Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study.

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.

Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study.

Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID.

Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells.

Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours.

Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass.

Understanding the regulation of islet cell mass has important implications for the discovery of regenerative therapies for diabetes. The liver plays a central role in metabolism and the regulation of endocrine cell number, but liver-derived factors that regulate α-cell and β-cell mass remain unidentified. We propose a nutrient-sensing circuit between liver and pancreas in which glucagon-dependent control of hepatic amino acid metabolism regulates α-cell mass.

PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance.

Purpose: To investigate the clinical relevance of PTEN in HER2-amplified and HER2-nonamplified disease.

Experimental Design: We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN immunohistochemical (IHC) assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion.

Results: In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.

HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer.

HSP90 inhibitors are currently undergoing clinical evaluation in combination with antimitotic drugs in non-small cell lung cancer (NSCLC), but little is known about the cellular effects of this novel drug combination. Therefore, we investigated the molecular mechanism of action of IPI-504 (retaspimycin HCl), a potent and selective inhibitor of HSP90, in combination with the microtubule targeting agent (MTA) docetaxel, in preclinical models of NSCLC. We identified a subset of NSCLC cell lines in which these drugs act in synergy to enhance cell death.

Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer.

Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumours and 32 cell lines. Meta-analysis of exome data and previously published data sets reveals 24 significantly mutated genes in microsatellite stable (MSS) tumours and 16 in microsatellite instable (MSI) tumours.

Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes.

Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n=392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of-function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes.

Oncogenic ERBB3 mutations in human cancers.

The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers.

High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck.

Purpose: Tumors with oncogenic dependencies on the HER family of receptor tyrosine kinases (RTKs) often respond well to targeted inhibition. Our previous work suggested that many cell lines derived from squamous cell carcinomas of the head and neck (SCCHNs) depend on autocrine signaling driven by HER2/3 dimerization and high-level co-expression of HRG. Additionally, results from a Phase I trial of MEHD7495A, a dual-action antibody that blocks ligand binding to EGFR and HER3, suggest that high-level HRG expression was associated with clinical response in SCCHN patients.

Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005).

A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined.

Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD.

Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.

In this multicenter phase Ib study, drozitumab was given in combination with the mFOLFOX6 regimen and bevacizumab in patients with previously untreated, locally advanced recurrent or metastatic colorectal cancer on day 1 of every 14-day cycle. Nine patients were treated at 2 different cohort dose levels of drozitumab. No dose-limiting toxicities occurred at either dose level and the maximum tolerated dose was not reached.

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events.

Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples.

Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.

Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines.

Proapoptotic activation of death receptor 5 on tumor endothelial cells disrupts the vasculature and reduces tumor growth.

The proapoptotic death receptor DR5 has been studied extensively in cancer cells, but its action in the tumor microenvironment is not well defined. Here, we uncover a role for DR5 signaling in tumor endothelial cells (ECs). We detected DR5 expression in ECs within tumors but not normal tissues.

PPM1H is a p27 phosphatase implicated in trastuzumab resistance.

The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance.

Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients.

Purpose: The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity.

Improving treatment of HER2-positive cancers: opportunities and challenges.

Amplification of the ERBB2 gene, which encodes human epidermal growth factor receptor 2 (HER2), causes the overexpression of a major proliferative driver for a subset of breast and gastric cancers. Treatments for patients with HER2-positive cancer include the monoclonal antibody trastuzumab and, in the case of metastatic breast cancer, the tyrosine kinase inhibitor lapatinib. Despite significant improvement in patient outcome as a result of these therapies, challenges remain.

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients.

Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported, but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and nontumor genomes (>80× coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites.

DNA methylation profiling defines clinically relevant biological subsets of non-small cell lung cancer.

Purpose: Non-small cell lung cancers (NSCLC) comprise multiple distinct biologic groups with different prognoses. For example, patients with epithelial-like tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) pathway than patients with mesenchymal-like tumors. Here, we test the hypothesis that epithelial-like NSCLCs can be distinguished from mesenchymal-like NSCLCs on the basis of global DNA methylation patterns.

Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1.

Clinical use of recombinant fibroblast growth factor 21 (FGF21) for the treatment of type 2 diabetes and other disorders linked to obesity has been proposed; however, its clinical development has been challenging owing to its poor pharmacokinetics. Here, we describe an alternative antidiabetic strategy using agonistic anti-FGFR1 (FGF receptor 1) antibodies (R1MAbs) that mimic the metabolic effects of FGF21. A single injection of R1MAb into obese diabetic mice induced acute and sustained amelioration of hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis.

Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer.

Purpose: To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non-small-cell lung cancer (NSCLC).

Patients And Methods: Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1) or with dulanermin 8 mg/kg for 5 days (arm 2). Patients with nonsquamous NSCLC received PCB alone (arm 3) or with dulanermin 8 mg/kg for 5 days (arm 4) or 20 mg/kg for 2 days (arm 5).

miR-221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer.

Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT).