Multiple Factors Tied to Hearing Loss in Children Given Cisplatin

NEW YORK (Reuters Health) – Although cumulative dose is important, how cisplatin is administered to young patients with cancer also appears to have a significant and additive effect on development of cisplatin-induced hearing loss (CIHL), according to a large multicenter study.

“Cisplatin is a very effective chemotherapy agent but causes permanent hearing loss that is devastating to the children who survive their cancers,” said Dr. Etan Orgel of Children’s Hospital Los Angeles.

“This study helps us understand how we might be able to make small changes in how we deliver the drug to cure the disease while also improving the child’s quality of life for the decades that follow,” he told Reuters Health by email.

In a paper in The Lancet Child and Adolescent Health, Dr. Orgel and colleagues observe that most reports on the condition are limited by small numbers of patients, single-institution cohorts and inconsistencies leading to conflicting results.

In an effort to avoid these problems the researchers examined data on 1,481 young patients treated with cisplatin at multiple cancer centers across Canada and the U.S. Of these patients, 1,275 were less than 15 years old and the remaining 206 were older; 96% had had audiometry done at their latest follow-up a mean of 3.9 years after diagnosis.

Overall, 44%) developed moderate or severe CIHL, and the highest prevalence (59%) was seen in patients under 5. In addition, more than half of patients with CNS tumors, hepatoblastoma, and neuroblastoma had moderate or severe CIHL, but this was the case in less than a third of patients who received cisplatin for germ-cell tumors, osteosarcoma, or other cancers.

After accounting for cumulative cisplatin dose, the team also found that higher fractionated doses were significantly associated with CIHL risk. For each 10mg/m2 increase per day, the adjusted odds ratio was 1.15. For each 50 mg/m2 increase per cycle, the corresponding aOR was 2.16.

In addition, vincristine treatment was newly identified as a significant risk factor for CIHL (aOR, 3.55).

The team found no difference in progression-free survival or overall survival between patients who developed moderate or severe CIHL at the end of therapy and those who did not.

“Variations in cisplatin dosing confer additive risk for developing CIHL,” they conclude, “and warrant investigation as a potential approach to decrease the burden of therapy.”

SOURCE: The Lancet Child and Adolescent Health, online February 11, 2021.

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A region within GLI1 gene could potentially be targeted as cancer treatment

Scientists from the Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago found that a region within the DNA of the cancer-promoting GLI1 gene is directly responsible for regulating this gene's expression. These findings, published in the journal Stem Cells, imply that this region within GLI1 could potentially be targeted as cancer treatment, since turning off GLI1 would interrupt excessive cell division characteristic of cancer.

From previous research, we know that GLI1 drives the unrelenting cell proliferation that is responsible for many cancers, and that this gene also stimulates its own expression. We established in living human embryonic stem cells that removing the GLI1 regulatory region eliminated GLI1 expression and halted its activity. These findings are promising and could point to a therapeutic target for cancer."

Philip Iannaccone, MD, PhD, Co-Senior Author, Professor Emeritus at the Manne Research Institute, Lurie Children's and Northwestern University Feinberg School of Medicine

Dr. Iannaccone and colleagues used CRISPR gene editing technology to delete the binding region of the GLI1 DNA in human embryonic stem cells. They found that without this region, GLI1 remained turned off, which interfered with the gene's normal activity of driving embryonic development of blood, bone, and nerve cells.

"A surprising aspect of this work was that turning GLI1 off affected stem cell differentiation to all three embryonic lineages," says first author Yekaterina Galat, BS, Research Associate at the Manne Research Institute at Lurie Children's.

"The developmental function of GLI1 ends after birth, so if we manage to stop its expression in the context of cancer, it should not have negative consequences to normal biology," explains Dr. Iannaccone.

GLI1 expression is associated with about a third of all human cancers. In addition to promoting cell proliferation, GLI1 expression increases tumor cell migration and is associated with resistance to chemotherapy drugs.

"Our team plans to study GLI1 associated proteins that assist in regulation of GLI1 expression through its binding region," says Dr. Iannaccone. "Targeting these proteins as a means to stop GLI1 activity could prove to be a fruitful treatment strategy for cancer."


