Neoplasia : An International Journal for Oncology Research

BACKGROUND: Biliary tract cancers (BTCs) including intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder cancer, are rare but aggressive malignancies with few effective standard of care therapies. METHODS: We implemented integrative clinical sequencing of advanced BTC tumors from 124 consecutive patients who progressed on standard therapies (N=92 with MI-ONCOSEQ and N=32 with commercial gene panels) enrolled between 2011-2020. RESULTS: Genomic profiling of paired tumor and normal DNA and tumor transcriptome (RNA) sequencing identified actionable somatic and germline genomic alterations in 54 patients (43...

While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition...

The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which are approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which functions as a pro-apoptotic protein that transduces TRAIL death signaling to trigger apoptosis...

The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been explored, less is known about the cell biological characteristics of cancer cells that survive to eventually seed the recurrence. To identify the unique phenotypic characteristics associated with survival upon chemotherapy exposure, we characterized nuclear morphology and function as prostate cancer cells recovered following cisplatin treatment...

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Nicotinamide phosphoribosyltransferase (NAMPT) is a key metabolic enzyme in NAD+ synthesis pathways and is found upregulated in several tumors, depicting NAD(H) lowering agents, like the NAMPT inhibitor FK866, as an appealing approach for anticancer therapy. Like other small molecules, FK866 triggers chemoresistance, observed in several cancer cellular models, which can prevent its clinical application. The molecular mechanisms sustaining the acquired of resistance to FK866 were studied in a model of triple negative breast cancer (MDA-MB-231 parental - PAR), exposed to increasing concentrations of the small molecule (MDA-MB-231 resistant - RES)...

MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory. Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies...

Circadian clock orchestrates the intergenic biochemical, physiological and behavioral changes to form an approximate 24h oscillation through the transcription-translation feedback loop (TTFL). Mechanistically, a heterodimer of transcriptional activator formed by BMAL1 and CLOCK, governs the expression of its transcriptional repressors, CRY, PER and REV-ERBα/β proteins, thereby controlling more than 50 % of protein encoding genes in human. There is also increasing evidence showing that tumor microenvironment can disrupt specific clock gene functions to facilitate tumorigenesis...

BACKGROUND: Approximately 95% of Colorectal cancers (CRC) consist of adenocarcinomas originating from colonic Adenomatous polyps (AP). Increasing importance in CRC occurrence and progression has been attributed to the gut microbiota; however, a huge proportion of microorganisms inhabit the human digestive system. So, to comprehensively study the microbial spatial variations and their role in CRC progression, from AP to the different CRC phases, a holistic vision is imperative, including the simultaneous evaluation of multiple niches from the gastrointestinal system...

Tumor heterogeneity dominates tumor biological behavior and shapes the tumor microenvironment. However, the mechanisms of tumor genetic features modulate immunity response were not clearly clarified. Tumor associated macrophages (TAMs) exert distinct immune functions in the progression of hepatocellular carcinoma (HCC) based on the inducible phenotype. FOXO family members sense changes in the extracellular or intracellular environment by activating a series of signaling pathways. FOXO1, a transcription factor that a common suppressor in hepatocellular carcinoma, correlated with a better tumor biological behavior in HCC through shaping macrophages anti-tumour response...

Diffuse midline glioma (DMG) is the leading cause of brain tumor-related deaths in children. DMG typically presents with variable neurologic symptoms between ages 3 and 10. Currently, radiation remains the standard therapy for DMG to halt progression and reduce tumor bulk to minimize symptoms. However, tumors recur in almost 100% of patients and thus, DMG is still considered an incurable cancer with a median survival of 9-12 months. Surgery is generally contraindicated due to the delicate organization of the brainstem, where DMG is located...

The risk of overlapping pulmonary toxicity induced by thoracic radio(chemo)therapy and immune checkpoint inhibitor therapy in the treatment of patients suffering from non-small cell lung cancer (NSCLC) is one important challenge in successful radioimmunotherapy. In the present opinion we highlight factors that we find important to be considered before treatment initiation, during the treatment sequence, and after treatment completion combined or sequential application of radio(chemo)therapy and immune checkpoint inhibitor therapy...

Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options...

Recent insights into histopathological and molecular subgroups of glioma have revolutionized the field of neuro-oncology by refining diagnostic categories. An emblematic example in pediatric neuro-oncology is the newly defined diffuse midline glioma (DMG), H3 K27-altered. DMG represents a rare tumor with a dismal prognosis. The diagnosis of DMG is largely based on clinical presentation and characteristic features on conventional magnetic resonance imaging (MRI), with biopsy limited by its delicate neuroanatomic location...

Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule multi-kinase inhibitor, was demonstrated to have promising anti-tumor activity in various solid tumors. In the present study, we found that regorafenib markedly enhanced cisplatin-induced cytotoxicity in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER Stress), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways...

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment...

Multidrug resistance (MDR) hinders treatment efficacy in cancer therapy. One typical mechanism contributing to MDR is the overexpression of permeability-glycoprotein (P-gp) encoded by ATP-binding cassette subfamily B member 1 (ABCB1). Basic helix-loop-helix family member e40 (BHLHE40) is a well-known transcription factor that has pleiotropic effects including the regulation of cancer-related processes. However, whether BHLHE40 regulates MDR is still unknown. Chromatin immunoprecipitation-seq study revealed BHLHE40 occupancy in the promoter of ABCB1 gene...

Dendritic cells (DCs) can initiate both naïve and memory T cell activation, as the most potent antigen-presenting cells. For efficient anti-tumor immunity, it is essential to enhance the anti-tumoral activity of tumor-associated DCs (TADCs) or to potently restrain TADCs so that they remain immuno-stimulating cells. Combined phospholipids (cPLs) adjuvant may act through the activation of DCs. This study demonstrated the potential mechanism of tumor growth inhibition of cPLs adjuvant, and confirmed that cPLs adjuvant could induce the maturation and activation (upregulation of MHC-II, CD80, CD40, IL-1β, IL-12, IL-6 expression) of BMDCs in vitro...

Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion...

Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic...