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Arno Therapeutics to Collaborate with Veridex on Development of Diagnostic Test

Arno Therapeutics, Inc. (OTCQB:ARNI), a clinical stage biopharmaceutical company focused on the development of oncology therapeutics, recently announced that it has signed an agreement with Veridex, LLC, a Johnson & Johnson company, to develop a diagnostic test to detect the presence of activated progesterone receptors (APRs) as a potential biomarker of anti-progestin activity in circulating tumor cells (CTCs). The diagnostic will help identify patients whom could potentially benefit from treatment with anti-progestins including onapristone, an orally-administered, investigational type 1 progestin receptor antagonist being developed by Arno.

CTCs are cancer cells that have detached from a solid tumor in the body and are found in the bloodstream. The collaboration will allow Arno to utilize Veridex’s proprietary technology, CELLSEARCH®, which uses an advanced cell separation technique called microfluidic separation integrated with innovative magnetic sorting, to isolate CTCs and further analyze the cells for the presence of APR. The CELLSEARCH® CTC System is the first and only standardized, FDA-cleared, semi-automated system that captures, isolates, and counts CTCs with a high level of sensitivity and specificity.

In pre-clinical studies, the presence of APR has shown to be predictive of onapristone activity. Onapristone is believed to work by binding to progesterone receptor proteins, thereby inhibiting dimerization, phosphorylation and DNA transcription activity. Progesterone receptors (PRs) are found in particular cells including those of the female reproductive tissue and some cancers.i The hormone progesterone binds to the receptors and may cause the cells to grow. Preclinical studies have shown that PRs can play a role as drivers of malignant cell growth in certain cancers.

“We are pleased to work with Veridex as we believe its pioneering technology for isolating circulating tumor cells will serve as an important tool for the continued development and study of onapristone,” said Glenn Mattes, chief executive officer and president, Arno Therapeutics. “By taking blood samples from patients rather than obtaining tissue samples, we hope to create a simplified and less invasive process for identifying patients that are most likely to benefit from treatment with onapristone.”

The diagnostic test will be used in future clinical studies of onapristone, which the company is planning to begin in the second half of 2013.

Source: Arno Therapeutics

ApoCell Announces Delivery of First Prototypes of ApoStream Circulating Tumor Cell (CTC) Isolation Technology to National Cancer Institute

ApoCell, Inc. recently announced that the first prototypes of its ApoStream™ circulating tumor cell (CTC) isolation system have been delivered to select investigator sites including SAIC-Frederick Inc. (SAIC-F) in support of the National Cancer Institute (NCI). The delivery is part of a $2.9 million subcontract awarded to ApoCell in Q1-2011 by SAIC-F to develop a device capable of isolating live cancer cells from small volumes of blood. While ApoStream™ has been used in ApoCell’s laboratories since 2010; this first external placement of the technology is a significant milestone in the company’s plan to commercially offer the device as a vital tool in the development of targeted therapies for the prevention and treatment of cancer.

“The NCI research environment has provided an ideal first external placement for ApoStream™ and the performance of the device to date has been consistent with our own findings,” said Darren Davis , ApoCell president and CEO, adding that results were presented at the Molecular Medicine Triconference on February 15, 2013. ApoCell has shipped four ApoStream™ prototypes to NCI and will deliver a total of 12 by year end, Davis said.

ApoCell has incorporated ApoStream™ into a number of ongoing early and late stage clinical trials as part of the company’s service offering. The recent external placement of ApoStream™ prototypes enables the company to begin its beta-testing program for third party validation of the technology. ApoCell is now looking to place ApoStream™ prototypes at additional investigator sites around the world as part of the beta testing phase. The company plans to commercially launch the technology for research-use-only in 2014.

CTCs have long been known to exist in cancer patients’ blood and clinical correlations have been established between CTC counts and disease progression. These circulating cells represent an attractive target for clinicians seeking to assess a patient’s disease state; however the clinical promise of using CTCs to select appropriate treatments and monitor effectiveness has yet to be fully realized. One reason is that CTCs are extremely rare and difficult to isolate using the commercially available technologies, many of which rely on antibodies that attach to specific cancer cell antigens such as EpCAM.