Ann & Robert H. Lurie Children's Hospital of Chicago

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Blood, Bone, Cancer, Cancer Treatment, Cell, Cell Division, Cell Migration, Cell Proliferation, Chemotherapy, Child Health, Children, CRISPR, DNA, Drugs, Embryonic Development, Embryonic Stem Cells, Gene, Hospital, Medicine, Nerve, Proliferation, Research, Stem Cells, Tumor

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Srudy shows how tissue’s microscopic geometry affects spread of cancer

Oregon State research shows how tissue's microscopic geometry affects spread of cancer

Oregon State University research has revealed a crucial mechanism behind one of humankind’s most deadly physiological processes: the movement of malignant cells from one part of the body to another.

Published in the Proceedings of the National Academy of Sciences, the study led by OSU biophysicist Bo Sun shows the role that tissues’ microscopic geometry plays in cancer metastasis, the internal spreading of the disease that’s responsible for 95% of all cancer deaths.

To develop drugs that effectively combat metastasis, it’s fundamentally important to understand what directs the metastatic process, Sun said.

“Our results show the level of tissue fiber alignment, particularly collagen fiber alignment, is a crucial part of what’s happening,” Sun said.

Collagen is a protein that serves as the primary component of human connective tissue, which supports, protects and provides structure for other tissues and organs in the body. Collagen is also a key part of the extracellular matrix, the non-cellular part of tissues and organs that acts as a scaffold and also performs important biochemical and biomechanical functions.

“Clinical studies have shown that the microscopic geometry of tissue is significantly correlated with the progression of breast cancers,” Sun said. “Our study reveals the underlying biophysical mechanism. In the era of precision medicine, we think taking into account the physical properties of a patient’s tissue can be critical for the prediction and treatment of metastatic disease.”

The correlation is due to a cellular phenomenon known as “contact guidance,” which is analogous to a back-country hiker trying to pick a route based on the contours of the terrain and the network of downed trees on the ground.

“In navigating the three-dimensional extracellular matrix, where the fibers aren’t necessarily parallel, cells have to integrate multiple guidance cues that aren’t always clear and sometimes are conflicting,” Sun said. “Understanding the mechanisms and limitations of cell responses to imperfect guidance signals is pivotal for predicting and engineering cell behaviors—i.e., providing a patient with a precise diagnosis, prognosis and treatment.”

¬¬In this research, Sun and collaborators at OSU, the University of California San Diego and Northeastern University found that a breast cancer cell can switch between two distinct states: the mesenchymal, in which the cell shape is elongated, and the amoeboidal, in which it’s more round.

“In the mesenchymal state, a cell follows the orientation of tissue fibers, and the effect is strongest when the level of fiber alignment is highest,” Sun said. “In the amoeboidal state, the same cell moves rather randomly. Another part of it is that the transition rate between the two states is also determined by the level of tissue fiber alignment—strong alignment leads to a stronger tendency for a cell to stay in the mesenchymal state.”

Collaborating with Sun were graduate research assistant Jihan Kim and Ph.D. candidate Christopher Eddy of OSU’s Department of Physics, Yuansheng Cao and Wouter-Jan Rappel of UC San Diego, and Youyuan Deng and Herbert Levine of Northeastern.

The U.S. Department of Defense, the National Science Foundation and the National Institute of General Medical Sciences supported this study, which builds on earlier research by Sun that showed human cells, including cancer cells, could mechanically and permanently remodel their surroundings—and thus affect an array of physiological processes from metastasis to wound healing to embryo development.

In that research, Sun found that a single pair of breast cancer cells could increase the local fiber density of reconstituted collagen matrices by more than 150%.

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Why Nigeria must include parents in plans to protect girls from cervical cancer

Why Nigeria must include parents in plans to protect girls from cervical cancer

Cervical cancer is the second most common cancer among women in Nigeria. There were 31,955 new cervical cancer cases in West Africa in 2018, and Nigeria accounted for almost half (14,943). There were also 10,403 deaths (28 deaths every day) from cervical cancer in the country in the same year.

About 70% of all cervical cancer cases are caused by the human papilloma virus (HPV) serotypes 16 and 18. The most common mode of transmission is through sex, but it can also be transmitted through the use of contaminated hospital equipment and from mother to child. The cancer is ranked second in the number of years lost to disability among women in Nigeria.

There are screening programs geared towards the prevention of this cancer, including Papanicolaou (Pap) smear and HPV screening. These are secondary preventive measures that detect early-stage cervical cell abnormality and the virus’s presence. However, only 8.7% of Nigerian women had a pap smear in 2018, and fewer had HPV screening.

