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Scientists Identify Biomarker to Predict Immune Response Risk After Stem Cell Transplants

Researchers from Indiana University, the University of Michigan, the Fred Hutchinson Cancer Research Center and the Dana-Farber Cancer Institute have identified and validated a biomarker accessible in blood tests that could be used to predict which stem cell transplant patients are at highest risk for a potentially fatal immune response called graft-versus-host disease.

Although transplant specialists have been able to reduce its impact, graft-versus-host disease remains a leading cause of death among patients who receive a stem cell transplant from another person, known as an allogeneic transplant. Such transplants are used to treat blood and bone marrow cancers such as leukemia and multiple myeloma, often as a last resort. Graft-versus-host disease occurs when immune cells from the transplant see the patient’s body as foreign and attack it.

Approximately 20,000 allogeneic stem cell transplants were performed worldwide in 2012. Thirty to 40 percent of stem cell transplant recipients whose donor is related will experience graft-versus-host disease. The percentage could rise to 60 to 80 percent if the patient and donor are not related.

The researchers found that patients with a high level of a protein named ST2 were more than twice as likely to have graft-versus-host disease that resisted standard treatment with steroids; and nearly four times as likely to die within six months of the transplant. Their findings were reported in the Aug. 8 edition of the New England Journal of Medicine.

“What we found particularly significant was that this marker was a better predictor than the clinical severity of the disease when it was diagnosed,” said Sophie Paczesny, M.D., Ph.D., associate professor of medicine at the IU School of Medicine and senior author of the study.

Thus, patients with low ST2 levels were more likely to respond to treatment regardless of how serious their graft-versus-host disease was graded, while patients with high ST2 levels were less likely to respond to treatment, whether their disease was graded less serious or more serious.

“This blood test, which is currently available to clinicians, will make informed treatment possible as the clinicians will now be able to adjust therapy to the degree of risk rather than treating every patient the same way,” Dr. Paczesny said.

In addition, while the disease most commonly appears about 30 days after the transplant, higher ST2 levels in blood samples taken as early as 14 days after transplant — far before the clinical signs of graft-versus-host disease are apparent — were associated with an increased risk of death from the toxicity of the transplant.

Therefore, the authors noted, early identification of patients who likely won’t respond to standard treatments is important and would allow physicians to consider additional therapies and early intervention. On the other hand, patients with low risk will not need to have additional medicine further suppressing their immune system. But, they cautioned, additional large prospective studies are needed to better define the levels of risk predicted by the ST2 marker.

Study: ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. [New England Journal of Medicine]

Source: Indiana University School of Medicine

MolecularMD Corp. Obtains License to Commercialize Predictive Diagnostic Based on Actionable Biomarker, DDR2, for Uses in Lung Cancer and Targeted Kinase Therapy

MolecularMD Corp. recently announced that it has entered into a license agreement granting the company exclusive patent rights to cancer diagnosis technology. Specifically, MolecularMD has obtained rights to commercialize patent-pending intellectual property pertaining to DDR2 mutations for diagnostic, prognostic and predictive uses for humans in the area of lung cancer. Such patent rights are jointly-owned by The Broad Institute and Dana-Farber Cancer Institute. The inventors named on the patent are Drs. Matthew Meyerson, Peter Hammerman, and Alexis Ramos.

About DDR2 Mutations in Lung Cancer

Research into understanding the genetic basis of cancer has led to identification of novel biomarkers that have been successfully exploited with targeted therapies. In non-small cell lung cancer (NSCLC), several such targets have been discovered for adenocarcinoma including EGFR, ALK, and MET. Unfortunately, these therapeutic targets are not relevant for squamous cell carcinoma (SCC), which is the second most frequent histological subtype in NSCLC. Recent discoveries identified mutations in the discoidin domain receptor 2 (DDR2) of SCC patient tumors that are oncogenic and also responsive to existing drugs targeting kinase inhibition. DDR2 is a membrane receptor tyrosine kinase involved in cell adhesion, proliferation and migration. In xenograft models, DDR2-mutant tumors regressed under treatment with the tyrosine kinase inhibitor, dasatinib. Remarkably, an SCC patient with no detectable EGFR mutation had a long-term response to the combination of erlotinib plus dasatinib. This patient was found to harbor a DDR2 mutation further suggesting that DDR2 mutations may be clinically relevant. Given the availability of a variety of therapies targeting tyrosine kinases, these findings provide a rationale for designing clinical trials for patients with SCC using existing FDA-approved drugs such as dasatinib, imatinib, nilotinib and ponatinib as well as novel, selective tyrosine kinase inhibitors for DDR2.

MolecularMD is developing DDR2 diagnostic assays, including next-generation sequencing tests, for clinical trials exploring efficacy of targeted therapies and DDR2 clinical utility. MolecularMD provides comprehensive clinical trial support through its CLIA-certified and CAP-accredited Clinical Reference Laboratory. In addition, MolecularMD provides IVD development and manufacturing capability to support companion diagnostic device commercialization. MolecularMD will also support commercialization of DDR2 technology through sublicensing to clinical reference laboratories and diagnostic assay developers and manufacturers.

According to Dr. Greg Cox, MolecularMD’s Director of Licensing, “DDR2 is potentially the first actionable biomarker available for SCC patients, whose treatment options are currently limited to chemotherapy. It’s exciting that these patients may benefit from existing FDA-approved targeted therapies, and we are eager to support clinical trials examining these novel treatment possibilities and enable widespread access to DDR2 diagnostics.”

Cancer Biomarker Study Data Presented at the 2013 AACR Meeting

As we’ve done in previous years here at Biomarker Commons (AACR 2011 and AACR 2012), here’s a roundup of eight research studies on cancer biomarkers that were presented last month at the American Association for Cancer Research (AACR) Annual Meeting in Washington, DC. The theme of this year’s meeting was “Personalizing Cancer Care Through Discovery Science.”

  • Biomarker Analysis Identified Women Most Likely to Benefit From T-DM1

    According to data from a subanalysis of a phase III clinical trial that led the U.S. Food and Drug Administration to approve trastuzumab emtansine (T-DM1) in February, the amount of HER2 in tumors of women with metastatic, HER2-positive breast cancer might determine how much they benefit from the drug. The findings were presented by José Baselga, M.D., Ph.D., physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York.

    Source: AACR

  • Novel Serum Biomarker Bilirubin Predicted Lung Cancer Risk in Smokers

    Researchers from MD Anderson Cancer Center in Houston, Texas, used a unique multiphase study design for the metabolomics profiling of serum samples from non-small lung cancer patients, and showed that bilirubin is a potential biomarker for lung cancer risk prediction. Men who were smokers and had low bilirubin levels had increased risk for cancer incidence and mortality.

    Source: AACR

  • Biomarkers Discovered That May Help Predict Response to Drugs Targeting KRAS-mutated NSCLC

    Massachusetts General Hospital scientists have identified biomarkers that may help predict whether patients with KRAS-mutated non-small cell lung cancer (NSCLC) will respond to concurrent treatment with an MEK inhibitor and a PI3 kinase inhibitor, a drug combination currently being investigated in ongoing clinical trials.

    Source: AACR

  • Screening Blood Samples for Cancer-driving Mutations More Comprehensive Than Analyzing Traditional Tumor Biopsy

    Using a tool called BEAMing technology, which can detect cancer-driving gene mutations in patients’ blood samples, researchers from Dana-Farber Cancer Institute and Harvard Medical School showed that were able to identify oncogenic mutations associated with distinct responses to therapies used to treat patients with gastrointestinal stromal tumors (GIST).

    Source: AACR

  • More Accurate Markers Identified for Detecting Response to Epigenetic Drugs for Myelodysplastic Syndromes

    Researchers from the University of Southern California, Los Angeles, have identified and validated two DNA methylation markers that could help physicians better determine a patient’s response to DNA methyltransferase inhibitors (DNMTi) for the treatment of myelodysplastic syndromes (MDS).

    Source: AACR

  • Cohort Study Indicates That Selenium May Be Protective Against Advanced Prostate Cancer

    According to a data presented by researchers from Maastricht University in the Netherlands, a greater level of toenail selenium is associated with a significant decrease in the risk for advanced prostate cancer.

