Combination Of Sunitinib Research Articles

Syringin as a novel therapeutic agent for renal cell carcinoma by targeting EGFR/PI3K/Akt pathway and enhancing sunitinib efficacy

Syringin, a natural bioactive compound extracted from Acanthopanax senticosus, has demonstrated potential therapeutic value in cancer treatment. However, its efficacy in treating renal cell carcinoma (RCC) remains unexplored. This study aims to investigate the therapeutic effects and underlying mechanisms of Syringin in RCC. In this study, network pharmacology, molecular docking validation, and bioinformatics were employed to predict the mechanisms by which Syringin affects RCC. In vitro experiments showed that Syringin inhibited RCC cell viability and reduced the IC50 of Sunitinib, enhancing its therapeutic effect. Syringin also inhibited RCC cell proliferation and migration and promoted apoptosis. The combination of Syringin and Sunitinib demonstrated an enhanced inhibitory effect. Western blot analysis confirmed that Syringin’s anti-RCC effects are mediated through the EGFR/PI3K/Akt pathway. In conclusion, our findings indicate that Syringin exhibits inhibitory effects on RCC cells and enhances their sensitivity to Sunitinib, offering a novel approach to exploring treatment strategies for Sunitinib-resistant RCC.

Hyaluronic acid-functionalized MOFs for combined sunitinib and siRNA therapy in renal cell carcinoma

Sunitinib is a first-line treatment for renal cell carcinoma (RCC), but suffers from drug resistance, causing therapy failure. Therefore, nano-scale delivery systems should be introduced for targeted delivery. Metal-organic frameworks (MOFs) are attractive drug carriers that not only enable multidrug combination therapies but also exert photodynamic effects by incorporating photosensitizers as components. Here, a Zr-based porphyrinic nanoscale MOF, PCN-224, was prepared as the carrier for the co-delivery of sunitinib and the siRNA against vascular endothelial growth factor receptor-2 (VEGFR-2). Drug-loaded PCN-224 is coated with hyaluronic acid (HA) to prevent drug molecular leakage and to exert tumor-targeting effects (CD44 in tumor cells). Photodynamic therapy was conducted under 660 nm laser (50 mW·cm−2, 10 min) irradiation. Compared with St/siVEGFR-2@PCN-224@HA without the HA coating, St/siVEGFR-2@PCN-224@HA significantly suppressed cell viability and promoted cell apoptosis. Laser irradiation further increased the anti-cancer effect of St/siVEGFR-2@PCN-224@HA by generating cytotoxic ROS. H&E staining of major organs revealed no signs of damage, indicating the biosafety of St/siVEGFR-2@PCN-224@HA. The prepared St/siVEGFR-2@PCN-224@HA system enables triple inhibition of tumor growth via a combination of targeted therapy and genetic and photodynamic therapy to enhance the therapeutic effects on RCC.

Effect of Sunitinib in the Management of Lung Cancer: A Systematic Review of Clinical Trials

Introduction Lung cancer is the most common cancer in terms of both incidence and mortality. Although usually managed with surgery, novel immunotherapies are gradually becoming more popular. The effect of sunitinib with and without erlotinib in the management of lung cancer is reviewed. Methods Eligible search engines and databases were screened to identify studies published in English. Any randomized clinical trials studying the effect of sunitinib, either alone or in combination with erlotinib, were included. Results Thirteen studies with a total sample size of 1,062 cases were included. Males (59.5%) were more common than females (40.5%), and the average age of patients was 64 ± 5.03. Most of the patients (71.5%) had a positive smoking status, and non-small cell carcinoma was the most common lung cancer type (95.4%). Almost all of the adverse events, such as headache (100%), weight loss (100%), constipation (100%), leukocytopenia (96%), pain (92.3%), hypertension (90%), dyspnea (88.7%), cough (84.3%), fatigue (81.6%), fever/chills (77.3%), thrombocytopenia (75%), nausea (73.8%), neutropenia (72%), anorexia (71.4%), vomiting (65.1%), anemia (61.3%), and diarrhea (54.5%) were more common in the sunitinib-only group. The mean overall survival for patients receiving sunitinib alone was 213 days, whereas, for patients receiving sunitinib combined with erlotinib, it was 270 days. Conclusion Adverse events may be encountered more frequently in treatment with sunitinib alone compared to the combination of sunitinib and erlotinib. However, sunitinib alone may result in higher disease stability and lower disease progression. Nevertheless, combination therapy may yield a longer median overall survival.