This low uptake results from poorly organized services, the relatively high cost, and the shortage of resources and skills required for the services.

The HPV vaccine is an effective primary prevention measure for cervical cancer. The vaccine is most effective when started before sexual debut, which is the reason for the recommendation of its administration in early adolescence.

There are, however, two main obstacles on this path. First, the vaccine is currently being marketed at exorbitant costs. It is therefore out of reach of the average family. The Nigerian government is seeking ways to meet the conditions for accessing subsidized HPV vaccines under the global assistance program.

Second, Nigeria is yet to identify an organized structure through which most of the eligible adolescents can be reached with the HPV vaccine. A multi-pronged approach will be required for this as many Nigerian adolescents are out of school.

Case for early vaccination

The HPV vaccine has been introduced in some African countries. But it is yet to be integrated into the routine vaccine schedule in Nigeria. Part of the preparation to ensure the successful introduction of the HPV vaccine is to ensure that all stakeholders have correct perspectives about the vaccine.

Vaccinating both girls and boys has been shown to be more cost-effective because it can lead to the development of herd immunity, curbing the spread of the virus, and prevent other HPV-related cancers like anogenital cancers and cancer of the head and neck.

Parents are essential stakeholders in the HPV vaccine program for adolescents because they are the primary caregivers. They will play significant roles in the decision making process for the uptake of HPV vaccination. If Nigeria uses the school-based or community-based HPV vaccination program, parents’ consent is crucial for the success of the program.

The importance of parental consent was emphasized by the parents of adolescents that we interviewed in five selected communities in Ibadan, a city home to 3.5 million in southwest Nigeria. This is not only right legally as these adolescents are minors, but the parents are their primary caregivers. They should be involved in decisions about the uptake of healthcare services, including HPV vaccination.

Almost all the parents we spoke to had the intention to vaccinate their adolescents with the HPV vaccine despite being informed that the virus was sexually transmitted. However, parents who were older than 45 years were reluctant to vaccinate their adolescents. Findings from this study showed that many parents in this age group did not believe that HPV was responsible for cervical cancer and did not appreciate the importance of the HPV vaccine in preventing cancer. Also, these older parents significantly did not have formal education. Older people have been reluctant in the uptake of new technology, which might have affected these parents’ views about the HPV vaccine.

Way forward

It is essential to carry all stakeholders along in this pre-introduction era of the HPV vaccine in Nigeria to ensure the program’s success in the future. A concerted effort is required to demonstrate the relationship between HPV and cervical cancer and the role of the vaccine in the prevention of cancer.

This will require special health education skills as most of the parents do not have formal education. All parents should also be involved at each stage of the introduction of the HPV vaccine for the program to succeed.

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Cancer: A new killer lymphocyte enters the ring

Cancer: a new killer lymphocyte enters the ring

Treatments for beating tumors are mainly based on CD8 T lymphocytes, which specialize in detecting and eliminating intracellular infections and in killing cancer cells. A large proportion of patients, however, do not respond to these treatments. This prompted a research team from the Swiss Cancer Centre Léman (SCCL, Switzerland) to bring together the universities of Geneva (UNIGE) and Lausanne (UNIL), the Ludwig Institute for Cancer Research (LICR), EPFL and CHUV to investigate CD4 T lymphocytes. While these play a supporting role with CD8 T cells, their ability to eliminate tumor cells directly has been a matter of controversy. Using innovative nanoimaging technologies designed at the EPFL laboratory, the scientists found that when the CD4 T lymphocytes were put in close contact to the cancer cells, up to a third of them could kill them. This discovery, the subject of an article in Science Advances, is significant and broadens the therapeutic perspectives based on administering CD4 T lymphocytes to patients who are resistant to conventional therapies.

When cancer cells proliferate, the immune system kicks in. The first line of fighters capable of destroying tumor cells are CD8 T lymphocytes known as cytotoxic T cells, backed up by CD4 T lymphocytes. The latter secrete factors that help the former in many ways. Camilla Jandus, last author of the study and a professor in the Department of Pathology and Immunology in UNIGE’s Faculty of Medicine and adjunct scientist at LICR, says, “That’s why lots of cancer treatments are based on CD8 T lymphocytes. Unfortunately, some patients don’t respond to these treatments, and so we have to find new ones.”

