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12 | AUGUST 2014 | GENengnews.com | Genetic Engineering & Biotechnology News Tumor Markers Continued from page 1 DRUG DISCOVERY CTCs can inform clinical decisions and guide drug development, according to Dr. McCormack, and clinicians are using CTCs to determine therapy effectiveness, elucidate mechanisms underlying therapy failure, and identify therapeutic options for individual patients. CellSearch ® from Janssen Diagnostics, the only in vitro device for the detection and isolation of CTCs that has been cleared by the FDA, is used in the clinical setting to capture and count CTCs in blood samples to determine the prognosis of patients with metastatic breast, colorectal, or castration- resistant prostate cancer. CellSearch and the majority of currently available methods use an enrichment step, or positive selection to detect CTCs based on antibody binding to epithelial cell markers, most notably epithe- lial cellular adhesion molecule, or EpCAM, which is found on the surface of most epithe- lial cell tumors, as well as cytokeratin. As Lori Millner, Ph.D., a clinical chemistry fellow at the University of Louisville, and her colleagues at PG XL Technologies have pointed out, an estimated 37–39% of patients with metastatic breast cancer have no detectable CTCs using epithelial cell surface markers as the criteria for isolation. "There is defnitely no consensus on what are CTCs or how to capture them," Dr. Millner remarked. It is possible for cancer cells to go through epithelial cell to mesenchymal cell transition and to downregulate certain markers, in- cluding EpCAM. Furthermore, Dr. Millner continued, there is evidence indicating that those patients with metastatic breast cancer who have no detectable CTCs using cur- rently available methods tend to have more aggressive types of breast cancer. Going through the epithelial-to-mesen- chymal transition may confer an advantage to CTCs in the circulation, helping them "avoid immune detection and be more ro- bust," Dr. Millner offered. "Arguably, they are the most dangerous cells." The researchers at Louisville are devel- oping a method of detecting and isolating CTCs designed to capture a more compre- hensive set of cells, including those that do not express EpCAM. With funds from a National Cancer Institute SBIR grant, they are completing a Phase I proof-of-concept study of a single-cell analysis method tested on four breast cancer cell lines. Their positive selection method is based on a multi-antigen approach, including the antibodies for Ep- CAM and HER2. CTC isolation is then carried out on a Silicon Biosystems DEP Array system, which sorts and separates cells using dielectropho- resis. The user can instruct the system to sort the cells into defned single-cell populations. Using this system, Dr. Millner's group has demonstrated the capability to perform sin- gle-cell Sanger sequencing. Future technology development will focus on using next-gener- ation sequencing (NGS) to do whole-genome and whole-transcriptome analysis, and a proposed Phase II trial would apply the CTC isolation method to patient samples. Next-Generation CTC Technology Commercially available since 2004, Cell- Search has open-channel capabilities built into the technology that allow users to include additional antibodies for further phenotypic specifcation, or for targeting a therapy (such as the identifcation of HER2 receptors). Jans- sen Diagnostics is collaborating with Mas- sachusetts General Hospital (MGH) on the development of next-generation CTC tech- nology that will isolate CTCs based on both positive and negative selection. The recently published results from the SWOG S0500 study demonstrated the pre- dictive value of CTC enumeration in patients with metastatic breast cancer as an indicator of the response to frst-line chemotherapy and to guide the decision to change to an al- ternative chemotherapeutic regimen with the aim of improving overall or progression-free survival (PFS). Patients with elevated CTC counts prior to the start of therapy who subsequently showed low CTC counts three weeks later had a signifcantly better PFS and overall survival (OS) than did patients whose CTC counts did not decrease after the start of therapy. The latter patients, however, did not ben- eft from an early switch to an alternative chemotherapy. The authors concluded that for these patients, participation in clinical > AstraZeneca, Max Planck Launch CVMD Collaboration AstraZeneca and the Max Planck Institute of Molecu- lar Physiology (MPI) will study new modalities chemistry by establishing a satellite unit in cardiovascular and met- abolic disease (CVMD) linked to AstraZeneca's CVMD In- novative Medicines unit (iMed) in Mölndal, Sweden. The value of the collaboration was not disclosed. The new satellite unit will focus on new chemistry and chemical biology in areas of new modality chemistry, such as stabilized peptides, macrocycles, and conjugation chemistry. AstraZeneca said its scientists will work with re- searchers from MPI's department of chemical biology. AstraZeneca's new collaboration with MPI is designed to support identication of new targets in the company's three areas of research focus in CVMD: cardiac regenera- tion, islet health (diabetes), and diabetic nephropathy. > HD Biosciences to Help Marshall University Advance Cancer Drugs HD Biosciences (HDB), the Marshall Institute for In- terdisciplinary Research (MIIR), and the Joan C. Edwards School of Medicine at Marshall University entered a new partnership to co-develop potential anticancer drugs. As part of the agreement, the partners will jointly own intellectual property and commercialization rights of the products developed through the collaboration. HDB will take lead compounds that have been discov- ered in Marshall University to continue to preclinical de- velopment. The partnership aims to provide innovative medicines for unmet healthcare needs and targets both international and Chinese markets. > Evotec, Fraunhofer Collaborate on Discovery Programs Evotec entered an exclusive collaboration with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME in several undisclosed disease areas for in- ternal and external drug discovery projects. According to the company, this alliance expands Evo- tec's existing drug discovery platform with access to a broad range of complementary and innovative platforms and capabilities to progress projects and provide ad- ditional capabilities for customers and partners of both organizations. The deal follows the joint decision of Evotec, Fraunhofer- Gesellschaft, and the City of Hamburg to integrate the Eu- ropean ScreeningPort into the IME thereby forming the rst Fraunhofer life science institution in the city. > University College Dublin Taps NextCODE to Aid in Autism, Rare Disease Research Sequence-based clinical diagnostics rm and deCODE genetics spinout NextCODE Health is partnering with the Academic Centre on Rare Diseases (ACoRD) at University College Dublin, allowing ACoRD to use NextCODE prod- ucts in research aimed at learning more about the causes and better ways to diagnose autism and rare diseases. NextCODE's Clinical Sequence Analyzer™, which the rm says can identify causal mutations in families with dif- ferent rare disorders, and Sequence Miner and the GOR™ database infrastructure, to be used for mining whole-ge- nome data for sequence variants linked to autism spec- trum disorders, are among the technologies to be used. > BIND, Amgen End Unsuccessful Collaboration Amgen and BIND Therapeutics have ended an unsuc- cessful 1-1/2 year collaboration to develop and commer- cialize a kinase inhibitor nanomedicine for solid tumors— a deal that could have netted BIND up to $299.5 million. The companies agreed in January 2013 to create tar- geted and programmable therapeutics called Accurins™ for solid cancer tumors by combining an undisclosed kinase inhibitor from Amgen with BIND's platform for targeted and programmable nanomedicines. Under their collaboration, Amgen had the option to select a novel Accurin candidate for further develop- ment "for all uses except for some vaccine applications," according to BIND's Form 10-Q for the rst quarter of this year, led with the U.S. Securities and Exchange Commission. n News DISCOVERY & DEVELOPMENT Researchers at the University of Louisville are developing a method of detecting and isolating circulating tumor cells that is designed to capture a comprehensive set of cells, including those that do not express the EpCAM (epithelial cellular adhesion molecule) marker. See Tumor Markers on page 14