) and is expressed as ICER = (C new-C alt)/(QALY new-QALY alt). The QALY’s were derived from what was reported in the study and based on the incremental disease-free survival.ResultsDrugs such as rituximab provide high value in the curative therapy for lymphoma. Drugs such as adjuvant dabrafenib and trametinib provide intermediate value in the treatment of melanoma, and similarly with maintenance lenalidomide in myeloma and adjuvant trastuzumab in breast cancer. Oncologic drugs that provide low value include adjuvant ipilimumab in melanoma, adjuvant sunitinib in renal cell carcinoma, adjuvant neratinib in breast cancer, adjuvant durvalumab in lung cancer, and brentuximab in the curative therapy for Hodgkin’s lymphoma.ConclusionThe ICER needs to be evaluated for newly approved FDA oncology chemotherapeutic drugs before incorporating them into routine clinical practice.

MP72-02 METABOLISM RE-PROGRAMMING AS A THERAPEUTIC TARGET FOR DRUG RESISTANT RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II1 Apr 2018MP72-02 METABOLISM RE-PROGRAMMING AS A THERAPEUTIC TARGET FOR DRUG RESISTANT RENAL CELL CARCINOMA Hirofumi Yoshino, Kazutaka Miyamoto, Masaya Yonemori, Satoru Sugita, Takashi Sakaguchi, Hideki Enokida, and Masayuki Nakagawa Hirofumi YoshinoHirofumi Yoshino More articles by this author , Kazutaka MiyamotoKazutaka Miyamoto More articles by this author , Masaya YonemoriMasaya Yonemori More articles by this author , Satoru SugitaSatoru Sugita More articles by this author , Takashi SakaguchiTakashi Sakaguchi More articles by this author , Hideki EnokidaHideki Enokida More articles by this author , and Masayuki NakagawaMasayuki Nakagawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2286AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It has been revealed that metabolism re-programming, such as Warburg effect, occurs in cancer cells. Recently, it was reported that anti-tumor effects of a HIF2a antagonist was greatly exceeded that of sunitinib in renal cell carcinoma (RCC) (Nature, 2016). However, drug-resistant acquisition will be a future problem. In this study, we aimed to elucidate the mechanism and conquest of drug resistant acquisition regarding HIF2a based on metabolism re-programming. METHODS First, we established a sunitinib-resistant RCC cell line (SU-R-786-o) in vivo by oral gavage treatment, followed by the establishment of HIF2a knockout cell line (HIF2a-KO-SU-R-786-o) by CRISPR/Cas9. We performed omics analyses using these cells. By using new inhibitors of phosphoglycerate dehydrogenase (PHGDH), which was selected as a candidate gene for drug resistance by omics analyses, we performed proliferation and apoptosis assay in vitro, and a xenograft assay. PHGDH-overexpressed cells by lentiviral vector were subjected to a colony formation assay. We also performed statistical analyses based on TCGA database of RCC patients. RESULTS SU-R-786-o showed significant sunitinib resistance both in vitro and in vivo. The expression of known HIF2a target genes was markedly suppressed in HIF2a-KO-SU-R-786-o. HIF2a-KO-SU-R-786-o significantly reduced cell proliferation compared to control cells, but it still survived, probably due to accelerated alternative pathways. Metabolomics analysis showed that metabolites were clearly divided among 786-o, SU-R-786-o, and HIF2a-KO-SU-R-786-o, and that serine biosynthesis was significantly activated in HIF2a-KO-SU-R-786-o. In addition, RNA sequence and quantitative proteome analyses showed that PHGDH, a key enzyme for serine synthesis, was accelerated in HIF2a-KO-SU-R-786-o. PHGDH inhibitor reduced cell growth in vivo and in vitro by inducing apoptosis in HIF2a-KO-SU-R-786-o more than in parent cells. Whereas, PHGDH overexpressed cells exhibited a significant increase in colony numbers compared to parent cells. TCGA database showed that patients with PHGDH gene amplification (n = 24) had poor overall survival (P = 0.0003) compared to patients without amplification (n = 500). CONCLUSIONS Metabolism re-programming occurred in drug-resistant RCCs. In addition, PHGDH can be a therapeutic target for patients showing activated serine biosynthesis after HIF2a deficiency. Furthermore, PHGDH inhibitor should be considered as a first treatment in patients with PHGDH amplification. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e952 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Hirofumi Yoshino More articles by this author Kazutaka Miyamoto More articles by this author Masaya Yonemori More articles by this author Satoru Sugita More articles by this author Takashi Sakaguchi More articles by this author Hideki Enokida More articles by this author Masayuki Nakagawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Adjuvant Sunitinib for Renal Cell Carcinoma: Still at the Beginning of the Road

Adjuvant Sunitinib for Renal Cell Carcinoma: Still at the Beginning of the Road

Phase II study of sequential first-line pazopanib (PAZ) followed by everolimus (EVE) in patients (pts) with advanced or metastatic renal cell carcinoma (RCC) (CATChEz Study).

