A Novel 2-Carbon-Linked Dimeric Artemisinin With Potent Antileukemic Activity and Favorable Pharmacology

Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented in vivo antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.

Case Report: Early Association of Vemurafenib to Standard Chemotherapy in Multisystem Langerhans Cell Histiocytosis in a Newborn: Taking a Chance for a Better Outcome?

Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients.

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation

Introduction: In the last decade immune checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017 the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability (MSI), regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden (TMB), likewise benefit from immune checkpoint therapy. Case report: Here we present two cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab. Conclusion: Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype especially in patients that are refractory to standard chemotherapy.

GPER Agonist G-1 Disrupts Tubulin Dynamics and Potentiates Temozolomide to Impair Glioblastoma Cell Proliferation

Glioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted that the expression of the membrane G-protein-coupled estrogen receptor (GPER) had an impact on GBM female patient survival. In this context, we explored for the first time the role of the GPER agonist G-1 on GBM cell proliferation. Our results suggested that G-1 exposure had a cytostatic effect, leading to reversible G2/M arrest, due to tubulin polymerization blockade during mitosis. However, the observed effect was independent of GPER. Interestingly, G-1 potentiated the efficacy of temozolomide, the current standard chemotherapy treatment, since the combination of both treatments led to prolonged mitotic arrest, even in a temozolomide less-sensitive cell line. In conclusion, our results suggested that G-1, in combination with standard chemotherapy, might be a promising way to limit the progression and aggressiveness of GBM.

Leiomyosarcoma of urinary bladder with unusual recurrence in intestinal mucosa and peritoneum: a case report

Background Leiomyosarcomas of urinary bladder constitute rare malignant sarcomas with very few cases reported in literature. Case presentation Here, we present a case of bladder leiomyosarcoma in a well-preserved female. She failed to respond to standard chemotherapy and had a rapidly downhill course with unusual metastases in anastomotic site and peritoneum soon after surgery. Despite multimodality management including resection of primary and metastatic site, systemic therapy and pelvic radiotherapy, our patient had dismal prognosis with an overall survival of 1.7 years. Conclusion Leiomyosarcomas of bladder are aggressive tumors and have a very poor prognosis; thus, future research should focus on optimizing more effective treatment regimes.

Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

Trabectedin in the treatment of soft tissue sarcomas: up to date data

Soft tissue sarcomas are a rare heterogeneous group of malignant tumors with mesenchymal nature. Soft tissue sarcomas accounts for less than 1 % of all cancers. Low efficiency of chemotherapy for soft tissue sarcomas, especially in advanced disease, is a burning issue. Trabectedin is one of the active agents approved for the treatment of advanced soft tissue sarcomas after the failure of standard chemotherapy. The article provides a literature review of the latest world-wide data of the effectiveness and role of trabectedin in the modern approach of soft tissue sarcomas treatment.