Search

Background: Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs., Materials and Methods: Safety data from the 352 patients who received lenvatinib plus pembrolizumab in the CLEAR study were analyzed. Key ARs were chosen based on frequency of occurrence (≥30%). Time to first onset and management strategies for key ARs were detailed., Results: The most frequent ARs were fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), and hypertension (56.3%); grade ≥3 severity ARs that occurred in ≥5% of patients were hypertension (28.7%), diarrhea (9.9%), fatigue (9.4%), weight decreased (8.0%), and proteinuria (7.7%). Median times to first onset of all key ARs were within approximately 5 months (approximately 20 weeks) of starting treatment. Strategies for effectively managing ARs included baseline monitoring, drug-dose modifications, and/or concomitant medications., Conclusion: The safety profile of lenvatinib plus pembrolizumab was consistent with the known profile of each monotherapy; ARs were considered manageable with strategies including monitoring, dose modifications, and supportive medications. Proactive and prompt identification and management of ARs are important for patient safety and to support continued treatment., Clinicaltrials.gov Id: NCT02811861., (© The Author(s) 2023. Published by Oxford University Press.)

PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Essegian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models., (© 2022. Springer Nature Limited.)

Renal cell carcinoma (RCC) is a fatal disease when advanced. While immunotherapy and tyrosine kinase inhibitor-based combinations are associated with improved survival, the majority of patients eventually succumb to the disease. Through a comprehensive pan-cancer, pan-kinome analysis of the Cancer Genome Atlas (TCGA), pregnancy-upregulated non-ubiquitous calcium-calmodulin-dependent kinase (PNCK), was identified as the most differentially overexpressed kinase in RCC. PNCK overexpression correlated with tumor stage, grade and poor survival. PNCK overexpression in RCC cells was associated with increased CREB phosphorylation, increased cell proliferation, and cell cycle progression. PNCK down-regulation, conversely, was associated with the opposite, in addition to increased apoptosis. Pathway analyses in PNCK knockdown cells showed significant down-regulation of hypoxia and angiogenesis pathways, as well as the modulation of the cell cycle, DNA damage, and apoptosis pathways. These results demonstrate for the first time the biological role of PNCK, an understudied kinase, in RCC and validate PNCK as a druggable target., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue., Methods: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV., Results: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV., Conclusion: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV., (Copyright © 2021. Published by Elsevier Inc.)

The tumor stroma acts as a barrier that limits the efficacy of systemically administered oncolytic viruses (OV). We previously demonstrated that stromal-selective, retargeted oncolytic measles viruses (MVs) delay in vivo tumor progression. To further characterize the contribution of stromal targeting to MV's overall in vivo efficacy in an experimental cancer model, a dual targeted oncolytic measles virus (MV-CD46-muPA) able to simultaneously infect murine stromal (via murine uPAR) and human cancer (via CD46) cells was developed. MV-CD46-muPA infected, replicated, and induced cytotoxicity in both murine and human cancer cells. Viral infection was successfully transferred from stromal to tumor cells in vitro, leading to tumor cell oncolysis. Systemic administration of MV-CD46-muPA led to improved antitumor effects in colon (HT-29) cancer xenografts compared to vehicle or CD46 only targeted MVs. These effects were associated with improved tumor viral deposition, increased apoptosis, and decreases in murine stromal endothelial cells and fibroblasts. MV-CD46-muPA modulated cell cycle, survival, proliferation, and metabolic pathways, as determined by functional proteomic analysis of treated tumors. The above findings further validate the concept that dual stromal and tumor cell viral targeting enhances the therapeutic effects of systemically administered OVs and support further preclinical and clinical development of stromal directed virotherapies.

Background: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma., Methods: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual., Findings: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths., Interpretation: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials., Funding: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC)., Materials and Methods: This retrospective study included 50 patients (23 women, 27 men; age range, 46-91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)-guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1-5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3-month intervals thereafter., Results: There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7-32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7-16.2 months) from time of IRE. Patients with tumors ≤ 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis (P = .002) and 16.2 vs 9.9 months from time of IRE (P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis., Conclusions: Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile., (Published by Elsevier Inc.)

Background: There is no standard chemotherapy regimen that is universally accepted for the treatment of advanced gastric cancer. Trastuzumab added to chemotherapy improves survival in patients with metastatic human epidermal growth factor receptor-2 (Her2/neu)-overexpressing gastric cancer. Data are lacking for the combination of trastuzumab with other chemotherapy regimens, apart from the cisplatin/fluorouracil backbone used in the pivotal TOGA trial., Patients and Methods: In this retrospective analysis, we included patients with gastric cancer with HER2 overexpression who received trastuzumab in addition to their first-line chemotherapy, with or without trastuzumab maintenance therapy. The end-points were response and tolerance to treatment., Results: We identified seven patients who met the search criteria; six had metastatic disease and one had locally advanced unresectable disease. Four patients received epirubicin/oxaliplatin/capecitabine/trastuzumab, and the others had non-anthracycline-based chemotherapy with trastuzumab. All patients had radiological responses to treatment - one had a complete response and six had partial responses. Among the four patients who received anthracycline-based chemotherapy with trastuzumab, there was a transient decline in cardiac ejection fraction in three, but all resolved without sequelae. All patients received a period of chemotherapy induction followed by trastuzumab monotherapy for maintenance. The median progression-free survival was 14.6 months and median overall survival was 16.4 months., Conclusion: Trastuzumab is an important agent for the treatment of HER2-overexpressing gastric cancer. We recorded an acceptable safety and efficacy profile in this small cohort treated with anthracycline-based chemotherapy with trastuzumab followed by trastuzumab maintenance.

Targeting tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin alpha(v)beta3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin alpha(v)beta3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 10(6) plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin alpha(v)beta3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors.