The four members of the ERBB (EGFR/HER) family of receptor tyrosine kinases are involved in an array of combinatorial interactions involving homo- and heterodimers. ERBB overexpression is associated with cancers of the breast, colon, prostate gland, lung, ovaries and brain. Although ERBB-directed therapeutics are effective against such ERBB-overexpressing cancers, their efficacy is limited and variable for reasons that are not well understood. For example, trastuzumab (Herceptin®) is a targeted therapy against ERBB2-overexpressing metastatic breast cancers, but the drug is effective in only a subset of such patients. One reason for efficacy limits is believed to be that the current diagnostic tests used to select appropriate patients are unable to identify and discriminate among active receptor dimers species. This remains a significant technical challenge with current technologies.

The aim of the Ensemble ERBB program is to develop a panel of assays that will elucidate the dimerization status of the EGFR (ERBB) family members in standard cancer pathology samples (formalin-fixed paraffin-embedded tissues). Such a panel would allow researchers to better understand the mechanisms of disease in ERBB-implicated cancers, allow drug developers to better understand the mechanisms of action of new ERBB-targeted compounds, and allow healthcare providers to better prescribe medications targeting the family, including those currently on the market, such as Herceptin®.

Ensemble’s multiplexed panel of assays hold the promise of enabling more highly accurate drug response and cancer prognosis predictions in individual patients based on complete ERBB family profiling of cancer tissue samples. Our goal is to develop and validate diagnostic assays that will improve diagnosis, treatment, and prognosis of all cancers in which ERBB proteins are dysregulated.

Ensemble molecular function test detects multiple ERBB dimers.

The blood cancer chronic myelogenous leukemia (CML) results from a chromosomal translocation whereby two genes, BCR and ABL, are fused, producing a chimeric fusion protein, BCR/ABL. ABL protein, in its normal state, is a kinase involved in signal transduction whose activity is highly regulated. In the fusion protein, regulation of the ABL domain is lost and the kinase is constitutively active. This dysregulation of ABL leads to uncontrolled proliferation of hematopoetic cells, resulting in the cancer. Patients with CML are usually very effectively treated with Gleevec® (imatinib), which inhibits the ABL kinase.  For a small percentage of patients there is no response to Gleevec® and for others there is relapse after some years of treatment. In collaboration with The Leukemia and Lymphoma Society, Ensemble is using its DPC™ biodetection technology to develop a Programmed Bioassay™ for the detection and isolation of BCR/ABL-containing cells in blood.  The assay will allow the drug-resistant population of cells to be monitored and isolated using a flow cytometer. In this way researchers can study the mechanism of drug resistance and relapse in patients and eventually select optimal second-phase therapies.

[ back to top ]