The effects of Gualou Qumai Wan combined with Sunitinib on VEGFA, HIF1A, and renal function in advanced clear cell renal cell carcinoma

[Objective:] To study the efficacy of Gualou Qumai Wan (GQW) combined with Sunitinib in the treatment of advanced clear cell renal cell carcinoma (ccRCC) and its effects on vascular endothelial growth factor A (VEGFA), hypoxia inducible factor 1A (HIF1A), and renal function. [Method:] A retrospective analysis was conducted on 20 patients with advanced ccRCC treated with GQW combined with Sunitinib at Shouguang Hospital of Traditional Chinese Medicine from January 2021 to January 2023. Analyze the patient's quality of life, serum VEGFA and HIF1A levels, renal function indicators, T lymphocyte subgroup levels, traditional Chinese medicine (TCM) symptom scores, and clinical efficacy. [Result:] The total effective rate of clinical efficacy in patients after treatment was 70%; The serum levels of VEGFA and HIF1A in patients were lower than before treatment, and the difference was statistically significant (P<0.05); The levels of serum creatinine (Scr), blood urea nitrogen (BUN), and urinary albumin (ALB) in patients were lower than before treatment, and the differences were statistically significant (P<0.05). Before and after treatment, there was no statistically significant difference in the levels of T lymphocyte subgroup among patients (P>0.05). After treatment, the TCM symptom score and EORTC QoL-C30 score of the patients all decreased compared to before treatment, and the difference was statistically significant (P<0.01). [Conclusion:] The combination of GQW and Sunitinib has a significant therapeutic effect on advanced ccRCC, and can effectively improve the levels of VEGFA, HIF1A, and renal function.

Venetoclax Synergizes Sunitinib in Renal Cell Carcincoma through Inhibition of Bcl-2.

More effective treatment options for patients with renal cell carcinoma (RCC) are needed, in particular advanced RCC. Sunitinib, a multitarget tyrosine kinase inhibitor, is a first-line treatment of metastatic RCC. However, the management of sunitinib-induced adverse events and resistance is complex. In hematological malignancies, effective targeting of anti-apoptotic proteins such as Bcl-2 has been achieved, but limited progress has been made in solid tumors. This work systematically investigated the therapeutic potential of the combination of sunitinib and venetoclax, a Bcl-2 inhibitor, in preclinical RCC models. Quantitative analysis of drug interactions was performed. Cell viability was examined after drug treatment or Bcl-2 siRNA depletion. RCC xenograft mouse model was applied to validate the efficacy of sunitinib and venetoclax. A strong synergistic interaction between sunitinib and venetoclax was observed across a range of different dose levels in all tested RCC cell lines. Sequential treatment studies show that the sequential addition of venetoclax and then sunitinib is superior to concurrent treatment and the sequential addition of sunitinib and then venetoclax in decreasing RCC cell viability. The sensitivity of RCC cell lines to venetoclax treatment negatively correlates with their Bcl-2 levels. Specific depletion of Bcl-2 mimics the synergistic effects of venetoclax with sunitinib. Treatment of mice implanted with high Bcl-2-expressing RCC cells reveals that a combination of venetoclax and sunitinib at a non-toxic dose displays complete regression of tumor growth throughout the whole duration of treatment. Our work demonstrates that inhibiting Bcl-2 by venetoclax synergistically enhances sunitinib's efficacy in RCC. Venetoclax holds great potential as a viable option for clinical use.