    Source: AACR

  • Comprehensive Genomic Analysis Identified Alterations in Head and Neck Cancer That Could Lead to Targeted Therapy

    A National Institutes of Health project to catalog the genetic alterations responsible for several types of cancer, in particular those with a poor prognosis, finds that head and neck squamous cell carcinomas are genomically heterogeneous. However, those cancer with certain distinctive patterns could be amenable to specific targeted therapies.

    Source: AACR

  • Novel Drug Combination Showed Antitumor Activity in Patients With Incurable BRCA-deficient Cancers

    Researchers from Dana-Farber Cancer Institute and Harvard Medical School have identified two orally available experimental drugs — sapacitabine and seliciclib — from phase I trial data that, when given sequentially, work together to elicit antitumor effects in patients with incurable BRCA-deficient cancers.

    Source: AACR

Firm Hopes Big Data Can Personalize Health Care

When Colin Hill’s father was diagnosed with later-stage prostate cancer last summer, he was treated the same as every other patient with the illness.

This standardized approach bothered Hill, who believes medicine should approach each patient’s illness as unique, with medication tailored to the person’s history and biology.

“You show up to the hospital, and it’s like Groundhog Day,” Hill said, with patients being cared for the same way, over and over again. “It’s this outdated standard of care created for this hypothetical average patient. But no one’s an average patient.”

A genetic analysis of the tumor in his 69-year-old father, Foster Hill, found he had a genetic variant of the cancer that does not usually respond well to the hormone therapy Lupron, the current standard of care. But not knowing what else would work, doctors gave Foster Hill Lupron anyway. Luckily, the treatment seems to be helping, and his father’s outlook is much improved.

Hill hopes a Kendall Square company he founded 13 years ago, GNS Healthcare, will eventually improve medical care for his father — and for countless others — by providing personalized treatment. GNS is among the leaders in using Big Data analytics to learn more about diseases, patients, and treatments.

With data from thousands of cases, GNS uses artificial intelligence to determine what treatment made the crucial difference for each patient.

The company is deploying enormous computing power to produce a more complete understanding of treatments for rheumatoid arthritis, diabetes, cancers, and other illnesses.

For example, it is working with the Dana-Farber Cancer Institute and Mount Sinai Medical School to build a computer model of multiple myeloma, so researchers can better understand what works well for patients today, as well as develop more effective treatments for the blood cancer. It is involved in a similar collaboration with Brigham and Women’s Hospital and several other partners to learn more about multiple sclerosis.

Harvard Medical School recently agreed to use a GNS computing platform to analyze how cells replicate or transform into different types, for insights into­ conditions such as cancer and neurodegenerative diseases, Hill said.

And the company has a partnership with the Centers for Medicare & Medicaid Services and Health Services Advisory Group to assess health care quality measures, as well as other recent deals with pharmaceutical companies, hospitals, and advocacy groups, and the insurance giants Aetna and Blue Cross Blue Shield.

“It’s exciting times for us,” Hill said, after 13 years of developing his approach to analyzing health care. “We are now in the thick of things.”

Hill did not always have such an absorbing interest in science. He went to college at Virginia Tech — mainly to play tennis. “I was more serious than I was good,” he quipped.

But while there, he became fascinated by physics and chaos theory — the idea that complex patterns could result from simple rules.

His imagination was stoked by a summer job in 1996 at Santa Fe Institute, an interdisciplinary research center focused on highly complex issues. Hill then went on to graduate from McGill and then Cornell University.

By then, the Human Genome Project was becoming a reality, capturing the attention of many scientists, including a young Hill.

“That’s when two and two came together,” Hill said. “It was like ‘Oh yeah, the stuff we’re doing, though it’s pretty theoretical, it is going to be the thing that links these pieces together,’ ” including chaos theory, genetics, Big Data, and health care.

Now he’s in the middle of the so-called Big Data revolution in health care. Companies such as GNS have an enormous capacity for crunching troves of information on patients, diseases, and medical outcomes collected by medical providers, insurers, and other big players.

Hill likes to say he wants GNS to capture the “data exhaust thrown off” by every interaction a patient has with the health care system, from the doctor’s office to the hospital to the pharmacy. A bad reaction to medication is a data point worth having; ditto for other side effects, as well as results of all kinds of procedures and interventions — bad or good.

