Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.This article is highlighted in the In This Issue feature, p. 211.The efficacy of anti-PD-1 treatment was enhanced by deletion of Pcsk9 or PCSK9 inhibition in mice.Timp1 status in Pten-null prostate cancer cells dictated whether senescence was detrimental in vivo.A massive 5 year-plus effort to find molecularly targeted therapies for patients with recurrent, advanced-stage squamous cell carcinoma of the lungs has demonstrated the feasibility of rapidly screening tumors for rare genomic alterations and assigning drug treatments accordingly. Yet, the Lung Cancer Master Protocol study has yet to identify a broadly effective targeted agent for patients with biomarker-defined subtypes of the disease.Pre-B cells in Ifitm3-/- mice were less able to transform into B-cell cancers than in wild-type mice.Mutating a conserved motif in the activation loop of MEC1 (ATR) revealed the activation mechanism.Metastases largely rely on hematogenous dissemination of tumor cells via the vascular system and significantly limit prognosis of patients with solid tumors. To colonize distant sites, circulating tumor cells must destabilize the endothelial barrier and transmigrate across the vessel wall. Here we performed a high-content screen to identify drugs that block tumor cell extravasation by testing 3,520 compounds on a transendothelial invasion coculture assay. Hits were further characterized and validated using a series of in vitro assays, a zebrafish model enabling three-dimensional (3D) visualization of tumor cell extravasation, and mouse models of lung metastasis. selleck chemical The initial screen advanced 38 compounds as potential hits, of which, four compounds enhanced endothelial barrier stability while concurrently suppressing tumor cell motility. Two compounds niclosamide and forskolin significantly reduced tumor cell extravasation in zebrafish, and niclosamide drastically impaired metastasis in mice. Because niclosamidepg.Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. SIGNIFICANCE This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

To explore the experiences, patient interactions and knowledge regarding the use of cannabis as a medicine in New Zealand doctors in an oncology setting.

An observational cross-sectional survey undertaken between November 2019 and January 2020 across four secondary-care hospital oncology departments within New Zealand (Auckland, Wellington, Christchurch and Dunedin). Participants were a convenience sample of doctors; consultants, registrars, medical officers of special status and house surgeons working in oncology departments. Of 53 individuals approached, 45 participated (85% Response Rate). The primary outcome was reporteddoctor-patient interactions. Secondary outcomes included knowledge of cannabis-based products, their efficacy, prescribing regulations and educational access.

Of 44 doctors, 37 (84%, 95% CI 70 to 93) reported patient requests to prescribe cannabis-based products and 43 (98%, 95% CI 88 to 100) reported patients using illicit cannabis for medical symptoms. Primary request reasons were pain, nausea/vomiting and cancer treatment.