Abstract 4811: Oxygen tension - dependent differences in cancer cell kinome

Abstract Current approaches to preclinical cancer research often fail to consider the impact of ambient oxygen (O2; ~21%) on cancer cells. This is also true for hypoxia studies that typically involves cancer cells previously grown in ambient O2 before subsequent transfer to hypoxia. However, the tumor microenvironment is characterized by significantly lower O2 levels. We have previously demonstrated the impact of ambient O2 on stem cell populations, signaling pathways and resistance to therapy. We developed an experimental approach that allows us to collect and process tumor tissues from transgenic mammary tumor mouse models and ovarian cancer patients under physioxia (3% O2), such that they are never exposed to ambient O2. In this study, our goal was to explore oxygen-dependent signaling pathway alterations and to determine how these pathways are influenced by targeted drugs in the context of physioxia or ambient air (AA). Our studies revealed increased basal phosphorylation levels of EGFR (Y1068) in the tumor cells in AA, relative to physioxia. However, downstream signaling effectors AKT and ERK showed higher phosphorylation levels under physioxia, compared to AA, suggesting that their activation is independent of EGFR signaling. These findings correlate with the decreased sensitivity of the tumor cells under physioxia to target drugs lapatinib and alpelisib. We then sought to examine basal and target drug induced kinome changes in tumor cells under physioxia and AA via Multiplexed Inhibitor Beads (MIBs) kinome assay. This assay revealed significant differences in the kinome of the tumor cells under physioxia compared to AA. Although direct comparison between vehicle and lapatinib treated cells in physioxia and ambient air showed very minimal changes, pairwise comparison between lapatinib treated physioxia cells and vehicle treated AA cells revealed an increase in the activity of PDGFRB in lapatinib treated physioxia cells. Similarly, a receptor tyrosine kinase (RTK) array and western blotting showed increased basal and lapatinib induced phosphorylation of PDGFRB (Y751) under physioxia. Next, we determined the potential role of PDGFRB in downstream signaling pathway activation of AKT and ERK and resistance to lapatinib. We found that sunitinib, a multitarget RTK inhibitor with high affinity for PDGFR effectively decreased PGDFRB activity under physioxia, with a concurrent decrease in the phosphorylation of AKT. Moreover, tumor cells under physioxia were more sensitive to sunitinib treatment, relative to ambient air. Furthermore, a combination of lapatinib and sunitinib rendered tumor cells under physioxia more sensitive to treatment than with lapatinib alone. These findings suggest that ambient and physioxic oxygen tensions differentially impact cancer relevant signaling pathways. Therefore, it may be necessary to carry out preclinical cancer studies in the context of physiologically relevant oxygen tensions to aid translatability. Citation Format: Adedeji K. Adebayo, Brijesh Kumar, Christopher Davis, Steven P. Angus, Harikrishna Nakshatri. Oxygen tension - dependent differences in cancer cell kinome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4811.

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors.

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.

Cannabidiol Enhances Sunitinib Effect in Human Renal Cell Carcinoma by Inducing Apoptosis and Inhibiting Stat3 Signaling Pathway

Background: Renal cell carcinoma (RCC) is considered to be the most frequent form of kidney cancer affecting both men and women worldwide. Monotherapy is not always effective and often results in resistance. Aim: To evaluate cannabidiol and sunitinib combination in human RCC using 786-O cells as an in vitro model. Study Design: Experimental study Place and duration of study: Dow International Medical College, Karachi from 15th November 2021 to 14th May 2022. Methodology: 786-O cells were culture and treated with sunitinib, cannabidiol and the combination of both and the growth inhibition was evaluated using MTT assay, while cell apoptosis was determine using flowcytometry. qPCR was used to analyze the expression of apoptotic genes and STAT3 in sunitinib and cannabidiol treated cells. Results: Sunitinib, cannabidiol and the combination of both drugs showed a dose dependent inhibition on growth of 786-O cells (p <0.001). The rate of apoptosis was 14.4% and 24.3% when treated with cannabidiol and sunitinib respectively. When the two drugs were combined, apoptosis was significantly increased to 50.3% (p <0.001). qPCR showed that cannabidiol enhanced sunitinib induced apoptosis by downregulating anti-apoptotic gene (Bcl-2) and upregulating pro-apoptotic gene (caspase-3 and -9) (p <0.001). Practical Implication Using single drug for treating RCC is not always effective and often results in resistance. Our study suggests that cannabidiol in combination with sunitinib may be a preferable chemotherapeutic option for treatment of RCC. Conclusion: Cannabidiol enhances sunitinib effect in inhibiting RCC and their combination achieved more strong inhibition than either drug alone. Keywords: Cannabidiol, Renal cell carcinoma, Sunitinib, Apoptosis, STAT3, qPCR

A Phase II Trial of Concurrent Sunitinib, Temozolomide and Radiation Therapy Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients with an Unmethylated MGMT Gene Promoter