ApoStream™ is antibody independent and utilizes a process known as dielectrophoresis (DEP) field-flow assist. The technology employs a non-uniform electrical field at specific frequencies to separate viable cancer cells from normal blood cells by relying on a cancer cell’s unique form and structure rather than surface antigen expression. ApoStream™ has been shown to detect significant quantities of intact CTCs from a wide range of cancer types, enabling more robust downstream analysis for greater understanding of each patient’s disease.

After the commercial launch of the research-use-only instrument, Davis said ApoCell plans to continue developing ApoStream™ technology for a clinical point-of-care device that would provide oncologists with more effective monitoring of targeted therapies for various cancer types. The company’s goal is to launch a clinical instrument in 2016.

“We believe ApoStream can play a significant role in the evolution of personalized cancer treatment,” Davis said.

Source: PR Newswire

Nektar Presents Target-Specific Biomarkers Being Assessed in Ongoing Phase 3 BEACON Study of Etirinotecan Pegol for the Treatment of Metastatic Breast Cancer at the 2013 American Society of Clinical Oncology Annual Meeting

Nektar Therapeutics (NASDAQ:NKTR) recently announced that it presented a series of target-specific biomarkers that are being evaluated in the development of etirinotecan pegol for the treatment of breast cancer. Etirinotecan pegol is a unique, next generation, targeted topoisomerase I inhibitor currently in Phase 3 clinical development as a potential treatment for patients with locally recurrent or metastatic breast cancer. The BEACON (BrEAst Cancer Outcomes with NKTR-102) Phase 3 Study is a randomized, open-label, international study that is evaluating single agent etirinotecan pegol in patients who have previously received an anthracycline, a taxane and capecitabine (ATC) versus a comparator arm consisting of an active single agent treatment of physician’s choice (TPC).

“One of our objectives in treating metastatic breast cancer is to prospectively identify patients that will respond to specific treatments so they can achieve the optimal individualized care,” said Hope Rugo, M.D., Director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Comprehensive Cancer Center and Member of the BEACON Study investigator steering committee. “The goal of evaluating these important biomarkers in patients enrolled into the BEACON study is to help us understand which breast cancer patients might have the best clinical outcomes from treatment with etirinotecan pegol.”

A series of assays for target-specific pharmacodynamic biomarkers for etirinotecan pegol, including the molecular target topoisomerase I, have been established and are being measured in the Phase 3 BEACON study. The biomarkers were identified from Circulating Tumor Cell (CTC) samples which were collected prior to patient treatment. Additional CTC patient samples are being collected at regular intervals during treatment and at the end of treatment. Preliminary results from the initial pre-dose samples found CTCs in over 90% of patient samples, with a median of 200 CTCs per 7.5 mL blood draw. Patient participation in the CTC sub-set of the BEACON study is projected to be over 75%. Measurements of each biomarker expression over time will be analyzed in order to identify potential predictive biomarkers for clinical response to etirinotecan pegol.

“We are pleased to have identified several baseline pharmacodynamic biomarkers, which are target-specific such as topoisomerase 1, and which can be reliably measured over the patient’s treatment period,” said Robert Medve, M.D., Chief Medical Officer of Nektar Therapeutics. “The measurement of these biomarkers in the BEACON study will help us understand and shape the future treatment of patients with etirinotecan pegol. Enrollment in the BEACON study is well ahead of schedule and we expect to complete the target enrollment of 840 patients in the third quarter of 2013.”

Circulating Tumor Cells are cancer cells shed from either the primary tumor or its metastases that circulate in the peripheral blood. CTCs are emerging tumor biomarkers, collected through a minimally invasive blood draw, providing a “liquid” biopsy sample and allowing for post-treatment monitoring of the patient. CTCs provide well-defined targets for the understanding of tumor biology and tumor cell dissemination, which offers a unique approach to identify novel therapeutic targets and understand resistance to established therapies.

