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Trial Testing Genetic Profiles for Personal Cancer Therapy

Apostolia M. Tsimberidou

Apostolia M. Tsimberidou (MD Anderson Cancer Center)

15 August 2014. MD Anderson Cancer Center in Houston and Foundation Medicine in Cambridge, Massachusetts are testing the benefit of genetic profiles of tumors in determining personalized therapies for patients with metastatic cancer. The researchers conducting the trial also believe genetic profiling can better match cancer patients to studies of new treatments, and lead to faster and less expensive clinical trials.

The study, called Initiative for Molecular Profiling in Advanced Cancer Therapy or Impact2, aims to enroll 1,362 patients with metastatic cancer, that is spreading from the original tumor to other parts of the body. Patients will have tissue from their tumors analyzed to reveal mutations and other variations in their genetic compositions. Foundation Medicine, a developer of genomic analysis systems, is conducting the profiles to find if any molecular factors are contributing to their cancer.

If any genetic alterations are found in the profile, and an FDA-approved treatment for that type of tumor is available, the patients will receive that treatment. In case genetic alterations are found, but no treatments are yet approved, the patients will be randomly assigned either to take part in a clinical trial of a treatment addressing the alteration, or receive the standard of care.

Likewise, if no genetic alterations are found, patients will receive the standard of care. The primary outcome measure is progression-free survival, the length of time following treatment that the patient survives, but without the cancer getting worse.

The new trial is a follow-up to a study of molecular profiling for cancer therapies conducted by MD Anderson called Impact1 and reported in 2011. That earlier trial enrolled more than 1,100 cancer patients, of which 40 percent were found with some kind of genomic alteration. Of those receiving the targeted treatments based on the genetic analysis, 27 percent of patients responded, compared to 5 percent of those receiving the standard of care.

This approach to identifying patients aims as well to speed up the recruitment process for clinical trials. The analysis by Foundation Medicine is expected to take three weeks following initial enrollment, after which physicians can guide their patients’ treatments, including participation in a clinical trial. Foundation Medicine says its system has a more advanced analytical engine than the system used earlier, thus more patients with genetic variations in their tumors are expected to be found.

“This is a collaborative and institutional-wide effort to improve patient care and accelerate the drug development process,” says Apostolia Tsimberidou, professor cancer therapeutics at MD Anderson and study director. “If the results of IMPACT1 are confirmed, cancer treatment will be transformed and comprehensive molecular profiling will become the standard of care.”

Tsimberidou tells more about the trial in the following video.

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System Tests Quality of Engineered Stem Cells, Tissue

Human embryonic stem cell colony (Clay Glennon/Univ of Wisconsin-Madison, NIGMS)

Human embryonic stem cell colony (Clay Glennon/Univ of Wisconsin-Madison, NIGMS)

14 August 2014. Biomedical engineers and systems biologists developed an online system that tests the fidelity of engineered cells and tissue to the real-life properties of the cells they aim to emulate. The system, known as CellNet, is the creation of researchers from Boston Children’s Hospital, Boston University, and the Wyss Institute for Biologically Inspired Engineering at Harvard University, and described in  pair of articles appearing in this week’s issue of the journal Cell (paid subscription required).

CellNet tests the quality in induced pluripotent stem cells, those reprogrammed from skin or blood cells, as well as specialized cells, — e.g., liver, heart, or brain cells — derived from induced pluripotent or embryonic stem cells, and specialized cells made from other specialized cells. In addition, CellNet highlights improvements in the engineering process to improve cell quality.

CellNet takes a cell’s gene expression profile and returns its likelihood of being classified into one of 16 human or 20 mouse cell and tissue types, which applies strict criteria to determine how close the engineered cells or tissues resemble the real thing, what CellNet calls “training data.” In this process, an algorithm compares the network of genes activated or inhibited in the engineered cell, known as the gene regulatory network, and returns specific improvements for improving the cell or tissue engineering process.

In one study, the team used CellNet to analyze gene expression data from 56 published studies for assessing the quality of 8 kinds of engineered cells created in those studies. In the second study, researchers tested with CellNet two specialized types of direct cell conversions: (1) skin to liver cells, and (2) immune system B cell lymphocytes to macrophages, white blood cells in the immune system that ingest foreign material. In both articles, the researchers found shortcomings in the conversions and highlighted fixes in the genetic engineering process to plug the gaps.

The team likewise identified a few patterns in the conversions for further gene or tissue engineering initiatives. The gene regulatory networks of engineered cells derived from induced pluripotent stem cells, for example, were very similar to the networks of cells from embryonic stem cells, suggesting induced pluripotent stem cells can provide a feedstock of about equal quality as embryonic stem cells.

In addition, the gene regulatory network of engineered cells grafted into lab mice begins to resemble the network of the target tissue, suggesting the body is sending signals to the engineered cells to enhance their performance. However, most specialized cells made from other specialized cells retain some of the properties of the original cells, which depending on their purpose, can be an advantage or disadvantage.

The team still notes, however, that transforming induced pluripotent stem cells into specific tissues remains a more effective strategy than converting one specialized cell into another, despite the laborious process of first creating pluripotent stem cells. With pluripotent stem cells, the engineered cells or tissue have gene regulatory networks more like the real-life cells or tissue.

“Most attempts to directly convert one specialized cell type to another have depended on a trial and error approach, says Patrick Cahan of Boston Children’s Hospital and the principle designer of CellNet in a Wyss Institute statement. “Until now, quality control metrics for engineered cells have not gotten to the core defining features of a cell type.”

CellNet is freely available online, and can be used as a hosted service or downloaded to run locally.

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Biotech, Institutes Discover Target for Multiple Tumors

EphA3 illustration (Protein Data Bank/Wikimedia Commons)

14 August 2014. Researchers in the U.S. and Australia identified an enzyme found in a range of cancerous tumor cells, but not normal adult tissue, and tested an engineered antibody to fight that enzyme in tumors. The team from the biotechnology company KaloBios Pharmaceuticals Inc. in South San Francisco, California, and Monash University and Ludwig Institute for Cancer Research, both in Melbourne, Australia published its findings in this week’s issue of the journal Cancer Research.

KaloBios develops engineered antibodies to treat cancer, cystic fibrosis, and asthma. One of its therapy candidates, code-named KB004, inhibits the actions of the gene Ephrin type-A receptor 3 or EphA3 that expresses an enzyme active in the development of many fetal organs, but also occurs in some blood-related cancers.

In the study led by Andrew Scott of the Ludwig Institute, the researchers found EphA3 enzymes over-expressed in the internal cellular environment of tumors. In tests where lab mice were grafted with human cancer cells, the team found EphA3 in stem cells derived from the mice’s bone-marrow, where the enzyme contributes to the growth of blood vessels feeding the tumors as well as the tumor’s supporting tissue.

Scott and colleagues also treated the cancer grafts with a specific antibody designed only to combat EphA3. The researchers found the antibody kills the stem cells in the tumors with EphA3. The antibody also severely disrupts the formation of blood vessels and supporting tissue in the tumors from cancer grafts. In addition, the researchers noted EphA3 appears only in the tumor cells and not in other cells in adult mice.

KB004 is now being tested in a combined early/intermediate-stage clinical trial with patients having several types of blood related cancers including various types of leukemia and multiple myeloma. In a company statement, Geoffrey Yarranton, KaloBios’s chief scientist and co-author of the paper, says the results of the study provide a rationale to expand the scope of KB004 to solid tumors as well as blood-related cancers.

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Middle, Inner Ear Drug Developer Raises $100M in IPO

Hearing loss (


13 August 2014. Otonomy Inc., a biopharmaceutical company in San Diego developing treatments for disorders of the middle and inner ear, raised $100 million in its initial public offering of stock. The company, trading on the NASDAQ under the symbol OTIC, priced its 6.25 million shares at $16.00.