<h3>Purpose/Objective(s)</h3> Despite advances in treatment modalities, the overall prognosis of Glioblastoma remains dismal, particularly for patients with unmethylated MGMT promoter. In this phase II trial, we tested for the first time the combination of Sunitinib with radiotherapy and Temozolomide in newly diagnosed MGMT unmethylated Glioblastoma patients. We hypothesized that this combination therapy would be safe and yield superior survival outcomes than the current standard of care for MGMT unmethylated Glioblastoma patients. <h3>Materials/Methods</h3> 37 patients diagnosed with WHO-Grade IV Glioblastoma and unmethylated MGMT promoter, age 18-70 and KPS ≥70 were eligible from two institutions. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent chemoradiation and 12.5 mg Sunitinib x6 weeks, then adjuvant Temozolomide x6 cycles. Primary objective was progression-free-survival (PFS) as per RANO criteria, secondary objectives were overall survival (OS), safety and Neutrophil-to-Lymphocyte ratio (NLR). <h3>Results</h3> Median follow-up time was 15.3 months (95% CI: 13.8-19.4). Median PFS was 7.15 months (95% CI: 5.4-10.5 months) and 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4 months) and 2-year OS was 17.1%. Having received >3 cycles of adjuvant Temozolomide and surgery at progression significantly predicted for better OS with hazard ratios of 0.32 (p=0.017) and 0.46 (p=0.049) respectively, whereas age >65 and post-treatment NLR>6 predicted for worse OS with hazard ratios of 3.92 (p=0.037) and 2.64 (p = 0.021) respectively. Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20% and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events. <h3>Conclusion</h3> Addition of Sunitinib to RT and Temozolomide was safe and survival outcomes are promising compared to the standard of care for GBM patients with unmethylated MGMT promoter status.

The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases.

Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRβ expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRβ was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRβ in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRβ immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRβ on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRβ activity after the discontinuation of denosumab treatmeant and the increased PDGFRβ activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.

Risk assessment and molecular mechanism study of drug-drug interactions between rivaroxaban and tyrosine kinase inhibitors mediated by CYP2J2/3A4 and BCRP/P-gp.

Cancer patients generally has a high risk of thrombotic diseases. However, anticoagulant therapy always aggravates bleeding risks. Rivaroxaban is one of the most widely used direct oral anticoagulants, which is used as anticoagulant treatment or prophylaxis in clinical practice. The present study aimed to systemically estimate the combination safety of rivaroxaban with tyrosine kinase inhibitors (TKIs) based on human cytochrome P450 (CYPs) and efflux transporters and to explore the drug–drug interaction (DDI) mechanisms in vivo and in vitro. In vivo pharmacokinetic experiments and in vitro enzyme incubation assays and bidirectional transport studies were conducted. Imatinib significantly increased the rivaroxaban Cmax value by 90.43% (p < 0.05) and the area under the curve value by 119.96% (p < 0.01) by inhibiting CYP2J2- and CYP3A4-mediated metabolism and breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated efflux transportation in the absorption phase. In contrast, the combination of sunitinib with rivaroxaban reduced the exposure in vivo by 62.32% (p < 0.05) and the Cmax value by 72.56% (p < 0.05). In addition, gefitinib potently inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism with Ki values of 2.99 μΜ and 4.91 μΜ, respectively; however, it almost did not affect the pharmacokinetics of rivaroxaban in vivo. Taken together, clinically significant DDIs were observed in the combinations of rivaroxaban with imatinib and sunitinib. Imatinib increased the bleeding risks of rivaroxaban, while sunitinib had a risk of reducing therapy efficiency. Therefore, more attention should be paid to aviod harmful DDIs in the combinations of rivaroxaban with TKIs.

