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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quarta-feira, 19.08.15

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Published on August 17, 2015 at 7:21 AM ·

United Therapeutics Corporation (NASDAQ: UTHR) announced today that the European Commission (EC) has granted Marketing Authorisation for Unituxin™ (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children's Oncology Group (COG).

Trial design and results

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030).

Frequently occurring adverse reactions

The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported – including anaphylactic reaction (18%) and bronchospasm (4%).

Posology and method of administration

Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days).

The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses.

Source:

United Therapeutics Corporation

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por cyto às 12:08

Quinta-feira, 23.07.15

Gold nanoparticles with functional surfaces regulate osteogenic differentiation of stem cells

 

Gold nanoparticles with functional surfaces regulate osteogenic differentiation of stem cells

Published on June 8, 2015 at 3:00 AM ·

Tissue Regeneration Materials Unit (Guoping Chen, Unit Director) at the International Center for Materials Nanoarchitectonics (MANA) (Masakazu Aono, Director General, MANA), NIMS (Sukekatsu Ushioda, President) successfully developed gold nanoparticles that have functional surfaces and act on osteogenic differentiation of stem cells.

In regenerative medicine, the technology to control stem cell functions such as differentiation and proliferation is indispensable. It has been reported that nanosized gold particles promote the differentiation of human mesenchymal stem cells into osteoblasts. Also, other studies suggested that various functional groups such as amino, carboxyl and hydroxyl groups promote or inhibit stem cell differentiation. Based on these reports, we assumed that gold nanoparticles with surface modified with functional groups is a promising candidate to control stem cell functions. However, specific effects of such particles on the differentiation of human mesenchymal stem cells was unknown.

We synthesized gold nanoparticles with surface modified with one of the following functional groups: a positively-charged amino group (-NH2), a negatively-charged carboxyl group (-COOH) or a neutral hydroxyl group (-OH), and identified how they affect the osteogenic differentiation of mesenchymal stem cells that were derived from human bone marrow. Among these three types of nanoparticles, those with the carboxyl groups were uptaken by cells and exhibited a strong bone differentiation-inhibitory effect compared to the other types of nanoparticles. Furthermore, we investigated the effect of gold nanoparticles with carboxyl groups on the gene expression profile of mesenchymal stem cell from human bone marrow. The results indicated that the nanoparticles inhibited several gene expressions related to osteogenic differentiation. Therefore, the influence of the gold nanoparticles on promoting or inhibiting osteogenic differentiation varied depending on the types of functional groups.

In view of regenerative medicine, it is essential to develop technology enabling controlling stem cell functions as well as safe and high-quality stem cells. In the present study, we attempted to control stem cell functions through material manipulation, and our findings will contribute to the creation of novel nanomaterials that facilitate the advancement of stem cell manipulation. We intend to build upon these results in our future endeavors in developing regenerative medicine.

Source:

International Center for Materials Nanoarchitectonics

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por cyto às 22:52

Quinta-feira, 23.07.15

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

 

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

Published on July 16, 2015 at 2:40 AM · 

Immunologists from Emory University have identified a distinct set of long-lived antibody-producing cells in the human bone marrow that function as an immune archive.

The cells keep a catalog of how an adult's immune system responded to infections decades ago in childhood encounters with measles or mumps viruses. The results, published Tuesday, July 14 in , could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

"If you're developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen," says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare's Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Co-senior author of the Immunity paper is Iñaki Sanz, MD, professor of medicine and pediatrics, chief of the Division of Rheumatology, Mason I. Lowance Chair of Allergy and Immunology and a Georgia Research Alliance Eminent Scholar. The research was started when Lee, Sanz and colleagues were investigators at the University of Rochester Medical Center, and continued when they arrived at Emory in 2012. The first author of the paper is Jessica Halliley, MS from Rochester.

As described in part of the Immunity paper, the researchers studied 11 older individuals (aged 43 to 70) who had not been immunized against measles or mumps, but who had antibodies in their blood indicating infection by those viruses in childhood. Measles and mumps vaccines first became available in the 1960s.

Antibodies in the blood have a half-life of just a few weeks, so researchers thought these individuals had long-lived plasma cells, or white blood cells secreting antibodies, dating from the childhood infection.

Examining bone marrow samples obtained from these volunteers, researchers divided plasma cells into four different groups based on the proteins found on their surfaces. Only one group ("subset D", CD19-, CD38high, CD138+) contained the cells that produce antibodies that react with measles or mumps virus.

"I like to call this group of cells the 'historical record' of infection or vaccination," Lee says.