Source: Nektar Therapeutics

Third-generation Device Significantly Improves Capture of Circulating Tumor Cells

A new system for isolating rare circulating tumor cells (CTCs) – living solid tumor cells found at low levels in the bloodstream – shows significant improvement over previously developed devices and does not require prior identification of tumor-specific target molecules. Developed at the Massachusetts General Hospital (MGH) Center for Engineering in Medicine and the MGH Cancer Center, the device rapidly delivers a population of unlabeled tumor cells that can be analyzed with both standard clinical diagnostic cytopathology and advanced genetic and molecular technology. The MGH team’s report has been published in Science Translational Medicine.

“This new technology allows us to follow how cancer cells change through the process of metastasis,” says Mehmet Toner, PhD, director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine, the paper’s senior author. “Cancer loses many of its tissue characteristics during metastasis, a process we have not understood well. Now for the first time we have the ability to discover how cancer evolves through analysis of single metastatic cells, which is a big step in the war against cancer.”

The new device – called the CTC-iChip – is the third microchip-based device for capturing CTCs developed at the MGH Center for Engineering in Medicine. The first two systems relied on prior knowledge of a tumor-specific surface marker in order to sort CTCs from whole blood and required significant adjustment for each different type of cancer. The systems also required four to five hours to process a single blood sample.

The only U.S. Food & Drug Administration-cleared, commercially available device for capturing and enumerating CTCs – the CELLSEARCH® system developed by Veridex, LLC – relies on magnetic nanoparticles that bind to the same epithelial protein used in the MGH -developed microchip-based devices and cannot always find CTCs present at very low numbers. In January 2011 the MGH entered into a collaborative agreement with Veridex and its affiliate Janssen Research & Development, LLC, to establish a center of excellence in research on CTC technologies.

Combining elements of both approaches – magnetic labeling of target cells and microfluidic sorting – the CTC-iChip works by putting a blood sample through three stages. The first removes from the sample, on the basis of cell size, all blood components except for CTCs and white blood cells. The second step uses a microfluidic process developed at the MGH to align the cells in a single file, allowing for extremely precise and rapid sorting. In the third stage, magnetically labeled target cells – either CTCs tagged via the epithelial marker or white blood cells tagged on known blood-cell antigens – are sorted out. Tagging white blood cells instead of CTCs leaves behind a population of unlabeled and unaltered tumor cells and doesn’t rely on the presence of the epithelial marker or other known tumor antigens on the cell surface.

The new system was able to process blood samples at the extremely rapid rate of 10 million cells per second, handling a tube of blood in less than an hour. Both the mode of sorting out tagged CTCs, called tumor-antigen-dependent, and the technique that depletes white blood cells, called tumor-antigen-independent, recovered more than 80 percent of tumor cells from different types of cancer that had been added to blood samples. Comparison of the antigen-dependent-mode CTC-iChip with existing commercial technology for processing blood samples from patients with prostate, breast, pancreatic, colorectal and lung cancer showed the CTC-iChip to be more sensitive at detecting low levels of CTCs.

In the antigen-independent mode, the CTC-iChip successfully identified CTCs from several types of cancers that had lost or never had the epithelial marker, including triple-negative breast cancer and melanoma. CTCs isolated through this mode were put through standard cytopathological analysis, which revealed structural similarities to the original tumor, and detailed molecular genotyping of CTCs from a single patient found significant differences in gene expression patterns among individual CTCs.

“We’re only beginning to identify potential applications of the ability to analyze how tumors mutate as they spread, but this should help improve our understanding of the fundamental genetic principles of metastasis,” says Toner, the Benedict Professor of Surgery at Harvard Medical School (HMS). “We hope to develop this technology to the point where it could be used for early diagnosis, which is the ‘Holy Grail’ that all of us working on CTC technology have been striving for.”

Ravi Kapur, PhD, of the Center for Engineering in Medicine, leader of the innovation team within the MGH Circulating Tumor Cell Center, says, “The CTC-iChip provides a first-in-class device for high-efficiency, high-speed tumor cell sorting from a clinically relevant blood volume. The chip is designed for mass manufacturing, and simple automation for clinical translation.” The team is working with collaborators at Veridex and Janssen to refine the system for commercial development.