Combination of sunitinib and 177Lu-labeled antibody cG250 targeted radioimmunotherapy: A promising new therapeutic strategy for patients with advanced renal cell cancer

Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT).We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/cnu/nu mice combining sunitinib and [177Lu]Lu-cG250 RIT (6.5 MBq/10 μg), specifically targeting RCC cells.pAXL and pMET were expressed in sunitinib-resistant SK-RC-52 and absent in sunitinib-sensitive NU12. NGS evaluation showed that expression of VEGFA, VEGFB, VEGFD, PGF and VEGFR1,2,3 was higher and expression of VEGFC and PDGFA was lower in NU12 than in SK-RC-52.Therapy studies combining sunitinib with [177Lu]Lu-cG250 RIT showed that the best response in mice with “resistant” SK-RC-52 tumors was observed with two cycles of Sunitinib and [177Lu]Lu-cG250 RIT, probably due to increased vascular permeability by sunitinib treatment. In the “sensitive” NU12 model, two cycles of [177Lu]Lu-cG250 RIT and two cycles of combination treatment were equally effective.Enhanced therapeutic efficacy was achieved when two agents ([177Lu]Lu-cG250 RIT and sunitinib) that on their own did not induce satisfactory response levels, are combined. Our findings provide a promising new therapeutic strategy for patients with advanced RCC.

Randomized phase II study of adjuvant sunitinib or valproic acid in high-risk patients with uveal melanoma: The final analysis of cohort 1.

9586 Background: Despite successful treatment of primary uveal melanoma (UM), tumors with monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 have high metastatic death rates. We report the final analysis of Cohort 1 in the randomized phase II clinical trial of 6 months of adjuvant sunitinib or valproic acid (VPA) in high-risk UM patients. Methods: High risk for systemic metastasis was defined as the following: A) M3 + 8q amp; B) Class 2. Patients within 6 months of initial treatment of primary UM were randomized 1:1 to receive either sunitinib 25 mg daily or VPA 750 mg daily for 6 consecutive months. The primary endpoint was to evaluate the improvement of 2-year overall survival (OS) rate from 70% (historical references) to 85% in each arm. Secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. Results: Eighty-eight patients were included in the final analysis. There were no differences in tumor size or T stage between the two treatment arms. Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). All but 9 patients (death due to metastasis, sunitinib n =4, VPA n = 5) were followed for at least 2 years. With a median follow-up of 52.6 months, both drugs met the primary end point with 2-year OS rates of 95.6% (sunitinib, 90% CI 86.5-98.6%) and 90.7% (VPA, 90% CI 80.1-95.8%). The 18-month RFS rates were 75.6% (sunitinib, 90% CI 63.1-84.3%) and 62.8% (VPA, 90% CI 49.4-73.5%). Although not statistically significant, there was a trend of superior RFS with sunitinib over VPA in primary UM with T-stage 3-4 (p=0.131) or &gt;12mm (p=0.129). There was no significant difference in median RFS in HLA-A*02:01 positive or negative status (24.6 vs. 24.8 months). It is of note that the potential survival benefit of sunitinib over VPA diminished after 3 years, indicating longer duration of sunitinib administration might be required. In the multivariable Cox analysis, the RFS was not significantly different in the two treatment arms, but increase of tumor diameter was associated with increase hazard of progression (HR=1.23, 95% CI: 1.13, 1.33; p&lt;0.001). Conclusions: Six months of adjuvant sunitinib or VPA resulted in 2-year OS of 95.6% and 90.7%, respectively, meeting the primary endpoint of the study. Sunitinib showed a tendency for a better outcome until 3 years after randomization, thus Cohort 2 was created to investigate the safety and prolonged improvement of RFS and OS with 12 months of sunitinib. Additionally, Cohort 3 with adjuvant sunitinib in combination with VPA for 12 months is currently ongoing. The size of primary tumor influenced the survival and should be adjusted for future adjuvant studies. Clinical trial information: NCT02068586.

Prognostic value of EZH2 expression for immunotherapy-based schemes in advanced soft-tissue sarcoma: A translational research from Spanish Group of Research on Sarcoma (GEIS).