While such data sets are getting easier to find, Hill said, genetic information is still too expensive to be truly useful.

“What we don’t have yet for my dad and for other men with prostate cancer is a large coherent set of data on prostate cancer patients that includes the molecular level,” Hill said.

With information aggregated from thousands of cases, Hill said, GNS uses artificial intelligence algorithms developed out of chaos theory to determine what treatment made the crucial difference for each patient, and with it what is likely to work best for the next patient — rather than simply trying one medication after another, as is often done today.

“What we’re trying to get at is not just patterns and trends, but reverse engineer the mechanisms that gave rise to the data,” he said. “We’re trying to find the cause-effect relationships within the data.”

This ability to predict results is what sets GNS apart, said Dr. Atul Butte of Stanford University, one of the academic leaders of the Big Data movement. That’s the “nifty part of their technology,” Butte said.

Alexis Borisy, a partner at the Boston life sciences venture capital firm Third Rock Ventures, said GNS is in the vanguard of Big Data companies analyzing health care information.

“They’ve had a chance to learn, refine, and they’ve kept with it so they’ve had a lot of experience to build on,” Borisy said.

He and Hill have known each other since they were young business executives more than a decade ago, and he said he has tremendous respect for Hill’s intelligence, persistence, and communication skills.

“He is one of the visionaries in the space,” said Borisy, who also serves as chairman of Foundation Medicine, a molecular information company, and interim chief executive of Warp Drive Bio, both of Cambridge. “I think it’s fair to say he’s kept GNS growing and building by the force of his personality and the force of his efforts.”

Source: The Boston Globe

Biomarker May Identify Neuroblastomas with Sensitivity to BET Bromodomain Inhibitors

Neuroblastoma, the most common malignant tumor of early childhood, is frequently associated with the presence of MYCN amplification, a genetic biomarker associated with poor prognosis. Researchers have determined that tumors containing MYCN amplification are sensitive to a new class of drugs, BET bromodomain inhibitors.

The researchers made this discovery in a preclinical study, which was funded in part by a Stand Up To Cancer Innovative Research Grant and was published in Cancer Discovery, a journal of the American Association for Cancer Research.

“BET bromodomain inhibitors are a class of drugs that many researchers are hopeful may offer a new therapeutic option for treating patients with certain cancers,” said Kimberly Stegmaier, M.D., assistant professor of pediatrics in the Department of Hematology/Oncology at Dana-Farber/Children’s Hospital Cancer Center in Boston, Mass. “The challenge has been identifying biomarkers that can help direct clinical translation of these drugs by pinpointing those patients with the highest likelihood of response.”

To identify genetic biomarkers of responsiveness to BET bromodomain inhibitors, Stegmaier and colleagues screened more than 600 cancer cell lines with known genetic characteristics for sensitivity to a prototypical BET bromodomain inhibitor.

Using this high-throughput, cell-based screening process, the researchers found that neuroblastoma cells in which the MYCN gene was amplified were sensitive to BET bromodomain inhibitors.

“Neuroblastoma is a devastating childhood cancer, and only a minority of children with high-risk disease will be cured with currently available treatments,” Stegmaier said. “Prior research has shown that MYCN amplification is common in neuroblastoma, but it has been an elusive drug target.”

To further validate their findings, the researchers tested a BET bromodomain inhibitor, from the laboratory of James E. Bradner, M.D., at the Dana-Farber Cancer Institute, using cultured MYCN-amplified neuroblastoma cell lines and three animal models of MYCN-amplified neuroblastoma. Together, they found that the drug decreased levels of MYCN protein in cultured cells, and that this led to impaired cell growth and cell death. In each animal model, including a mouse model of neuroblastoma that is known to be resistant to many standard therapies, the drug was shown to have anti-tumor effects and to prolong survival.

“My Stand Up To Cancer grant, which focused on modulating difficult drug targets in childhood cancers, was instrumental to us being able to do this exciting work,” Stegmaier said. “These types of studies are generally considered high-risk, particularly because they start with unbiased screening, and they are generally less likely to be supported by traditional sources of funding.”

Study: Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

Source: EurekAlert!