Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials.

Purpose: CT041 is a chimeric antigen receptor (CAR)-modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC).

An Antibody-Drug Conjugate Targeting MUC1-Associated Carbohydrate CA6 Shows Promising Antitumor Activities.

Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface-specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization.

Tumor mutation burden: from comprehensive mutational screening to the clinic.

The recent advent of immunomodulatory therapies into the clinic has demanded the identification of innovative predictive biomarkers to identify patients most likely to respond to immunotherapy and support the design of tailored clinical trials. Current molecular testing for selection of patients with gastrointestinal or pulmonary carcinomas relies on the prevalence of PD-L1 expression in tumor as well as immune cells by immunohistochemistry and/or on the evaluation of the microsatellite status. Tumor Mutational Burden (TMB) has emerged as a promising novel biomarker in this setting to further aid in patient selection.

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors.

Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT).

First-in-human, phase I study of PF-06647263, an anti-EFNA4 calicheamicin antibody-drug conjugate, in patients with advanced solid tumors.

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W).

Anti-miR-21 Suppresses Hepatocellular Carcinoma Growth via Broad Transcriptional Network Deregulation.

Unlabelled: Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options available to cancer patients. MicroRNA 21-5p (miR-21) has been shown to be upregulated in HCC, but the contribution of this oncomiR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miRNAs) and used them to interrogate dependency on miR-21 in a panel of liver cancer cell lines.

MicroRNAs as tools and effectors for patient treatment in gastrointestinal carcinogenesis.

In the last 20 years, microRNAs (miRNAs) have become the most promising class of diagnostic and prognostic biomarkers for human cancer. From a therapeutic perspective, advances in the understanding of the molecular role of miRNAs in the pathological processes have significantly influenced the selection of new therapeutic modalities. Moreover, the intrinsic characteristics that confer stability to miRNAs in vitro, allow a longer molecular/structural resistance and activity in vivo.

Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.

Background: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

Methods: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296).

Transcribed ultraconserved noncoding RNAs (T-UCR) are involved in Barrett's esophagus carcinogenesis.

Barrett's esophagus (BE) involves a metaplastic replacement of native esophageal squamous epithelium (Sq) by columnar-intestinalized mucosa, and it is the main risk factor for Barrett-related adenocarcinoma (BAc). Ultra-conserved regions (UCRs) are a class non-coding sequences that are conserved in humans, mice and rats. More than 90% of UCRs are transcribed (T-UCRs) in normal tissues, and are altered at transcriptional level in tumorigenesis.

Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitostatin.

Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the decorin-induced tumor suppressor gene, mitostatin.

Advanced precancerous lesions within the GI tract: the molecular background.

The mainstream carcinogenic processes involved within the gastrointestinal tract are characterized by phenotypic multistep progression cascades that eventually result in full-blown cancers. In this scenario, the understanding of the molecular dysregulations underlying the precancerous lesions is increasing but still remains incomplete. However, in recent years, the enthusiastic rise of innovative technologies (i.

MicroRNA dysregulation in esophageal neoplasia: the biological rationale for novel therapeutic options.

While the phenotypic changes involved in the esophageal oncogenic "cascade" are now well established, the molecular profiling of this pathway remains unreliable. Our understanding of the molecular dysregulations underlying the development/progression of cancer has recently been expanded by the characterization of a new class of small, noncoding RNA gene products, the microRNAs (or miRNAs). These "endogenous silencers" target a large number of genes, functioning as tumor suppressors or tumor promoters, depending on the activity of the targeted genes.

Role of miRNA in distinguishing primary brain tumors from secondary tumors metastatic to the brain.

Cancer is the result of complex processes that involve multiple molecular alterations. The understanding of such complexity has been improved by the advent of a new class of small, noncoding RNA gene products known as microRNAs (or miRNAs). miRNAs play an essential role in cancer development and progression by modulating gene expression binding to target mRNA, causing either mRNA degradation or translation inhibition.

Mitostatin is down-regulated in human prostate cancer and suppresses the invasive phenotype of prostate cancer cells.

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion.

MicroRNA expression profiling in human Barrett's carcinogenesis.

Barrett's esophagus (BE) is characterized by the native stratified squamous epithelium (N) lining the esophagus being replaced by a columnar epithelium with intestinal differentiation (Barrett's mucosa; BM). BM is considered as the main risk factor for esophageal adenocarcinoma (Barrett's adenocarcinoma; BAc). MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting messenger RNAs and they are reportedly dysregulated in BM.

Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition.

Trichoplein/mitostatin (TpMs) is a keratin-binding protein that partly colocalizes with mitochondria and is often downregulated in epithelial cancers, but its function remains unclear. In this study, we report that TpMs regulates the tethering between mitochondria and endoplasmic reticulum (ER) in a Mitofusin 2 (Mfn2)-dependent manner. Subcellular fractionation and immunostaining show that TpMs is present at the interface between mitochondria and ER.

Reprogramming of miRNA networks in cancer and leukemia.

We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer.

The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and mitogen-activated protein kinase-dependent activation of paxillin.

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. Aberrant IGF-IR signaling is implicated in several types of tumors, including carcinomas of the lung, breast, prostate, pancreas, liver, and colon. However, the contribution of the IGF-IR to the development of the transformed phenotype in urothelial cells has not been clearly established.

Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread.

ApoJ/Clusterin (CLU) is a heterodimeric protein localized in the nucleus, cytoplasm or secretory organelles and involved in cell survival and neoplastic transformation. Its function in human cancer is still highly controversial. In this study, we examined the prostate of mice in which CLU has been genetically inactivated.

Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.

Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged.

Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas.

MicroRNA expression profiling of male breast cancer.

Introduction: MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers.

MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets.

Small non-coding microRNAs (miRNAs) contribute to cancer development and progression, and are differentially expressed in normal tissues and cancers. However, the specific role of miRNAs in the metastatic process is still unknown. To seek a specific miRNA expression signature characterizing the metastatic phenotype of solid tumours, we performed a miRNA microarray analysis on 43 paired primary tumours (ten colon, ten bladder, 13 breast, and ten lung cancers) and one of their related metastatic lymph nodes.

BaS analysis: suggesting a new cephalometric model in follow-up of patients with craniostenosis who underwent craniofacial advancement surgery after 1 year from the end of the distraction protocol.

Evaluation of the relapse in patients with craniofacial malformation who underwent craniofacial advancement surgery is very difficult, and data are often unreliable. This is because common skeletal landmarks move from their original position, making standard cephalometries completely useless. To solve this problem, some authors proposed evaluations based on 2- and 3-dimensional computed tomographies, but the biologic risk and the economic outcome do not consent to repeat this kind of examination too often.

Prevention of urinary bladder cancer in the FHIT knock-out mouse with Rofecoxib, a Cox-2 inhibitor.

Objectives: Aberrant or increased expression of cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many diseases, including cancer. However, the exact mechanism by which COX-2 may influence tumorigenesis has yet to be described. To investigate the chemopreventive role of a COX-2 inhibitor, rofecoxib, in the development of urinary bladder cancer, we studied the effect of this drug in heterozygous and nullizygous fragile histidine triad (FHIT) gene-deficient mice in a chemically induced carcinogenesis model.