Research shows subopitmal reporting of adverse events in targeted therapy and immunotherapy trials

A significant number of trials of targeted therapies and immunotherapies in recent years show suboptimal reporting of adverse events, particularly the reporting of recurrent or late toxicities and the duration of the adverse events, researchers have told the ESMO 2016 Congress in Copenhagen.

“Reporting adverse events from clinical trials with new agents is a crucial point, as this will inform physicians and patients regarding the safety profile of that drug and what to expect when starting this therapy in a new patient in everyday clinical practice,” said principal investigator Dr Paolo Bossi, from the Head & Neck Unit at the Fondazione IRCCS – Istituto Nazionale dei Tumori, Milan.

In this study, researchers reviewed publications from 81 trials of targeted therapies and immunotherapies approved by the US Food and Drug Administration between 2000-2015 for solid malignancies in adult patients. Each publication was assessed according to a 24-point score card based on the Consolidated Standards of Reporting Trials (CONSORT) guidance.

More than 90% of trials scored poorly in their reporting of recurrent and late toxicities, and in reporting the duration of adverse events; 86% of trials did not adequately report on the time of the adverse event occurrence; and 75% of trials only reported on adverse events that occurred at a frequency above a fixed threshold. More than half of the analysed papers showed limitations in the method for presenting adverse events, in describing the toxicities leading to therapy withdrawal, and in the follow-up interval assessment, while dose reductions due to adverse events were not reported in one-third of trials.

He highlighted the issue of duration of an adverse event – the so-called ‘third axis’ (the other being severity and frequency) in the evaluation of toxicities – which is not regularly considered with a new drug comes to market.

Dr Bossi said that it was encouraging to see a trend towards improved adverse event reporting in recent years. Moreover, there are new instruments available that can help physicians to improve the quality of adverse event reporting and help them discuss potential toxicities with their patients.

“The most important and innovative one is the PRO-CTCAE form, which is the patient-reported outcome version of the common toxicity criteria of adverse events, and which will allow physicians to collect the symptoms as reported by the patients, considering also the severity, intensity and influence of the symptoms on their quality of life.”

Press release from European Society of Medical Oncology”

Uncovering antibiotic resistance in Pseudomonas aeruginosa

Pseudomonas aeruginosa is a common bacterium of our environment. It can however become a formidable pathogen causing fatal infections, especially in intubated patients, people suffering from cystic fibrosis or severe burns. The presence of certain metals in the natural or human environment of the bacterium makes it more dangerous and, in particular, resistant to antibiotics of last resort. A team of researchers from the University of Geneva (UNIGE), Switzerland, has shown that a specific protein of P. aeruginosa, called Host factor q (Hfq), is essential for reacting to these metals and acquire these new properties. The results, presented in the special issue Virulence Gene Regulation in Bacteria of the journal Genes, single out the Hfq protein as the Achilles heel of P. aeruginosa. Indeed, blocking its action could make this pathogen unable to adapt to a new environment and to resist to certain antibiotics.


‘We had discovered that high concentrations of metals, such as zinc, could induce a resistance to carbapenems, which are antibiotics of last resort, as well as an increase in the production of virulence factors’, says Karl Perron, researcher at the Department of Botany and Plant Biology of the UNIGE Faculty of Science. This metal may be present in abnormal amounts in the lung secretions of cystic fibrosis patients and in some urinary catheters, contributing to an increase in the pathogenicity of the bacterium and to treatment failure.

Some antibiotics must penetrate the bacteria to exert their effect. Carbapenems, for example, pass through a specific porin, a sort of channel normally used to import nutrients. When the bacterium is present in an environment containing an excess of zinc, it becomes resistant to carbapenems. ‘We had observed that zinc and other metals induce a suppression of the production of this porin, but we did not know exactly how’, specifies Verena Ducret, biologist in the Geneva group and first author of the article.

The team of Karl Perron has solved this enigma by uncovering the central role of a bacterial protein called Host factor q (Hfq). ‘This chaperone, a molecular assistant that allows the bacterium to adjust the synthesis of various proteins according to its needs, inhibits the synthesis of certain porins by intervening at several levels of the production chain’, explains Verena Ducret. By studying a bacterium that does not express Hfq, the scientists have thus discovered a real Achilles heel, because the mutant is unable to respond to zinc and other metals. Therefore, it cannot express its virulence or become resistant to carbapenems in the presence of these metals.

Since the different pathways leading to the inhibition of the production of this porin use Hfq, this chaperone becomes a promising therapeutic target. ‘We are looking for different inhibitors of Hfq that act on Pseudomonas aeruginosa strains. These drugs should counter all of the pathogen’s direct and indirect effects without affecting the host cells, because they do not have proteins such as Hfq’, says Karl Perron.