Otonomy was founded in 2008 by physicians and researchers in otolaryngology — ear, nose, and throat specialists — from University of California at San Diego and biotechnology investors, including Jay Lichter from Avalon Ventures, who developed Ménière’s disease, a chronic inner-ear disorder that affects balance and hearing. The company focuses on treatments for middle and inner ear disorders, which it says are not being adequately met with current therapies.

Inner and middle ear conditions include Ménière’s disease, ear infections, tinnitus (ringing in the ears), and hearing disorders. One reason for the lack of adequate therapies, says the company, is the inner and middle ear anatomical structure, including the eardrum and other membranes, that limits access to areas needing the treatments, or prevents fluid treatments from being retained. In addition, treating middle ear infections with repeated antibiotics, the current standard therapy, runs the risk of developing resistance to the antibiotics.

Otonomy’s technology offers a drug delivery system to overcome these limitations that provide therapeutics directly to affected regions and are retained in the ear for a period of time after a single dose. The system combines drug microparticles in a suspension with a heat-sensitive polymer. The polymer is administered as a liquid injected into the middle ear that at body temperature becomes a gel, which is more readily retained.

The company’s lead product is AuriPro, a formulation of the antibiotic ciprofloxacin to treat bacterial infections associated with middle ear effusion, the build-up of fluid in the middle ear, requiring surgical placement of a tube to equalize the pressure. About one million of these surgeries are performed each year, mainly in children age 5 and younger. Ontonomy says two late-stage clinical trials of AuriPro with children show the treatments achieved their desired outcomes compared to a sham procedure, with regulatory filings for the drug expected soon.

The company has two other drug candidates in development. OTO-104 is a treatment for Ménière’s disease currently being tested in an intermediate-stage study of 140 patients in the U.S. and Canada, with results expected in the first quarter of 2015. OTO-311 is a treatment for tinnitus that reformulates gacyclidine, a drug with neuroprotective properties, into a single-dose treatment. Otonomy expects to file a new drug application for OTO-311 next year.

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Hat tip: Fortune/Term Sheet

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Genetically Engineered Medflies Found to Control Wild Types

Mediterranean fruit fly

Mediterranean fruit fly (Oxitec Ltd.)

13 August 2014. Researchers at the biotechnology company Oxitec Ltd. in Oxford and University of East Anglia in Norwich, both in the U.K., created a modified form of the Mediterranean fruit fly that tests show can reduce the population of this pest responsible for extensive crop damage in many parts of the world. Results of the research from the team that includes colleagues in Greece, where field work was conducted, appear online today in the journal Proceedings of the Royal Society B.

Mediterranean fruit fly, known by the short-hand term medfly, infests more than 300 wild and cultivated fruits, vegetables, and nuts worldwide. Damage from medflies affects crops in southern Europe, Middle East, Australia, Pacific Islands, Africa, Central and South America, Caribbean, and parts of the U.S. The pest is difficult to control, and techniques for containing or eliminating medflies — quarantines, baited traps, insecticides, and inflicting natural enemies on the species — return mixed results. Some of these techniques, such as traps and insecticides, can involve dangerous chemicals.

Yet another control method is the sterile insect technique that introduces forms of the male medfly into the population prevent further generations of the pest by producing weakened offspring that die off before maturity or only males. This technique also produces mixed results, with the radiation for generating the sterile forms believed to cause weakened medflies that cannot compete with stronger wild types.

The Oxitec/East Anglia team took a different approach to controlling medflies, creating a robust form of the male insect genetically-engineered to produce only male offspring. The technique, known as release of insects carrying a dominant lethal or RIDL, in this case adds a gene to the males where the RIDL is lethal only to females. Releasing these robust yet engineered male medflies into the wild population, therefore, should over time cause the wild medfly population to collapse.

The researchers tested this premise in greenhouses at University of Crete in Greece, having cages that simulated fruit orchards with a lemon tree and food and water sources. The team released into each cage a precise number of wild-type medflies in the pupal stage, between larva and adult. After 6 weeks, the researchers began releasing genetically engineered male medflies each week into half of the cages, with the other cages serving as controls.

The results show the cages with the modified males experienced declining numbers of wild medflies until the wild types disappeared. The researchers found after 6 weeks, production of eggs in the cages with the engineered males began declining. In addition, more males with the added female-lethal gene increased in the test cages, until the original wild-type form of medfly became extinct by about week 17. At the same time, the number of wild-type medflies in the cages without the modified males remained about the same.

Oxitec is now seeking approvals to carry out open-field studies with engineered medflies.  The company develops RIDL-based solutions for medflies and other species: diamond back moth, pink bollworm, mexfly, and olive fly.

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23andMe, Pfizer Partner on Bowel Disease Genetics

DNA strand (


12 August 2014. The pharmaceutical company Pfizer and personal genetics company 23andMe in Mountain View, California are researching genetic factors associated with inflammatory bowel disease, for which Pfizer is testing several treatments. Financial aspects of the collaboration were not disclosed.

Inflammatory bowel disease is the name given to disorders of the digestive tract, such as Crohn’s disease and ulcerative colitis. Centers for Disease Control and Prevention says the conditions are responsible for 700,000 doctor visits as well as 100,000 hospitalizations each year in the U.S., and because there is no cure, they require a lifetime of care.

Crohn’s disease results in inflammation of the digestive tract lining and can spread deep into affected tissues. The disorder is characterized by diarrhea and abdominal pain, and can lead to malnutrition. With ulcerative colitis, the inflammation usually affects the inner lining of the large intestine and rectum. Symptoms can range from pain, diarrhea, and rectal bleeding to unintended weight loss, dehydration, and shock.

Under the agreement, the companies will explore genetic factors influencing the onset of inflammatory bowel disease, as well as its progression, severity, and variations in response to treatments. Some 10,000 participants residing in the U.S.  with inflammatory bowel disease will be recruited for the study. There will be no charge for participants, with all data kept anonymous, according to 23andMe.

Each participant will be asked to provide a saliva sample that 23andMe will analyze for genomic composition. Participants will also be asked to complete a 15-minute online survey about their experiences with the disease. People taking part will receive 23andMe’s standard personal genome analysis, including ancestry, as well as a DNA profile that their physicians can review for medical implications.

Pfizer is testing several compounds and biologics in clinical trials for inflammatory bowel disease. Its current rheumatoid arthritis drug tofacitinib, marketed under the name Xeljanz, is in a late-stage trial as a treatment for ulcerative colitis. Pfizer is also testing tofacitinib for Crohn’s disease in an intermediate-stage study.

The biologics code-named PF-00547659, PF-04236921, and PF-05285401 are likewise in intermediate-stage trials for Crohn’s disease and ulcerative colitis. In addition, the biologic code-named PF-06480605 is in an early-stage trial to treat Crohn’s disease.

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Heart Assn Challenge Seeks Heart Disease Prevention Tools

Heart angiogram


11 August 2014. American Heart Association seeks new products to better prevent and manage heart disease and stroke in an open-innovation challenge for early-stage companies in the Midwest. The top three winners will be eligible for awards of up to $20,000, and a chance to pitch their ideas at a November forum on health care innovation in Chicago. The deadline for applications is 12 September 2014.

The competition, sponsored by American Heart Association’s Chicago affiliate, is looking for new ideas from life science and medical technology start-ups that help patients or health care providers prevent or manage cardiovascular disease and stroke. The solutions sought in the challenge should help American Heart Association achieve its goal to improve the cardiovascular health of all Americans by 20 percent while reducing death from cardiovascular diseases and stroke by 20 percent by the year 2020.

The group defines early-stage companies as those raising less than $5 million in investment capital and generating less than $150,000 in revenue. The competition is open to entrants with a presence in the states of Illinois, Indiana, Iowa, Michigan, Missouri, or Wisconsin.

The challenge has two phases. In phase 1,  competitors submit their applications through an online portal, due by 12 September. A panel of judges will review the applications and select 10 finalists, who will seek public support through social media and crowdfunding on the MedStartr platform. That campaign will run from 30 September through 5 November.

The 10 finalists will be evaluated on technical and innovative merit by a team of judges, which will make up half of the total score. Donations and social media shares accumulated during the campaign will comprise 30 and 20 percent respectively of the total score.The announcement of the top three finalists will be made on 8 November.

The three top winners will have an opportunity pitch their ideas at this year’s Heart Innovation Forum in Chicago on 14 November. American Heart Association says the one-day meeting brings together business leaders with physicians and researchers to find new ways of speeding the translation of science into treatments for heart disease and stroke. The group anticipates a turnout of 250 for the forum with entrepreneurs and investors among those expected to attend.

Based on their presentations, the first-place winner will win a grant of $20,000, with two runners-up receiving grants of $2,500 each — in addition to funds raised earlier on MedStartr.

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Licensing Deal Combines Genomics, Placenta Stem Cells

Two pregnant women (Michelle Tribe/Flickr)

(Michelle Tribe, Flickr)

11 August 2014. A new licensing agreement will make available research by Celgene Cellular Therapeutics on stem cells from the placenta to Human Longevity Inc., a company specializing in genomics for age-related disorders. Financial aspects of the agreement were not disclosed, but as part of the deal, Celgene is expected to make an equity investment in Human Longevity.

Celgene Cellular Therapeutics, a division of the biopharmaceutical company Celgene in Warren, New Jersey, develops therapies derived from the placenta and umbilical cord blood. The division includes LifeBankUSA, a placenta and cord blood banking service.

Celgene Cellular Therapeutics is testing in clinical trials placenta-derived stem cells to treat Crohn’s disease, peripheral artery disease, and diabetic foot ulcers. Another early-stage trial is testing the safety of placenta-derived stem cells to treat a range of blood-related cancers and genetic blood diseases.

Human Longevity Inc. in La Jolla, California was founded last year to design therapies and diagnostics based on genomics, stem cells, and informatics to address health issues related to human aging. The company says it aims to build the most comprehensive database of genetic variables and associated physiological traits. Human Longevity’s founders include genomics pioneer Craig Venter, stem cell researcher Robert Hariri, and entrepreneur Peter Diamandis, also creator of the X-Prize challenges.

Under the agreement, Human Longevity is licensing Celgene Cellular Therapeutics’s work on placenta-derived stem cells to develop into therapies for age-related conditions such as sarcopenia, associated with the degenerative loss of muscle mass and strength. Much of Human Longevity’s work is based on the premise that the genome changes as the body ages, including degradation to specialized cells, such as stem cells.

Human Longevity says it wants to explore placenta-derived stem cells as another source of healthy regenerative cells for combating the effects of age. The company plans to apply genomic sequencing to Celgene’s placenta-derived stem cells to learn more at the molecular level of their properties and therapeutic potential.

The two companies are hardly strangers. In addition to co-founding Human Longevity, Hariri is the founder of Anthrogenesis, the company acquired by Celgene in 2003 that became Celgene Cellular Therapeutics. Hariri is also senior author of a study by Celgene researchers published in May on the ability of placenta-derived stem cells to stimulate immune system responses.

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Trial Shows Stem Cell Treatment Feasibility for Stroke

CT scan of stroke victim's brain (National Library of Medicine)

CT scan of stroke victim’s brain (National Library of Medicine)

8 August 2014. An early-stage clinical trial shows treating stroke patients with their own bone-marrow stem cells is safe and feasible, and provides evidence of improving cognitive and motor functions. The study conducted by Imperial College London and affiliated hospitals in the U.K. appears today in the journal Stem Cells Translational Medicine (registration required).