In contrast, cells producing anti-influenza antibodies were found spread across three of the subsets. Because study participants were likely to have been exposed to influenza by annual vaccination or infection more recently than measles or mumps, the researchers inferred that cells specific to recent exposures can reside in multiple subsets while subset D represents the long-lived plasma cells.

In separate experiments, volunteers who were vaccinated against tetanus did have some plasma cells producing anti-tetanus antibodies within three weeks in several subsets, but over time tetanus-specific plasma cells were found in subset D.

The team proved that subset D cells were exclusively responsible for producing the measles- and mumps-specific antibodies in the blood of one of the older volunteers, through proteomics and RNA sequencing techniques.

Compared with other subsets, subset D cells are more quiescent: they displayed less signs of proliferation. In addition, subset D cells have a distinct "fried egg" appearance, containing bubble-like vacuoles or lipid droplets, which are rare in bone marrow cell samples, and a tighter, more condensed nucleus than other white blood cells.

Plasma cells differ from many other cells in the body in that they undergo changes in their DNA -- specifically, their antibody genes. In the patients the researchers examined, antibody genes from subset D are much more diverse than those from other plasma cells. Lee says this finding also reflects subset D's role as an archive, which does not devote too much cellular space to any one vaccination or infection.

Source:

Emory Health Sciences

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por cyto às 22:43

Terça-feira, 21.07.15

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

 

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

Published on July 16, 2015 at 3:04 AM 

Studying telomeres, the structures that protect the ends of chromosomes, has become a key issue in biology. In recent years, not only has their relation to ageing been confirmed; defective telomeres seem to be linked to more and more illnesses, including many types of cancer. The review published by Paula Martínez and María Blasco from the CNIO in Trends in Biochemical Sciences, stresses the importance of investigating these structures to improve diagnoses and develop possible treatments for many diseases. Telomeres, in the opinion of these researchers, will become increasingly important in clinical studies.

The chromosomes in every single cell are made up of DNA and shaped like strands, with a kind of protective cap at the end of each strand of DNA. Without this end protective cap, the DNA strands would chemically bond to other strands, i.e. the chromosomes would merge and that would be lethal for the cell. The structures that prevent this catastrophe are the telomeres. They were discovered in the 1930s but decades elapsed before someone decided to study them in any depth and since the late 1990s they have always been on the cutting edge of biology research. Biologists are often surprised by their amazing and unexpected complexity, and their health-related significance.

"The biology of telomeres is extremely complex and the more we discover the more we realise what remains to be discovered", says Paula Martínez from CNIO's Telomere and Telomerase Group. "What surprises me most is the high number of factors we are finding that are essential to the preservation of telomeres and, above all, the precise coordination that is required between them all".

The fact that telomeres have been tightly preserved throughout the evolutionary tree -in most eukaryotes: vertebrates, plants and even unicellular organisms such as yeast- indicates their importance. In addition to preventing the merger of chromosomes, telomeres are needed to prevent the loss of genetic information each time a cell divides.

PREVENTING INFORMATION LOSS

When a cell replicates, the molecular machinery in charge of duplicating the chromosomes - so that each daughter cell has a copy -cannot reach the tip. This is inherently impossible due to the way the DNA replication machinery works, and it implies that any genetic material at the end of a chromosome with significant information for the cell would be lost. Telomeres prevent this from happening: they consist of a DNA sequence that does not contain genes and that is repeated numerous times- in humans and other species the sequence is TTAGGG; the letters correspond to three of the building blocks that make up the DNA: thymine, adenine and guanine.

Consequently, the shortening of the DNA with every division is not significant. At least not until a certain limit is reached. When the telomeres become too short, we see the problems associated with ageing: cells reach a point where they interpret critically short telomeres as irreparable damage and react by no longer dividing, which prevents tissue from regenerating.

This happens in healthy cells but not in cancer cells. There is an enzyme, telomerase, which is capable of lengthening the telomeres de novo. This enzyme is not present in most cells of an adult organism but it is active in tumour cells. By repairing the telomeres, the telomerase enables cancer cells to proliferate and become virtually immortal.

This link to ageing and cancer, has led to the intense study of telomere-based strategies to combat cancer and diseases associated with ageing. Blasco's group has recently shown that it is possible to make cancer cells mortal by acting on the telomeres.

ZOOMING IN TO THE TIP OF THE BUFFER

The above-mentioned description of telomeres however is a simplified version of the story. We now know that there is a protective structure enveloping telomeric DNA consisting of six proteins known as shelterins, which are crucial. Another more recent discovery is that there are proteins that, although not in the telomeres themselves, interact with them at specific times to enable them to perform their functions.