Publication: OprD Repression upon Metal Treatment Requires the RNA Chaperone Hfq in Pseudomonas aeruginosa
doi:10.3390/genes7100082
Press release from University of Geneva faculty of science

New Imaging technique to detect Chromatin in the cell (Partial Wave Spectroscopic Microscopy)

When scientists finished decoding the human genome in 2003, they thought the findings would help us better understand diseases, discover genetic mutations linked to cancer, and lead to the design of smarter medicine. Now it’s 13 years later, and not all of these ideas have not yet come to fruition.

It turns out that genes are just one piece of a much larger puzzle. To help put this puzzle together, Backman has developed a new way to image chromatin, a complex of macromolecules — including DNA, RNA, and proteins — within living cells that house genetic information and determines which genes get expressed.

Chromatin’s organization plays a major role in many molecular processes, including DNA transcription, replication, and repair. The structures within chromatin that regulate these processes span from nucleosomal (10 nanometers) to chromosomal (longer than 200 nanometers) length scales. Little is known about chromatin’s dynamics between these length scales due to lack of imaging techniques. Because they require toxic fluorescent dyes to enhance contrast, previous techniques could not image chromatin in living cells without killing or perturbing the cells. Understanding this missing length scale is crucial, however, because it is the exact area where chromatin undergoes a transformation when cancer is formed.

“Changes in chromatin’s structure have been linked to the regulation in genes often implicated in cancer,” Backman said. “The organization of chromatin correlates both with the formation of tumors and their invasiveness. We want to understand how chromatin regulates these genes.”

Backman’s new imaging technique allows researchers to peer inside of chromatin at the missing, mysterious length scale (20-200 nanometers). Not only is the technique label-free, allowing researchers to study chromatin within unharmed, living cells, but it does so with high-throughput and at very low cost. Called live cell Partial Wave Spectroscopic (PWS) microscopy, the technique detects chromatin by using scattered light. Particles smaller than the diffraction limit of light cannot be visualized but their presence and organization can be sensed by analyzing the light they scatter. The approach can measure the nano-architecture in live cells within seconds, opening the door for large-scale screens. Researchers can run high-throughput screens on thousands of compounds and drugs, for example, and watch how they affect cells in real time.

Supported by the National Science Foundation, National Institutes of Health, and Chicago Biomedical Consortium, the research is described online on October 4 in the Proceedings of the National Academy of Sciences.

Publication: Label-free imaging of the native, living cellular nanoarchitecture using partial-wave spectroscopic microscopy
doi: 10.1073/pnas.1608198113
Press release from Northwestern University

Human apoptosome structure determined and model recreated

Programmed cell death, or apoptosis, plays a central role in the maintenance of human health by providing a line of defense against unrestricted cell growth that occurs in many cancers and AIDS as well as in neurodegenerative diseases and stroke.

Researchers from Boston University School of Medicine (BUSM) have for the first time mapped an active human apoptosome. This model, which appears online in the journal eLife, helps provide a better understanding of how cell death occurs and may lead to treatment options to either enhance or suppress this process.

Cellular signaling in the programmed death pathway culminates in a complex assembly of proteins termed the “apoptosome.” This large wheel-like structure recruits and activates specific proteases (enzymes that split proteins) to dismantle proteins in the cytoplasm and the nucleus. Thus, the cell is broken down into pieces from the inside by this “wheel of death.”

The research team, led by Christopher W. Akey, PhD, BUSM professor of physiology & biophysics, determined the near atomic structure of the apoptosome using cryo-electron microscopy and were able to build a three-dimensional model.

According to the researchers the apoptosome is a wheel-like structure with seven spokes. On top of the wheel is a spiral-shaped disk formed by protease docking, while active domains of the proteases are flexibly-tethered to the disk. When active the apoptosome is a dynamic molecular machine with three to five protease molecules tethered to it at any given time. The number of proteolytic units parked on the wheel could vary, resulting in a changing level of dismantling activity. A soluble protease is in turn cleaved and activated by the active apoptosome and this soluble protease then targets cellular components.

Publication: A near atomic structure of the active human apoptosome
DOI: http://dx.doi.org/10.7554/eLife.17755
Press release from Boston University School of Medicine (BUSM)

University of Texas researchers developing radiotherapeutic gold nanoseeds to fight inoperable tumors

Many solid tumors are considered inoperable because they adhere to vital structures or the surgery would cause irreversible damages to the patients. In order to prevent the tumor growth or provide complete tumor resolution without surgery, chemotherapy and radiation are currently in clinical practice. Since these tumors are already locally advanced or have begun to metastasize, the outlook today for these cancer patients is bleak and survival rate remains very low.