11549 Background: Immunotherapy-based treatments had shown to be active in several solid tumors, including in selected subtypes of sarcomas. IMMUNOSARC (NCT03277924) is a phase Ib/II trial [from Spanish (GEIS) and Italian (ISG) sarcoma groups], that tested the combination of nivolumab (anti-PD-1 inhibitor) plus sunitinib (anti-angiogenic agent) in advanced sarcomas. Among the 65 soft-tissue sarcoma (STS) patients (pts) enrolled, 48% were free of progression at 6 months, meeting the trial’s primary endpoint. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 and it has been described to play an important role in the transcriptional repression of genes involved in T-cell migration and T-cell-mediated anti-tumor activity. The aim of this study was to explore the value of EZH2 gene expression as potential prognostic biomarker of the activity of immunotherapy-based schemes. Methods: The expression of EZH2 was evaluated in 64 paraffin tumor blocks, by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Data was normalized with DESeq2 and the cut-off of EZH2 expression was calculated with MAXSTAT R package. Gene expression was correlated with progression-free survival (PFS) by RECIST, overall survival (OS) and clinical benefit (patients with response or stable disease vs patients with progressive disease as best response). Results: Among the 64 pts analyzed, 52 (81%) showed overexpression of EZH2, considering a cut-off of 570.15 read counts. Undifferentiated pleomorphic sarcoma (UPS) and epithelioid sarcoma were the subtypes with higher expression of EZH2 with a median of read counts of 1888.04 (n = 10) and 1261.79 (n = 7), respectively. The lowest expressions were observed in extraskeletal myxoid chondrosarcoma (ECM) and alveolar soft-part sarcoma (ASPS) with a median of read counts of 461.42 (n = 4) and 680.84 (n = 7), respectively. Low expression of EZH2 was associated with better PFS (16.8 months vs. 3.9 months; p = 0.001) and better OS (NR vs. 20.0 months; p = 0.006). Moreover, low expression of EZH2 was also significantly associated with a clinical benefit of the patients treated with nivolumab plus sunitinib [relative risk (RR): 13; 95% CI: 3.0-56.9; p = &lt; 0.001). Conclusions: Low expression of EZH2 was associated with better outcome in advanced STS patients treated with immunotherapy-based schemes. These results might support the rationale for the combination of EZH2 inhibitors with immune-modulating agents for future studies.

Dual-Functional Polymeric Micelles Co-Loaded with Antineoplastic Drugs and Tyrosine Kinase Inhibitor for Combination Therapy in Colorectal Cancer.

The aim of this research was to evaluate the receptor tyrosine kinase inhibitor Sunitinib combined with SN-38 in polymeric micelles for antitumor efficacy in colorectal cancer. First, SN-38 and Sunitinib co-loaded micelles were developed and characterized. We studied cell viability and cellular uptake in HCT-116 cells. Then, subcutaneous HCT-116 xenograft tumors were used for ex vivo biodistribution, antitumor efficacy, and histochemical analysis studies. Results of cellular uptake and ex vivo biodistribution of SN-38/Sunitinib micelles showed the highest accumulation in tumors compared with other normal organs. In the antitumor effect studies, mice bearing HCT-116 tumors were smallest at day 28 after injection of SN-38/Sunitinib micelles, compared with other experiment groups (p < 0.01). As demonstrated by the results of inhibition on multi-receptors by Sunitinib, we confirmed that SN-38/Sunitinib co-loaded micelles to be a treatment modality that could inhibit VEGF and PDGF receptors and enhance the antitumor effect of SN-38 (p < 0.05). In summary, we consider that this micelle is a potential formulation for the combination of SN-38 and Sunitinib in the treatment of colorectal cancer.

Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types

The efficacy/safety of combining palbociclib (a CDK4/6 inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) was evaluated, using patient-derived xenograft (PDX) models. Twenty-three PDX mice models were developed from patients with various solid tumors. The mice were randomized to 4 groups (5–6 mice in each): control/palbociclib (100 mg/kg)/sunitinib (50 mg/kg)/combination. Drugs were administered orally, 5 days/week. In 17/23 PDX models (74%), the combination demonstrated a synergistic inhibitory effect vs the monotherapies (“responder” models) with no unexpected toxicities. In 13/17 responder models, where standard-of-care (SOC) was an additional comparator, the combination was more effective than SOC in 7 models, as effective in 4, and less effective in 2. The mean ± SEM experiment duration in 15/17 responder models (2/17 were excluded due to technical issues) was 86 ± 12 and 31 ± 5 days for the combination and control groups, respectively (p = 0.0002). The effect of the combination was dose-dependent. Cell-viability experiments in A549/MDA-MB-231/HT-29 cell lines and experiments using tumor-derived primary cell spheroids supported the PDX findings. In conclusion, combination of palbociclib and sunitinib exerts a synergistic anti-tumor effect without adding unexpected toxicity. A clinical trial assessing this combination is underway.