The SCCL team turned their focus to CD4 T lymphocytes, which offer invaluable support to the immune system, as Pedro Romero, a professor in the Department of Fundamental Oncology in UNIL’s Faculty of Medicine and Biology, explains: “These have a much wider spectrum of functional specializations than CD8 T lymphocytes, and for a long time, we didn’t know for sure whether they had the capacity to differentiate into killer lymphocytes.”

20,000 individual “boxing rings”

To address this question, the scientists examined CD4 T lymphocytes from around 20 patients with melanoma who were being treated at CHUV. “Although melanoma isn’t the most common skin cancer, it is the deadliest, and it’s particularly sensitive to immunotherapies,” says Professor Jandus. The researchers isolated the CD4 T lymphocytes from both the blood and fragments of the tumors with the idea of comparing them directly. Dissociated tumor cells and CD4 T cells were co-incubated to observe their behavior individually. Observation tools were then required to provide high resolution down to the single-cell level.

“We created chips of over 20,000 mini-wells of 65 picolitres (1 picolitre = 10-12 liters) that can accommodate a CD4 T cell and a tumor cell in each of them, and function like boxing rings,” says Hatice Altug, a professor in EPFL’s Bionanophotonic Systems Laboratory. The researchers then photographed all these thousands of wells simultaneously every five minutes for 24 hours in order to observe the interactions occurring between the two cells from a large set of pairs. “We know that it takes about two and a half hours for a CD8 to kill a tumor cell, and we decided to observe these boxing rings for 24 hours without knowing how, or if, the CD4s would react,” says Professor Altug.

A third of the CD4s emerged victorious

The high-throughput integration of dynamic imaging data showed that up to one-third of the CD4 T lymphocytes succeeded in killing the tumor cells to which they were closely linked within five hours. Professor Romero says, “These direct observations at the level of individual lymphocytes, which were revealed for the first time at such a level of sensitivity, definitively confirm the existence of CD4 T lymphocytes capable of killing tumor cells. And this happens while the tumor cells sometimes manage to divert them from their function of providing protective support to make allies of them.”

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Retroviruses invading the koala germline contribute to high cancer rates

Koalas are facing multiple environmental and health issues which threaten their survival. Along with habitat loss – accelerated by last year’s devastating bush fires – domestic dog attacks and road accidents, they suffer from deadly chlamydial infections and extremely high frequency of cancer.

An international team of scientists led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) now demonstrate that a retrovirus invading the koala germline explains the high frequency of koala cancer. The results are reported in the journal Nature Communications.

The koala retrovirus (KoRV) is a virus that, like other retroviruses such as HIV, inserts itself into the DNA of an infected cell. At some point in the past 50,000 years, KoRV has infected the egg or sperm cells of koalas, leading to offspring that carry the retrovirus in every cell in their body.

The entire koala population of Queensland and New South Wales in Australia now carry copies of KoRV in their genome. All animals, including humans, have gone through similar "germline" infections by retroviruses at some point in their evolutionary history and contain many ancient retroviruses in their genomes.

These retroviruses have, over millions of years, mutated into degraded, inactive forms that are no longer harmful to the host. Since in most animal species this process occurred millions of years ago, the immediate health effects on the host at that time are unknown but it has been suspected for some time that the invasion of a genome by a retrovirus may have considerable detrimental health effects.

The koala is at a very early stage of this process when the retrovirus is still active and these health effects can be studied.

Since retroviruses can cause cancer, it was thought that there is a link between KoRV and the high frequency of lymphoma, leukaemia and other cancers in koalas from northern Australia. To investigate this link, scientists at the Leibniz-IZW sequenced DNA from wild koalas suffering from cancer.

This allowed them to accurately detect the number of copies of KoRV in the koala genomes and identify the precise locations where the retrovirus had inserted its DNA. By comparing this information between healthy and tumour tissues in single koalas, and by comparing insertion sites between koala individuals, they found multiple links between KoRV and genes known to be involved in the kind of cancers to which koalas are prone.

"Each koala carries around 80 – 100 inherited copies of KoRV in its genome. The genomic locations of most of these are not shared between koalas, indicating a rapid expansion and accumulation of KoRV copies in the population. Each time a retrovirus copies and re-inserts itself into the genome, it causes a mutation, potentially disrupting gene expression, which could be detrimental to the host," says Prof Alex Greenwood, Head of Department of Wildlife Diseases at the Leibniz-IZW.