Yaowu Hao, an associate professor in the Materials Science and Engineering Department at The University of Texas at Arlington, has earned a three-year, $477,000 R15 grant from the National Institutes of Health to develop radiotherapeutic nanoseeds that will work from inside inoperable solid tumors and cause less damage to healthy cells.

One way of applying the radiation is to surgically implant a 2-millimeter-by-5-millimeter “Seed” with therapeutic isotopes into the tumor. Because the nanoseeds are injectable, they can be used in tumors in other areas of the body, such as the brain, lungs and liver.  “We chose gold because it is inert and biocompatible. The nanoseed is about 100 nanometers in size, so it is small enough to be injected in solution but large enough that it will not spread out of the tumor.” This type of radiation therapy is highly effective in attacking a tumor, but is also safer for the surrounding tissue because the radiation is contained within the tumor.

Press release: Using nanotechnology to target inoperable tumors from the inside out

Research shows tumor-targeted radiosensitization using antibody drug conjugates may redues toxicity and improve outcome

Many types of cancer become drug resistant, making them difficult to treat. Researchers with University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to selectively sensitize certain cancer cells to radiation therapy that may improve tumor control and reduce treatment-related side effects.

In a paper published in Nature Communications, researchers report that in mouse models tumors testing positive for a protein called human epidermal growth factor receptor 2 (HER2) were sensitized to a combination of radiation therapy and an antibody drug conjugate (ADC) called ado-trastuzumab emtansine (T-DM1). ADC is a new technology that chemically links an antibody to a targeted cell receptor to deliver a drug to specific cells — in this case a very potent chemotherapy to HER2 positive tumors — while sparing normal tissue.

“A biomarker-driven, tumor-targeted radiosensitization approach to treating cancer is a potentially significant advancement from current chemotherapy and radiation therapy,” said Sunil J. Advani, MD, associate professor in the Department of Radiation Medicine and Applied Sciences and the paper’s senior author. “Non-targeted, highly toxic chemotherapies continue to remain the most effective treatments for patients treated concurrently with chemotherapy and radiation, but these treatments have significant toxicity and we need alternatives that are molecularly guided based on mutations found in specific patients.

The study shows promise in HER2 cancers, which occur in a percentage of lung, esophageal, gastric and bladder cancers. T-DM1 is already approved for use in metastatic HER2 positive breast cancer treatment. Researchers repurposed the existing drug to sensitize cancer cells to radiation therapy among patients who simultaneously receive chemotherapy and radiation therapy at the beginning of the treatment process, instead of waiting until the cancer spreads or becomes resistant to treatment.

Intensifying a dose of non-targeted chemotherapies increases normal tissue toxicities, often precluding further radiation therapy or chemotherapy escalation. Using targeted ADC with radiation therapy would reduce toxicity, reduce the risk of tumor resistance and attacks both known tumors as well as cancer cells that may have metastasized, while sparing normal tissue.

Type of study: Mouse model
Publication: Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
doi:10.1038/ncomms13019
Antibody drug conjugates may help personalize radiotherapy for patients with cancer

Genetic targets in Colorectal Cancer: role of KRAS, MEK and TAK1 genes Identified.

Researchers from Boston University School of Medicine have discovered a possible strategy to treat colon cancers that are caused by the mutant KRAS gene, which is responsible for approximately half of all colon cancer cases. The findings, which appear online in the journal Molecular Cancer Research, may lead to better therapeutic agents to treat this disease.

Colon cancer is the third leading cause of cancer-related deaths in the U.S. Routine screenings by undergoing a colonoscopy have helped reduce mortality rates if the disease advances to malignancy, it can be very difficult to treat. Cancers with the KRAS gene mutation respond poorly to currently available therapeutic agents.

“Our study provides a new strategy to treat colon cancers driven by the mutant KRAS gene, which is based on targeting additional genes that cooperate with KRAS to promote tumor growth. These additional genes, notably MEK and TAK1, can be blocked by selective therapeutic agents to suppress colon cancer cellular proliferation and viability,” explained corresponding author Anurag Singh, PhD, assistant professor of pharmacology & experimental therapeutics at BUSM. The researchers tested 40 colon cancer cell lines that were derived from human colon cancer samples for sensitivity to inhibitors of MEK and TAK1.

They found that treating those cell lines with MEK and TAK1 inhibitors suppressed the growth of mutant KRAS-driven colon cancer cells significantly as compared to the control group. “With this study we have uncovered a novel pathway in a subset of colon cancers driven by mutant KRAS gene activation, representing an important axis of vulnerability with the potential to selectively treat these types of tumors in the clinic,” he added.

