Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases.

Background: Circulating cell-free tumor DNA (ctDNA)-based mutation profiling, if sufficiently sensitive and comprehensive, can efficiently identify genomic targets in advanced lung adenocarcinoma. Therefore, the authors investigated the accuracy and clinical utility of a commercially available digital next-generation sequencing platform in a large series of patients with non-small cell lung cancer (NSCLC).

Methods: Plasma-based comprehensive genomic profiling results from 8388 consecutively tested patients with advanced NSCLC were analyzed.

Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC.

Introduction: EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.

Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions.

EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset.

Phase II Study of Dovitinib in Patients Progressing on Anti-Vascular Endothelial Growth Factor Therapy.

Background: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment.

Methods: Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible.

Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non-Small-Cell Lung Cancer.

Background: Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non-small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET.

Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform.

New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies.

Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results.

Purpose: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy.

Methods: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle.

L-BLP25 vaccine plus letrozole induces a TH1 immune response and has additive antitumor activity in MUC1-expressing mammary tumors in mice.

Purpose: In this study, we examine the immunomodulatory effects and antitumor activity of tamoxifen and letrozole when combined with the human epithelial mucin (hMUC1)-specific vaccine, L-BLP25, in the hMUC1-expressing mammary tumor (MMT) mouse model.

Experimental Design: Dose-finding studies were conducted for both tamoxifen and letrozole. Letrozole and L-BLP25 combination studies used 69 MMT female mice assigned to five groups: untreated, cyclophosphamide + placebo, cyclophosphamide + L-BLP25, letrozole 0.

Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model.

Objective: Ospemifene, a new drug indicated for the treatment of vulvovaginal atrophy, has completed phase III clinical trials. A condition affecting millions of women worldwide, vulvovaginal atrophy has long been treated with estrogen therapy. Estrogen treatment carries with it risks of thromboembolism, endometrial proliferative effects, and breast cancer promotion.

EGFR mutations detected in plasma are associated with patient outcomes in erlotinib plus docetaxel-treated non-small cell lung cancer.

Purpose: Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility.

Methods: An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system (DxS, Ltd) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib.

GCP, a genistein-rich compound, inhibits proliferation and induces apoptosis in lymphoma cell lines.

Genistein combined polysaccharide (GCP), derived from soy bean extract, is comprised of deglycosylated isoflavones, such as genistein and daidzein. The goal of this work was to determine if GCP is effective in lymphoid cancers. In three human and four canine lymphoid cell lines, GCP inhibited proliferation and induced G2/M arrest.

Genistein combined polysaccharide enhances activity of docetaxel, bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines.

Objective: To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP).

Materials And Methods: The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment.

Impairment of the DNA repair and growth arrest pathways by p53R2 silencing enhances DNA damage-induced apoptosis in a p53-dependent manner in prostate cancer cells.

p53R2 is a p53-inducible ribonucleotide reductase that contributes to DNA repair by supplying deoxynucleotide triphosphate pools in response to DNA damage. In this study, we found that p53R2 was overexpressed in prostate tumor cell lines compared with immortalized prostatic epithelial cells and that the protein was induced upon DNA damage. We investigated the effects of p53R2 silencing on DNA damage in LNCaP cells (wild-type p53).