Functional Assessments of Gynecologic Cancer Models Highlight Differences Between Single-Node Inhibitors of the PI3K/AKT/mTOR Pathway and a Pan-PI3K/mTOR Inhibitor, Gedatolisib.

: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited.

Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy.

Background: Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions.

New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

Purpose: HER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient's live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies.

Methods: The CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2-/HSFs+).

Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells.

Background: Approximately 18-20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2.

A functional signal profiling test for identifying a subset of HER2-negative breast cancers with abnormally amplified HER2 signaling activity.

The results of clinical trials evaluating the efficacy of HER2 inhibitors in patients with breast cancer indicate that the correlation between HER2 receptor levels and patient outcomes is as low as 50%. The relatively weak correlation between HER2 status and response to HER2-targeting drugs suggests that measurement of HER2 signaling activity, rather than absolute HER2 levels, may more accurately diagnose HER2-driven breast cancer. A new diagnostic test, the CELx HER2 Signaling Profile (CELx HSP) test, is demonstrated to measure real-time HER2 signaling function in live primary cells.

Validation of an optical microplate label-free platform in the screening of chemical libraries for direct binding to a nuclear receptor.

Optical microplate-based biosensors combine the advantages of label-free detection with industry-standard assay laboratory infrastructure and scalability. A plate-based label-free platform allows the same basic platform to be used to quantify molecular interactions of macromolecules and to screen and characterize drug-like small-molecule interactions. The ligand-binding domain of orphan estrogen-related nuclear receptor-γ (ERRγ) is utilized, as a model system of a challenging type of target, to illustrate the rapid development and utility of a range of biochemical assay formats on these biosensors.

Advantages and application of label-free detection assays in drug screening.

Background: Adoption is accelerating for a new family of label-free optical biosensors incorporated into standard format microplates owing to their ability to enable highly sensitive detection of small molecules, proteins and cells for high-throughput drug discovery applications.

Objective: Label-free approaches are displacing other detection technologies owing to their ability to provide simple assay procedures for hit finding/validation, accessing difficult target classes, screening the interaction of cells with drugs and analyzing the affinity of small molecule inhibitors to target proteins.

Methods: This review describes several new drug discovery applications that are under development for microplate-based photonic crystal optical biosensors and the key issues that will drive adoption of the technology.

Microplate-based, label-free detection of biomolecular interactions: applications in proteomics.

This review describes a new type of label-free optical biosensor that is inexpensively manufactured from continuous sheets of plastic film and incorporated into standard format microplates to enable highly sensitive, high-throughput detection of small molecules, proteins and cells. The biosensor and associated detection instrumentation are applied to review two fundamental limiting issues for assays in proteomics research and drug discovery: requirement for quantitative measurement of protein concentration and specific activity, and measurements made with complex systems in highly parallel measurements. SRU BIosystems, Inc.

Label-free assays on the BIND system.

Screening of biochemical interactions becomes simpler, less expensive, and more accurate when labels, such as fluorescent dyes, radioactive markers, and colorimetric reactions, are not required to quantify detected material. SRU Biosystems has developed a biosensor technology that is manufactured on continuous sheets of plastic film and incorporated into standard microplates and microarray slides to enable label-free assays to be performed with high throughput, high sensitivity, and low cost per assay. The biosensor incorporates a narrow band guided-mode resonance reflectance filter, in which the reflected color is modulated by the attachment/detachment of biochemical material to the surface.