Press Release: Researchers investigate new strategy to block growth of colon cancer cells

Research indicates role of protein c-Cbl in Colorectal Cancer

The discovery, published online by Oncotarget journal, may lead to new therapies in managing patients with Colorectal Cancer (CRC). CRC is a complex disease caused by several genetic mutations and their consequences. In more than 80-percent of CRC patients, some of these mutations can lead to an increase in ?-catenin, a vital protein, leading to cancer initiation.

Researchers from Boston University School of Medicine, led by Vipul Chitalia, MD, PhD, assistant professor of Medicine, have identified a new role of the protein, c-Cbl that it may be capable of degrading ?-catenin in CRC patients. “We believe these findings could have clinical implications in managing patients with CRC,” explains Chitalia.

C-Cbl could be used as a biomarker of patient survival. The discovery may also lead to new strategies to suppress CRC growth.” According to Chitalia, another aspect of this study is related to the method by which researchers analyze human biopsy samples. BUSM researchers, led by Vijaya Kolachalama, PhD, principal investigator at the Whitaker Cardiovascular Institute at BUSM, developed a more accurate, automated and high-throughput image processing technique that was capable of uncovering hidden relationships between important proteins in cancer.

“We are excited about this discovery and the treatments that could improve the quality of life for CRC patients,” says Chitalia and his collaborators Kevan Hartshorn, MD, professor of Medicine, and Nader Rahimi, PhD, associate professor of Pathology and Laboratory Medicine “c-Cbl targeted therapy may provide a means to suppress the growth of CRC and possibly with lower side effects.”

Every year about 150,000 new cases of colorectal cancer are diagnosed in the United States. Despite surgery and new therapies, about one third of patients with the disease die from CRC annually, making it the second most common cause of cancer death.

Press release: New research indicates key protein may directly impact development of colon cancer

NIH panel discuss roadmap for advancing research to prevent youth suicide.

An independent panel convened by the National Institutes of Health has developed a 10-year roadmap for advancing research to prevent youth suicide.

To help close research gaps related to youth suicide and to assess the scientific evidence, NIH convened the Pathways to Prevention Workshop on March 29-30, 2016. The report includes recommendations to address these four critical issues over the next decade:

  • The need for surveillance by linking data from multiple sources (e.g., state all-payer databases, emergency room data, electronic health records data).
  • The need to improve measurement across diverse populations and time scales of personal characteristics such as sexual orientation and identity, and environmental contexts that have been associated with suicide risk.
  • The need to help practitioners in identifying effective suicide prevention programs.
  • The need for coordinated education and training opportunities for health care providers, schools, agencies, families, and communities to remove the stigma associated with suicide.

The panel cited several barriers that impede efforts to combat youth suicide. There is limited availability of linked data systems to facilitate identifying important risk factors for youth suicide.
Researchers have not assessed measures of suicide risk and protective factors at multiple levels over time. The stigma associated with suicide has resulted in the misclassification and underreporting of suicide and suicide attempts and has reduced opportunities for successful intervention.

Press release: Panel develops plan for preventing youth suicide

Gut bacteria boost chemotherapy drugs in a research trial

Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report in Immunity.The study identifies a new role for Enterococcus hirae and Barnesiella intestinihominis in activating cancer-fighting T cell immune responses, thereby enhancing the effects of the chemotherapy drug cyclophosphamide.

“The anti-cancer drug’s efficacy relies on a complex interplay between the microbiome of cancer patients and their ability to mount an efficient immune memory response against some bacteria of the gut microbiota,” says co-senior study author Mathias Chamaillard, Inserm research director of the Center for Infection and Immunity of Lille.

In a few cases, the antitumor effects of intestinal bacteria can also contribute to the effectiveness of chemotherapy drugs.It has not been clear which specific bacterial species activate antitumor immune responses in response to chemotherapy, and exactly how they do so.

In the new study, Chamaillard and senior study author Laurence Zitvogel of the Institut de Cancérologie Gustave Roussy Cancer Campus showed that two intestinal bacteria, E. hirae and B. intestinihominis, both act to orchestrate the anticancer therapeutic effects of cyclophosphamide-an immunosuppressive chemotherapy drug used to treat a wide range of cancers.

Using mouse models, the researchers showed that oral treatment with E. hirae activated antitumor T cell responses in the spleen in parallel with the direct toxic effects of cisplatin on the tumor, thereby curbing tumor growth. On the other hand, oral treatment with B. intestinihominis achieved a similar effect by promoting the infiltration of T cells in various mouse tumors.

Press release: How gut microbes help chemotherapy drugs