Study co-author Daniel Haber, MD, PhD, director of the MGH Cancer Center and Isselbacher/Schwartz Professor of Oncology at HMS, adds, “The study of cancer metastasis has been limited by the inability to quickly and reliably isolate tumor cells in transit in the blood. This new approach is likely to be a game changer in the field.”

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: EurekAlert!

Next-Generation Circulating Tumor Cell Test Demonstrates High Efficiency and Accuracy in New Study

Veridex, LLC (Veridex) recently announced that the first study of the company’s next-generation circulating tumor cell (CTC) technology, developed in collaboration with researchers at Massachusetts General Hospital (MGH), has been published in Science Translational Medicine. The collaboration, initially announced in January 2011, has led to the development of a next-generation CTC (or “liquid biopsy”) technology that offers enhanced specificity and sensitivity and enables more extensive characterization of captured cells.

The new technology tests for CTCs from the blood of cancer patients using advanced microfluidic separation techniques integrated with innovative magnetic sorting to isolate a broad spectrum of rare circulating cancer cells. This technology will allow physicians to get information about a patient’s cancer at the time treatment is being administered, one of the key components to enabling personalized medicine.

Results from the in vitro study showed the integrated system enabled the processing of large blood volumes with high throughput and efficiency, and also allowed for the ability to isolate CTCs from both epithelial and non-epithelial cancers.

In the study, the technology was used to identify the presence of CTCs in patients with cancers of the lung, prostate, pancreas, breast, as well as melanoma.

“Veridex is proud to have introduced CELLSEARCH®, the first and only FDA-cleared CTC test, and we’re excited to work with the team at Massachusetts General Hospital on our next-generation test,” said Nicholas C. Dracopoli , Ph.D., Vice President and Head of Oncology Biomarkers, Janssen Research & Development, LLC. “Together, Veridex and the MGH team bring more than 25 years of experience in rare cell technology to this project. We’re encouraged by the positive results from this study and the potential role this technology may play in helping to advance physicians’ ability to monitor their patients and develop more personalized treatment approaches.”

“These results show the possibility of its use for patients in ‘real time’ as they are receiving treatment. We hope that this next-generation CTC technology will become an everyday tool for doctors treating patients with cancer,” said Mehmet Toner , Ph.D., director of the BioMicroElectroMechanical Systems Resource Center in the Massachusetts General Hospital.

How It Works

The system used two modes of immunomagnetic sorting to isolate CTCs: a positive selection mode to identify and tag target CTCs based on expression of the epithelial surface marker EpCAM (“epithelial cell adhesion molecule”), and a negative selection mode, in which the blood sample is depleted of leukocytes by tagging them with specific antibodies. The test’s ability to isolate CTCs in this manner allows for RNA-based, single cell molecular characterization and expression analysis of CTCs. It will also allow for the test to be used in a broader range of cancers, including cells undergoing epithelial-mesenchymal transition (EMT) and cancer stem cells.

The technology integrates three sequential processes in a single automated system to capture clinically significant CTCs. First, after whole blood samples have been labeled with magnetic beads, the system separates nucleated cells, including CTCs and white blood cells, from red blood cells and platelets with minimal cell loss. Next, the system aligns nucleated cells in a single file within a sorting channel. Finally, the magnetically tagged cells are deflected into a collection channel for identification. These three integrated functions replace the need for separate cell lysis (break down), centrifugation and sorting steps.

About Circulating Tumor Cells

Circulating tumor cells are cancer cells that have detached from the tumor and are found at extremely low levels in the bloodstream. The value of capturing and counting CTCs is evolving as more research data is gathered about the utility of these markers in monitoring disease progression and potentially guiding personalized cancer therapy.

Study: Inertial Focusing for Tumor Antigen–Dependent and –Independent Sorting of Rare Circulating Tumor Cells

Source: PR Newswire