benzofurans and Carcinoma--Renal-Cell

Everolimus monotherapy use for metastatic renal cell carcinoma (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients. To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent, were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus + BNC105P. Median PFS (mPFS) was 4.9 (95% CI, 2.8-6.2) months. A four-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus ± BNC105P [AUC, 86.9% (95% CI, 79.2-94.7)]. This was validated in 130 patients from CheckMate 025 treated with everolimus [AUC, 60.2% (95% CI, 49.7-70.7)]. Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus + BNC105P was associated with significantly longer mPFS compared with everolimus alone (10.4 vs. 6.9 months; HR, 0.49; 95% CI, 0.24-1.002;

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Biomarkers, Tumor; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Male; Middle Aged; Organophosphates; Prognosis; Survival Rate; Transcriptome; Validation Studies as Topic

Topics: Acetylation; Adult; Aged; Alanine Transaminase; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Benzofurans; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm; Epigenesis, Genetic; Fatigue; Female; Gene Expression; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Pyrimidines; Sulfonamides; Thrombocytopenia; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult

BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).. A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.. In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.. Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Carcinoma, Renal Cell; Disease-Free Survival; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Matrix Metalloproteinase 9; Middle Aged; Organophosphates; Sex Hormone-Binding Globulin; Treatment Outcome

Eukaryotic translation initiation factor 4E (eIF4E) is deregulated in patients with renal cell carcinoma (RCC) and associated with poor prognosis, and is activated and regulated by Mnk kinases. In this study, we investigated the anti-RCC potential of a unique Mnk inhibitor cercosporamide. We showed that cercosporamide is active against RCC cells via suppressing growth, survival and migration. Combination indices value indicated that the combination of cercosporamide with sunitinib or temsirolimus are synergistic in RCC. In two independent RCC xenograft mouse models, complete tumor growth arrest or reverse was observed throughout the duration of drug treatment in the combination of cercosporamide with sunitinib or temsirolimus groups. Of note, cercosporamide inhibited RCC angiogenesis via negatively regulating a number of RCC endothelial cellular events including morphogenesis, migration, growth and survival. Mechanistically, we found that cercosporamide suppressed pro-angiogenic factors VEGF and HIFα, inhibited EMT and reduced pro-survival and cell cycle proteins; and furthermore this was attributed to cercosporamide's ability in inhibiting eIF4E. This work demonstrates the anti-RCC activity of cercosporamide through targeting both RCC tumor cells and angiogenesis, and provides the first preclinical proof-of-concept of evidence of Mnk inhibition for RCC treatment.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzofurans; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Eukaryotic Initiation Factor-4E; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Mice, SCID; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases

Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4-5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.

Topics: Apoptosis; Benzofurans; Carcinoma, Renal Cell; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Kidney Neoplasms; RNA, Messenger; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand