Search for brain tumor biomarkers in urine strikes gold

By Tom Ulrich

A good biomarker is one whose levels go up or down as a patient’s disease worsens or wanes. A great biomarker also gives key insights into disease development. A really great biomarker does both of these things and also serves as a treatment target.

With a protein called netrin-1, Edward Smith, MD, and Michael Klagsbrun, PhD, seem to have hit the trifecta. In a recent paper in Cancer Research, they report a clear relationship between urine netrin levels and medulloblastoma, the most common malignant brain tumor of children.

And show that netrin fuels the tumor’s invasion into healthy brain tissue.

And that blocking netrin may, at least in the laboratory, check the tumor’s spread.

From brain to bladder

For years, Smith – a brain surgeon and Boston Children’s Hospital’s director of pediatric cerebrovascular surgery – has been searching for ways to use urine to watch for relapses in children with brain tumors.

Vector

The search started when Smith attended a seminar by Marsha Moses, MD, PhD, director of the hospital’s Vascular Biology Program (VBP), who studies urine biomarkers for ovarian and breast cancer. Inspired, he started learning from her how to isolate proteins from urine and assess them as potential biomarkers.

In 2008, the pair showed that a panel of urine biomarkers correlated with the presence of a variety of brain tumors. But just knowing a tumor is there wasn’t enough for Smith. As a surgeon, he wanted to know what the tumor is doing.

“The biggest problem I face as a surgeon is invasion,” he says. “Invasive tumors put fingers out into the surrounding tissue, making them harder to operate on. They’re also harder to treat with chemotherapy and radiation and more prone to metastasis.”

While gene signatures can tell us something about a medulloblastoma’s behavior, reading those signatures requires having tumor tissue on hand. Gene signatures also can’t help track a brain tumor’s response to treatment – at least not without taking additional biopsies – or raise an alarm if a tumor returns. Those are things that are best detected using markers pulled from an easily collected fluid. And urine is probably the easiest, least invasive fluid of all.

Marker hunters

Michael Klagsbrun, PhD
Michael Klagsbrun, PhD

To home in on urine markers that could provide intel on tumor presence and behavior, Smith teamed up with Klagsbrun. For more than 40 years, Klagsbrun has been working in the VBP to tease apart the intricate web of chemical signals influencing blood vessel growth (angiogenesis) and cancer development. He is particularly interested in semaphorins, a family of axon guidance factors that influences nerve growth during development and also seem to play a role in angiogenesis.

Netrin is also an axon guidance factor. During fetal development, netrin and semaphorins work in opposition. Netrin creates a trail of chemical breadcrumbs that young nerve fibers follow as they grow. Semaphorins block or deflect nerve growth.

“There’s a balance between them,” Klagsbrun says, “between pro-growth and anti-growth.” Or, as Smith puts it, “Netrin is like the gas, semaphorins the brakes.”

Looking at cell lines, the pair found that netrin holds a great deal of pro-growth sway over medulloblastomas. Adding netrin to medulloblastoma cell lines caused a jump in tumor cell invasion while also activating a signaling pathway known to be involved in cancer development (thus making netrin a potential therapeutic target.) At the same time, blocking netrin using a variety of techniques (e.g., receptor blockade, siRNA, neutralizing antibodies and small molecules) reduced invasion.

Nimbler tumor screening

Michael Klagsbrun, PhD
Edward Smith, MD

Turning to patient samples, Smith and Klagsbrun found that the tumor cells of one patient produced significantly more netrin than adjacent, normal brain cells. They also found that urine from 16 medulloblastoma patients contained between five and 10 times as much netrin as urine from 12 healthy controls, and that urine netrin levels drop after a patient undergoes surgery.

As a bonus, urine levels alone could single out patients with highly invasive tumors, the ones that had spread more aggressively.

“You can’t always see on an MRI if a child will have an invasive tumor,” Smith notes. “But here we saw a gradient of netrin levels that increased as we looked from healthy controls across to high-risk patients.”

For the moment, Smith envisions cheaper, measurable and more frequent screening of medulloblastoma patients after treatment.

“Measuring urine netrin could help guide decisions about when a patient might need a scan and additional treatment,” he says. “The ‘pie-in-the-sky’ scenario would be to use urine biomarkers like netrin to tailor a patient’s treatment regimen. Because urine proteins change more quickly than scans, we could be more nimble with our treatment approach.”

RSS From Medical Design & Outsourcing

  • Molex delivers ISO 13485-compliant, medical-grade surgical cables from its class 100,000 clean room facility
    Molex, LLC operates a fully ISO 146441-1:1999 Class 8-certified clean room, satisfying strict particulate contamination levels specified by ISO-compliant requirements. Located in Thailand, the facility has less than 100,000 particulates (≥0.5µm) per cubic foot of air and manufactures a variety of ISO 13485-compliant medical cables and surgical cables used in operating theatres, hospitals, laboratories and […]
  • Swept-Source OCT: Patent license agreement between Massachusetts General Hospital and Heidelberg Engineering
    Heidelberg Engineering has entered into a patent license agreement with Massachusetts General Hospital (MGH) in Boston. The agreement grants global and exclusive rights to 77 basic patents and patent applications which relate to swept-source OCT technology and its application in ophthalmology. Spectral domain OCT has become indispensable to eye care professionals worldwide to diagnose and […]
  • MIT’s MultiFab presents a stark challenge to incumbent 3D Printer manufacturers’ hardware, software, and business Models
    MIT’s Computational Fabrication Group recently announced the MultiFab, a low-cost 3D printer that can combine up to 10 different resins in one part and also includes a 3D scanning system to identify and fix errors during production. According to Lux Research, these capabilities are rare in commercial 3D printers today due to the manufacturers’ need […]
  • AVX releases Accu-P MP medical grade film chip capacitors for medical devices
    AVX Corporation, a leading manufacturer of passive components and interconnect solutions, has released a new series of thin film chip capacitors specifically designed to meet the demanding performance specifications for implantable medical devices. Delivering extremely tight capacitive tolerances, exceptionally repeatable performance, and remarkably low ESR and high Q at high frequencies—including VHF, UHF, and RF […]
  • RIVANNA commences manufacturing of its Accuro device
    Rivanna Medical announced that it has begun manufacturing its FDA-cleared Accuro device, a handheld and untethered smart-phone-sized device that is designed to guide spinal anesthesia with automated 3D navigation technology in addition to ultrasound imaging of abdominal, musculoskeletal, cardiac and peripheral vascular anatomies. The product will be launched at the ASA annual meeting in San […]
  • FDA seeks public input on Quality Metrics guidance
    by Oliver Wolf, Senior Product Manager, MasterControl In line with the general shift towards risk-driven approaches in the quality management world, FDA is now taking steps towards applying those same principles to its own auditing schedule. At the end of July, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation […]
  • First ‘Ear Wear’ for Active Adults Debuts with MDHearingAid FIT
    If you’ve burned out your ears with earbuds, headphones or decades of other audio abuse but aren’t ready for your grandmother’s hearing aids, not to worry! The new MDHearingAid FIT gets you back in the game with a tiny, FDA-registered, one-size-fits-most solution that doesn’t block your ear canal like old-fashioned in-the-ear hearing aids. The FIT feels […]
  • CardioGenics enters into manufacturing agreement with Ontario-based Plasticap
    CardioGenics Holdings, developer for the In-Vitro-Diagnostics (“IVD”) testing market, announced that it has entered into a manufacturing agreement with Plasticap of Ontario, Canada, pursuant to which Plasticap will manufacture CardioGenics’ proprietary self-metering cartridges for its QL Care analyzer. The term of the agreement is three years and the purchase price for each cartridge shall be […]
  • MTD Micro Molding releases micro materials menu
    MTD Micro Molding, a long-time leader in micro-injection molding, has released an updated “Materials Menu” of materials that can be successfully micromolded to help guide engineers at medical device companies. Material selection is a crucial step in product manufacturability. The correct material drives tolerance, dimension, strength, usabality, speed-to-market, design, critical features, and cost. Through MTD’s […]
  • MedTech Chat: Elastic technology for drug delivery
    Dr. Zhen Gu and Dr. Yong Zhu from North Carolina State University are both co-senior authors of a research paper describing their recent work. Dr. Gu, Dr. Zhu and other researchers from North Carolina State University and the University of North Carolina at Chapel Hill have developed a drug delivery technology that consists of an […]
  • B. Braun’s OEM Division offers large bore normally closed low-pressure check valves
    Infusion therapy and pain management device manufacturer B. Braun said today it is offering normally closed large-bore low-pressure check valves through its valve-focused contract manufacturing OEM division. The valves, offered by Bethlehem, Pa.-based B. Braun, are designed for the intermittent injection of fluids during medical treatment and open automatically when pressure is applied. The newly […]

Leave a Reply