648 Background: EVE following failure of sorafenib or sunitinib for RCC was first approved by the FDA in 2009. CATChEz (NCT01545817) was designed to test the activity of EVE following first-line PAZ in pts with advanced or metastatic RCC who had not received prior systemic therapy. Methods: From 2012 to 2016, pts received first-line PAZ followed by EVE until progressive disease (PD), death, unacceptable toxicity, consent withdrawal, or study termination. Pts with PD during or within 6 months of stopping PAZ were eligible for EVE. Pts off study treatment were evaluated for PD, survival, and updates on anticancer treatment every 8 weeks until death or end of study. The primary efficacy endpoint was median progression-free survival (mPFS) for the second-line EVE treatment period; secondary endpoints included other survival measures, and safety evaluations were for second-line EVE and grade 3/4 toxicities attributable to PAZ and EVE. Results: Of 74 pts who started first-line PAZ, 38 received ≥1 dose of second-line EVE. The primary endpoint of mPFS from the start of second-line EVE and the secondary endpoint of mPFS with first-line PAZ (Table) were consistent with previous reports; no unexpected adverse events (AEs) were reported. All pts had ≥1 treatment-emergent AE, 83.8% had grade ≥3 AEs, and 71.6% had serious AEs. Of 34 total deaths, 29 were due to PD and 5 were due to AEs (2 related to EVE [lower respiratory tract infection; pulmonary sepsis]; 3 unrelated to study treatment). Conclusions: Efficacy and safety outcomes were consistent with published phase III data. The CATChEz study supports sequential first-line use of PAZ followed by EVE for the treatment of pts with advanced or metastatic RCC. Clinical trial information: NCT01545817. [Table: see text]

Monitoring the Vascular Response and Resistance to Sunitinib in Renal Cell Carcinoma In Vivo with Susceptibility Contrast MRI.

Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P < 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P < 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P < 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P < 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume. Cancer Res; 77(15); 4127-34. ©2017 AACR.

An evaluation of abemaciclib activity in combination with sunitinib in renal cell carcinoma.

452 Background: The majority of therapeutic agents used in renal cell carcinoma (RCC) target the vascular endothelial growth factor and mammalian target of rapamycin pathway. Exceptions include the immunotherapy agents interleukin-2 and nivolumab. To change the natural history of RCC and improve upon current treatment regimens we believe new therapeutic targets are necessary. CDK4/6 and PIM1 kinase have both been identified as possible therapeutic targets in RCC. Abemaciclib is a potent inhibitor of both CDK4/6 and PIM1 kinases. We have demonstrated that abemaciclib causes increased apoptosis and decreased cellular viability in RCC cell lines and tumor responses in mice (submitted). Here we report the results of an additional pre-clinical study of the effects of abemaciclib alone and in combination with sunitinib. Methods: Tumors were established in nude mice by subcutaneous flank injection of 786-O cells. Tumors were allowed to establish and grow to about 1 cm. Mice were treated by oral gavage with vehicle, sunitinib, abemaciclib, or combination. Tumors were measured with calipers to determine response. Mice that received sunitinib were subsequently treated with combination therapy and response determined by caliper measurement. At the conclusion of the course of treatment mice were euthanized and the tumors removed, weighed, fixed, and embedded in paraffin. Results: Mice treated with vehicle had continued tumor growth during the course of therapy. Mice treated with sunitinib showed mostly disease stabilization, paralleling the response seen in clinic. Mice in the abemaciclib cohort showed gradual decline in tumor size over the course of treatment. Mice in the combination therapy cohort exhibited a rapid reduction in tumor size with sustained response. Interestingly mice in the sunitinib cohort experiencing stable disease or growing tumor had rapid decrease in tumor size with the initiation of combination therapy. Conclusions: Abemaciclib is active in a mouse model of RCC. The combination of abemaciclib/sunitinib causes rapid reduction in tumor size in treatment naïve and sunitinib pre-treated mice. These data support the use of combination abemaciclib/sunitinib therapy in a human clinical trial.