This means that by frequently copying itself to new locations in the genome, KoRV is currently conferring a high mutational load on the koala population. Tumour tissues contain many new copies of KoRV, indicating that KoRV is more active in tumour cells.

These copies generally were located close to genes associated with cancer. New KoRV insertions in tumour tissues affected the expression of genes in their vicinity. Such changes in gene expression associated with cancer can cause increased cell growth and proliferation, which leads to tumours.

Although other factors may also contribute to cancer in koalas, the mutational burden from KoRV likely increases the frequency of cells becoming cancerous and may shorten the time for cancer to develop.

In one koala, a copy of KoRV was found that had incorporated an entire cancer-related gene from the koala genome into its DNA sequence. This greatly increased the expression of this gene and most likely caused cancer in this particular koala.

If this mutated virus is transmissible, it would be of grave concern for koala conservation efforts. Comparing the genomic location of KoRVs between koalas also suggests that KoRV may predispose related koalas to particular tumours, with koalas sharing KoRV insertions in specific cancer-related genes suffering from similar types of cancer which they can pass on to their offspring.

Across all koalas studied, there were "hot spots" in the genome where KoRV frequently inserts itself. These hot spots were also located in proximity to genes associated with cancer.

In summary then, we find multiple links at the genomic level between cancer-related genes and KoRV, revealing ways in which KoRV underlies the high frequency of cancer in koalas."

Gayle McEwen, Scientist, Leibniz Institute for Zoo and Wildlife Research (IZW)

The results highlight the detrimental health consequences that wildlife species can suffer following germline infection by retroviruses.

Germline invasions have been repeatedly experienced during vertebrate evolution and have shaped vertebrate genomes, including the lineage leading to modern humans. These were most likely associated with severe detrimental health effects, which must be endured and overcome to ensure species survival.

The scientists at the Leibniz-IZW have previously shown that old retroviruses present in the koala genome aid the rapid degradation of KoRV. The koala finds itself in a race to survive the effects of KoRV long enough for the virus to be degraded. Considering the many threats to koalas, it is a race they need to win.


Leibniz Institute for Zoo and Wildlife Research (IZW)

Journal reference:

McEwen, G. K., et al. (2021) Retroviral integrations contribute to elevated host cancer rates during germline invasion. Nature Communications.

Posted in: Genomics | Life Sciences News

Tags: Cancer, Cell, DNA, Evolution, Frequency, Gene, Gene Expression, Genes, Genome, Genomic, Germline, HIV, Leukemia, Lymphoma, Mutation, Proliferation, Research, Retrovirus, Sperm, Virus

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Critical step forward for radiotherapy with a new method to treat cancer

Critical step forward for radiotherapy with a new method to treat cancer

A new research development from The University of Manchester and the Christie NHS Foundation Trust has shown progress for developing a potential new cancer treatment using high energy electron beams.

The collaborative research team have published their findings in Nature’s journal, Scientific Reports, and demonstrated that Very High Energy Electron (VHEE) beams can have a positive effect for treatment with damage to DNA at similar levels to those conventional X-Rays and proton therapy, whilst harnessing the unique technological qualities of electron beams.

Human cells are composed of DNA and this new result is a fundamental step forward for VHEE radiation as a treatment for a number of cancers. This new treatment has the potential to extend conventional treatment with electron beams used in hospital which only penetrate a few centimeters into the body and struggle to reliably reach deep seated tumors.

This new technology has the potential to extend the toolbox of radiotherapy techniques that can be used in hospitals to treat cancer, in particular an ability to treat deep seated tumors with electrons in a robust manner.

Earlier work from The University of Manchester group indicated this radiation is insensitive to intervening media—meaning if the dimension of the lung changes for example (the patient’s breathing) then the radiation will remain targeted to the tumor, limiting the damage to healthy tissue. The results in this new paper are a first to quantify damage to Double Strands of DNA with high energy electrons.

Following experiments carried out by The University of Manchester, at CERN’s CLEAR 250 MeV facility and at Daresbury Laboratory, the findings show Very High Energy Electron (VHEE) beams are effective at causing DNA damage, important for killing cancer cells, for radiation given over the course of several minutes and for the rapidly evolving field of sub-second FLASH radiation.