SYST-08. A phase II trial of concurrent Sunitinib, Temozolomide and Radiation Therapy followed by adjuvant Temozolomide for newly diagnosed Glioblastoma patients with an unmethylated MGMT gene promoter (A01-M121-11A, McG1132)

INTRODUCTIONDespite advances in treatment modalities, the overall prognosis of GBM remains dismal, particularly for patients with unmethylated MGMT promoter. Thus, alternative treatment strategies are warranted. Our group has previously shown that addition of Sunitinib (SU11248) to standard therapy significantly improved the response of unmethylated MGMT cells through decreased angiogenicity and tumorigenicity. In this phase II trial, we tested for the first time the combination of Sunitinib with RT and Temozolomide in newly diagnosed MGMT unmethylated GBM patients.METHODSPatients with histologically confirmed WHO Grade IV GBM and MS-PCR confirmed unmethylated MGMT promoter, age 18-70, KPS ≥70, life expectancy ≥6 months were eligible. 41 patients treated between 2012 and 2017 were screened, 37 of which were eligible. Patients received 12.5 mg of daily Sunitinib for 7 days, followed by concurrent RT, Temozolomide and 12.5 mg Sunitinib for 6 weeks, then adjuvant Temozolomide x6 cycles. RT and Temozolomide doses were as per standard of care. Primary objective was PFS as assessed by RANO criteria, secondary objectives were OS and safety.RESULTSMedian follow-up time was 15 months. Median PFS was 7 months (95%CI, 6.7-7.2) and 6-month PFS was 59.3%. Median OS was 13 months (95%CI, 12.62-13.37) and 2-year OS was 17.8%. Two patients had OS >50 months, with one surviving 71 months. Having received >3 cycles of adjuvant Temozolomide, surgery at progression or age ≤65 significantly predicted for better OS, with hazard ratios of 0.184 (p=0.001), 0.402 (p=0.026) and 10.017 (for age >65, p=0.002) respectively. Grade ≥3 thrombocytopenia occurred in 18.9% of patients, grade ≥3 neutropenia in 10.8% and grade ≥3 thromboembolic events in 13.5%. There were no grade 5 evens.CONCLUSIONAddition of Sunitinib to RT and Temozolomide was well tolerated and survival outcomes compared favorably to the current standard of care for GBM patients with unmethylated MGMT promoter status.

Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC).

Simple SummaryClear cell renal cell carcinoma (ccRCC) is a frequent cancer that causes more than 100,000 deaths every year. Treatment with drugs that target enzymes that help tumours grow such as sunitinib have greatly improved the prospects for ccRCC patients, however a large proportion of patients become resistant. We created sunitinib resistant cell lines and identified consequent changes in gene (and miRNA) expression by microarray analyses. Using this approach, we identified different pathways of resistance suggesting that tumour cells have many ways to overcome sunitinib treatment. We were able to overcome resistance in cells by inhibiting a protein, PD-L1, that is targeted by many immunotherapeutics currently in use for ccRCC patients suggesting a combination of immunotherapy and sunitinib may benefit patients. In addition, we identified miRNAs that are common to multiple resistance mechanisms suggesting they may be useful targets for future studies.The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

Angiogenesis Inhibitors in Small Cell Lung Cancer.

Inhibition of angiogenesis has been demonstrated to be an efficacious strategy in treating several tumors. Vascular endothelial growth factor (VEGF) is the most important protein with proangiogenic functions and it is overexpressed in small cell lung cancer (SCLC). Bevacizumab, a monoclonal antibody directed against VEGF, showed a promising activity in combination with etoposide and cisplatin as first-line treatment of patients with extended stage (ES)-SCLC and two randomized studies confirmed that bevacizumab improved PFS, but failed to prolong OS. Instead, disappointing results have been observed with endostar, sunitinib, sorafenib, vandetanib, and thalidomide in combination with chemotherapy in the first-line setting, with sunitinib in the maintenance setting, with sunitinib, cediranib and nintedanib as single agents or ziv-aflibercept in combination with topotecan in second-line setting. Only anlotinib improved OS and PFS as third-line therapy in Chinese patients with SCLC, and it was approved with this indication in China. Future challenges are the evaluation of the role of angiogenesis inhibitors in combination with immune- checkpoint inhibitors and chemotherapy in SCLC patients and the identification of predictive biomarkers of response to both agents.

Thrombomodulin is upregulated in the kidneys of women with pre-eclampsia

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.