The study was led by Nagy Habib, a professor in Imperial’s medical school and surgeon at Hammersmith Hospital Campus. Habib is also founder of OmniCyte Ltd, one of the study’s funders and a spin-off company from Imperial College commercializing research by Habib on stem cells. Myrtle Gordon, an Imperial medical faculty colleague of Habib’s, is a co-author of the paper and a principal with OmniCyte.

The clinical trial tested a therapy from a certain type of stem cell, known as CD34+ stem/progenitor cells, as a treatment for ischemic stroke, where a blood vessel to the brain becomes obstructed. CD34+ cells are derived from bone marrow and have been shown in earlier studies with animals to promote blood vessel formation. Ischemic stroke accounts for about 7 of every 8 stroke cases.

In this study, Habib and colleagues tested the ability of CD34+ stem cells to stimulate growth of healthy blood vessel and brain tissue in the area of the brain affected by stroke. The paper reports on 5 patients who received transplants of their own CD34+ cells within 7 days of a severe stroke. The CD34+ cells were delivered with a catheter into the middle cerebral artery.

The main purpose of the trial was to test the treatment’s safety, and the authors say the procedure was well tolerated by all patients, with no adverse affects. The study also looked for evidence that the treatments had some clinical benefit for the patients, measured by standard observational scales of disability and cognitive and motor functions. The authors report the patients showed improvement on the observational scales, as well as lower brain lesion volumes in the 6 months following the treatments.

The results from a small sample are still not considered conclusive, but the authors say they provide enough evidence to keep working on therapies with this technology. “Scientific evidence from our lab further supports the clinical findings,” says Habib in an Imperial College statement, “and our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room.”

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Graphene Sensor Designed for Wearable Disease Detection

Girish Kulkarni and Zhaohui Zhong

First author Girish Kulkarni, left, and Zhaohui Zhong testing the graphene sensor (Joseph Xu, University of Michigan)

7 August 2014. Engineers at University of Michigan in Ann Arbor designed a sensor from graphene that makes it possible to embed the technology into wearable devices for disease detection. The team from the labs of electrical engineering professor Zhaohui Zhong and biomedical engineering professor Sherman Fan published their results last month in the journal Nature Communications (paid subscription required).

The Michigan team is aiming at a market for wearable technologies that is expected to grow to $70 billion by 2024, according to market analysis company IDTechEx. The university filed a provision patent on the technology and the researchers are taking part in Innovation Corps, a National Science Foundation program to help academic scientists become entrepreneurs and turn their discoveries into marketable goods and services. In June, NSF extended the Innovation Corps program to National Institutes of Health to move more biomedical discoveries into the marketplace.

Zhong, Fan, and colleagues designed the sensor to detect chemical indicators of disease, exhaled or emitted through the skin. Current nano-electronic sensors for this purpose detect a change in the electric charge between the molecules being detected and the sensor. With today’s technology, say the researchers, the molecules being detected develop a strong bond with the sensor, which slows the sensor’s action and requires a higher concentration in the air or solution.

The Michigan technology takes a different approach. The researchers adapted a process known as heterodyne mixing that interacts two or more signals to generate a new frequency. In this case, the sensor detects the interaction of imbalances in polarity among the chemical molecules, called molecular dipole moments. With graphene in the sensor, the team used a material related to graphite, consisting of a single atomic layer of carbon atoms arrayed in a hexagonal mesh pattern that’s light, strong, chemically stable, and can conduct both heat and electricity.

The researchers report the sensor detects various chemical vapors in the lab that can serve as indicators of disease, such as acetone for the detection of diabetes, and nitric oxide to detect asthma. In addition, the sensor detects test substances in tenths of a second, much faster than current technology, and in concentrations measured in a few parts per billion.

The team says the technology would be part of a miniature gas chromatography system that integrates the graphene sensors in a single low-power chip, embedded in a badge-sized device worn on the body. The device could also be applied to sensing the presence of dangerous chemicals or monitoring environmental air quality.

“With our platform technology, we can measure a variety of chemicals at the same time, or modify the device to target specific chemicals,” says Zhong in a university statement. “There are limitless possibilities.”

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