In the newly published paper the research group focussed on experimentally determining the DNA Double-Strand Break yield and this was used to evaluate the Relative Biological Effectiveness (RBE)—a key value to evaluate the effectiveness of this type of radiation compared to existing radiation treatments. These results, a first in the field, were found to be consistent with established radiotherapy modalities.

Kristina Small, a Ph.D. student, carried out the experiments, Kristina said: “Electron beam treatment has been identified as a candidate for treatment of lung cancer, a cancer which sadly still has a low survival rate. We have shown, through experiments at CERN and Daresbury Laboratory that VHEEs cause a similar level of damage to DNA compared to protons and X-rays.”

Similarities in physical damage between VHEE and conventional modalities gives confidence that biological effects of VHEE will also be similar—key for clinical implementation. The researchers also made detailed Monte-Carlo (statistically based) simulations—and these complicated simulations were consistent with previous experiments.

Professor Roger Jones from The University of Manchester and Cockcroft Institute said: “This paper represents a significant step in verifying the potential of Very High Energy Electron beams to treat cancer. It relies on a seamless collaboration of The University of Manchester’s Department of Physics and Astronomy, The Division of Cancer Sciences, Daresbury Laboratory and CERN, and The Christie NHS Foundation Trust.

“It is the first to quantify both single strand breaks (SSB) and double strand breakage (DSB) in DNA using VHEE beams. To do this we used plasmids which effectively freeze the damage (as plasmids are not equipped with repair mechanisms that living cells possess) and hence enabled us to process the results obtained at CERN back at the Manchester Cancer Research Centre. These results compare well with detailed Monte Carlo simulations. It also explores the exciting regime of FLASH Radiotherapy—which entails delivering a high dose over a sub-second timescale and where early experiments worldwide show potential to spare healthy cells during treatment. This work points the way for a potential new paradigm in radiotherapy.

“Advantages of this technique over existing methods include—potentially more precise and rapid delivery to tumors with reduced fractionation (number of times the patient has to have a follow up radiation treatment) which result in fewer patient visits needed with a more conformal high dose delivered. Recent results in the area of ultra-high dose rate radiotherapy indicate considerable sparing of healthy tissue.”

The next step is to further demonstrate these exciting results in future experiments. In the long term, researchers hope that VHEE therapy will make a valuable addition to the radiotherapy toolkit in order to improve future cancer treatment.

Dr. Michael Merchant (Division of Cancer Sciences, The University of Manchester) said: “This is an exciting first measurement of DNA damage for very high energy electrons. These measurements will help to build understanding of how to harness the medical applications of very high energy electrons.”

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Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern


UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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Combination therapy produces clinical benefit for early stage non-small cell lung cancer

The first randomized Phase II clinical trial to report on single and combined neoadjuvant immune checkpoint inhibitor therapy in stage I-III non-small cell lung cancer (NSCLC) found combination therapy produced a significant clinical benefit, as assessed by major pathologic response (MPR) rate, as well as enhanced tumor immune cell infiltration and immunological memory. Researchers from The University of Texas MD Anderson Cancer Center published the study results today in Nature Medicine.

The NEOSTAR trial tested combined neoadjuvant therapy of nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with eight of 21 treated patients (38%) achieving major pathological response, defined as ≤10% viable tumor at surgery.

MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in five of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable, early stage disease.

More than 50% of patients with localized non-small cell lung cancer will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity. The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

Tina Cascone, MD., Ph.D., Assistant Professor, Thoracic/Head & Neck Medical Oncology and Study Lead Author

Study design and secondary endpoints

The Phase II single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years old, and 64% were male. Participants were 84% white, 9% Black and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomized to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial and two patients underwent surgery off trial after additional therapies.

Among the 37 patients who had surgical resection on the study, the combination arm showed higher MPR rates (50% versus 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% versus 50%). Combination therapy also showed better pathological complete response rates than monotherapy (38% versus 10%). After a median follow-up of 22 months, median overall survival and lung cancer-related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare (NIF), or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory analyses reveal immune impact, potential biomarkers

In an exploratory analysis of resected tissues, investigators found — and reported for the first time — higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3+ and CD3+CD8+ T lymphocytes, tissue-resident memory and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells.

The researchers analyzed the gut microbiome, as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year. A fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.

"The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting," Cascone said. "This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients."

The NEOSTAR trial was supported by the Lung Cancer Moon Shot®, part of MD Anderson's Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients' lives. Boris Sepesi, M.D., associate professor of Thoracic and Cardiovascular Surgery, served as co-principal investigator of the study. A full list of co-authors and author disclosures can be found in the paper.


University of Texas M. D. Anderson Cancer Center

Journal reference:

Cascone, T., et al. (2021) Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nature Medicine.

Posted in: Drug Trial News | Medical Condition News

Tags: Biopsy, Cancer, Cardiovascular Surgery, CD3, Cell, Chemotherapy, Clinical Trial, Efficacy, Imaging, Immunotherapy, Laboratory, Lung Cancer, Malignant, Medicine, Melanoma, Microbiome, Neck, Non-Small Cell Lung Cancer, Oncology, PD-L1, Perioperative, pH, Research, Small Cell Lung Cancer, Smoking, Surgery, Translation, Tumor

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Scientists discover two unique subtypes of a prominent mutation in patients with AML

Using advanced RNA sequencing, scientists have identified two unique subtypes of a prominent mutation present in many patients with Acute Myeloid Leukemia (AML) called NPM1 that could help predict survival and improve treatment response for patients whose leukemic cells bear the mutation.

In research published Feb. 16, in Nature Communications, a team led by Princess Margaret Cancer Centre Senior Scientists, Drs. Benjamin Haibe-Kains, Aaron Schimmer and Mark Minden, have discovered that within the NPM1 mutation of AML there exists two unique subtypes, one of which can be effectively treated with drugs already in use.

It is the first study to classify within the common NPM1 mutant form of AML two subtypes, one being "primitive" and the other "committed." Furthermore, the research shows that each subtype has a different response to treatment and long-term survival, cracking open opportunities to personalize treatment plans and introduce new targeted therapies in the future.

"Patients with NPM1 mutated AML face a relapse rate of around 40 per cent," says Dr. Schimmer, Research Director and acute leukemia physician at the Princess Margaret, which is part of University Health Network. "While we're getting better at incorporating new monitoring techniques, we're still not at a point where we can adequately predict what side of the curve a patient might fall.

By going deeper with our sequencing, we can better predict outcomes and adjust treatment accordingly for each patient."

NPM1 mutated AML makes up around 30 per cent of all AML cases, but therapeutic discoveries for these patients have been limited.

While the NPM1 mutation is relatively common, AML is a rare disease to begin with. Generating enough data to be able to sequence and understand the biology of this mutation is very challenging."

Dr Haibe-Kains,  Associate Professor, Medical Biophysics, University of Toronto

This was made possible in large part thanks to a team led by Dr. Minden, Senior Scientist and medical oncologist, and Andrea Arruda, staff scientist at the Princess Margaret Cancer, who have been collecting samples to enable deeper learning since the mid-1980s thanks to the willingness, generosity and foresight of patients.

"Recognizing those 'needles in a haystack'the small groups of patients that don't benefit from certain treatments is critically important for improving personalized medicine," says Dr. Minden. "Now we can start to improve outcomes for this more discreet patient population."

An advanced computational model was custom-built to analyze RNA from patient leukemic cells obtained from the Leukemia Live Cell Tissue Bank, along with other data published from NPM1 mutant leukemia studies.

"We developed a unique machine-learning model that was able to clearly discriminate two subtypes of NPM1 mutant AML in datasets collected from patients," says Dr. Haibe-Kains.

These two subtypes both contain mutant AML but they express different genes that can now separate them into two clear subtypes based on their RNA.

The study also suggests that certain drugs already used to treat other types of cancer could be effective in the primitive subtype.

"Once we were able to identify the pattern of each subtype, we analyzed existing pharmacogenomics data to narrow a list of drugs that might be able to target one subtype or the other," explained Dr. Haibe-Kains. "We found two drugs that seemed to effectively target the primitive subtype in the lab, with potential to move to clinical trials in the future."

"This finding could change the way we treat patients," says Dr. Schimmer. "It opens up the opportunity to better refine and time treatmentswhether it's the decision for a stem cell transplant early on, or choosing more effective and less toxic therapies throughout the course of treatment.

Our goal with all of our patients is to get better and better outcomes. This is one step towards doing better."


University Health Network

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Cancer, Cell, Drugs, Education, Genes, Hospital, Leukemia, Medicine, Mutation, Pharmaceuticals, Rare Disease, Research, RNA, Transplant

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