These proteins enable the telomeres to unwind, for example; because, the sequence repeated in telomeres, TTAGGG, ends in a single strand of DNA that curves forming a loop and connects to the original strand of the double chain forming a triple chain. "Yes, it is very complicated", admits Martínez. "Structures of up to four chains of DNA can form".

When a cell divides, the telomeres are also replicated. This implies that the end loop must unwind first and then form again. This process also contributes to the shortening of telomeres and we now know that some of the shelterins as well as other associated proteins that interact with telomeres are key elements in this process.

TELOMERE SYNDROMES

According to Martínez, "there is now more evidence about relationship between telomere maintenance and several illnesses".

Telomere syndromes, or telomeropathies, have been identified in patients with mutations of the telomerase enzyme. This group includes, for example, pulmonary fibrosis and problems related to the malfunction of the bone marrow. A direct relationship between telomere dysfunctions and many types of cancer has also been found. More recently, we have also discovered that mutations of the proteins that protect telomeric DNA, the shelterins, and those that interact with the telomeres, are linked to various diseases, such as dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome or Revesz syndrome.

"These discoveries underline the plethora of components and pathways that control telomere functions", write the authors in the paper. "In the future, research will bring to light more unknown factors that will improve our understanding of the mechanisms governing cancer and syndromes linked to the shortening of telomeres. We hope that this knowledge will be transferred to the clinic in order to improve the diagnosis and treatment of diseases".

Source:

Centro Nacional de Investigaciones Oncologicas (CNIO)

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por cyto às 18:18

Terça-feira, 21.07.15

Patients' own genetically engineered immune cells show significant success against multiple myeloma

 

Patients' own genetically engineered immune cells show significant success against multiple myeloma

Published on July 21, 2015 at 2:37 AM 

In recent years, immunotherapy has emerged as a promising treatment for certain cancers. Now this strategy, which uses patients' own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable. The results appeared in a study published online today in Nature Medicine.

Patients received an infusion of altered immune cells known as T-cells - roughly 2.4 billion of them - after undergoing a stem cell transplantation of their own stem cells. In 16 of 20 patients with advanced disease, there was a significant clinical response. The scientists found that the T-cell therapy was generally well-tolerated and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are found, and showed a long-term ability to fight the tumors. Relapse was generally associated with a loss of the engineered T-cells.

"This study suggests that treatment with engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," says first author Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine. "Our findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better results for our patients."

The trial is the first published use of genetically modified T-cells for treating patients with multiple myeloma. The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

More than 77,000 people in the United States have multiple myeloma, with about 24,000 new cases diagnosed each year. Patients are treated with chemotherapy and in many cases an autologous stem cell transplant, but long-term response rates are low, and median survival is three to five years.

"The majority of patients who participated in this trial had a meaningful degree of clinical benefit," Dr. Rapoport notes. "Even patients who later relapsed after achieving a complete response to treatment or didn't have a complete response had periods of disease control that I believe they would not have otherwise experienced. Some patients are still in remission after nearly three years."

The research is a collaboration between the University of Maryland School of Medicine, the Perelman School of Medicine at the University of Pennsylvania and Adaptimmune, a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study. Dr. Rapoport and co-authors Edward A. Stadtmauer, MD, of the University of Pennsylvania Abramson Cancer Center, and Gwendolyn K. Binder-Scholl, PhD, of Adaptimmune, contributed equally to the research. Dr. Rapoport is the study's principal investigator.

In the clinical study, patients' T-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen, or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1 and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1, which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is the first published study of lentiviral vector mediated TCR gene expression in humans.

Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment. Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment. Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center. Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant. In addition, patients did not experience side effects which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.

The study was originally developed by Carl H. June, MD, of the University of Pennsylvania Abramson Cancer Center, and Dr. Rapoport, who have been research collaborators for 18 years.

"Multiple myeloma is a treatable but largely incurable cancer. This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body's ability to attack the cancer and provide patients with better treatments and control of their disease," says E. Albert Reece, MD., PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "This trial is also an excellent example of significant scientific advances that result from collaborations between academic medical institutions and private industry."

Source:

University of Maryland Medical Center

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por cyto às 18:10

Terça-feira, 21.07.15

Single molecule appears to be central regulator driving cancer metastasis

 

Single molecule appears to be central regulator driving cancer metastasis

Published on July 14, 2015 at 6:21 AM · 

Cancer is a disease of cell growth, but most tumors only become lethal once they metastasize or spread from their first location to sites throughout the body. For the first time, researchers at Thomas Jefferson University in Philadelphia report a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published online July 13th in Cancer Cell, offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well.

"Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins," says Karen Knudsen, Ph.D., Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University, the Hilary Koprowski Professor and Chair of Cancer Biology, Professor of Urology, Radiation Oncology, and Medical Oncology at Jefferson.

Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA - mutations - that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to anchor down in a new location, such as the bone, the lungs, the liver or other organs, where new tumors start to grow. Although these processes are fairly well characterized, there appeared to be many non-overlapping pathways that ultimately lead to these traits.

Now, Dr. Knudsen and colleagues have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is a DNA repair kinase called DNA-PKcs. The kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments. Importantly, Dr. Knudsen's work showed that DNA-PKcs has other, far-reaching roles in cancer.

The researchers showed that DNA-PKcs also appears act as a master regulator of signaling networks that turn on the entire program of metastatic processes. Specifically, the DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other gene networks involved in other steps in the metastatic cascade, such as cell migration and invasion.

In addition to experiments in prostate cancer cell lines, Dr. Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNA-PKcs production or function. And in mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, the researchers analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels to the patients' medical records. They saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

"These results strongly suggest that DNA-PKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumors may go on to metastasize," says Dr. Knudsen.

"The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected, and the discovery was made possible by key collaborations across academia and industry," explains Dr. Knudsen. Key collaborators on the study, in addition to leaders of the Sidney Kimmel Cancer Center's Prostate Program, included the laboratories of Felix Feng (University of Michigan), Scott Tomlins (University of Michigan), Owen Witte (UCLA), Cory Abate-Shen (Columbia University), Nima Sharifi (Cleveland Clinic) and Jeffrey Karnes (Mayo Clinic), and contributions from GenomeDx.

Although not all molecules are easily turned into drugs, at least one pharma company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase 1 study (NCT01353625). "We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. This new trial will be for patients advancing on standard of care therapies, and will be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium, of which we are a member," explained Dr. Knudsen.

"Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumor agents. In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier," says Dr. Knudsen. "Given the role of DNA-PKcs in DNA repair as well as control of tumor metastasis, there will be challenges in clinical implementation, but this discovery unveils new opportunities for preventing or treating advanced disease."

Source:

Thomas Jefferson University

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por cyto às 18:05

Quinta-feira, 25.06.15

Acute Lymphoblastic Leukemia, Blood, Blood Cancer, Blood Disorder, Bone, Bone Marrow, Cancer, Cardiology, Cell, DNA, Education, Gene, Genetic, Genetics, Hematology, Hospital, Leukemia, Neurology, Neurosurgery, Oncology, Pediatrics, Platelets, Thrombocytop

Researchers track down key gene mutation responsible for causing acute lymphoblastic leukemia

Published on June 18, 2015 at 8:52 AM ·

After collecting data on a leukemia-affected family for nearly a decade, Children's Hospital of Michigan, Detroit Medical Center (DMC), Hematologist and Wayne State University School of Medicine Professor of Pediatrics Madhvi Rajpurkar, M.D., joined an international team of genetic researchers in an effort to track down a mutation partly responsible for causing the disease. Their findings, recently published in one of the world's leading science journals, have "major implications" for better understanding the genetic basis of several types of cancer, including leukemia.

Says Children's Hospital of Michigan Hematology/Oncology Researcher and Wayne State University Assistant Professor of Pediatrics Michael Callaghan, M.D., an investigator who co-authored the recently published study in Nature Genetics: "This is a very exciting new finding in cancer research - and I think a lot of the credit has to go to Dr. Rajpurkar for identifying the family (with the genetic mutation). This is a great example of how an astute clinician can help accomplish a breakthrough in research by paying careful attention to patients and then thinking long and hard about what she is seeing in the treatment room."

Two medical researchers from the Children's Hospital of Michigan and the Wayne State University School of Medicine have published the results of a nearly 10-year investigation that identified a key gene mutation that can trigger acute lymphoblastic leukemia, or ALL, and several other types of cancer.

Recently published in Nature Genetics, the findings assembled by the Children's Hospital of Michigan and Wayne State University School of Medicine duo and a team of international investigators have for the first time pinpointed a mutation that allows a lymphoblastic leukemia "precursor" to set the biochemical stage for the blood disorder.

ALL is a blood cancer that attacks an early version of white blood cells manufactured in bone marrow. Investigators have long suspected that it is caused in part by a mutation in a gene that is supposed to "turn off" excessive blood-cell growth. When the mutation suppresses the controlling mechanism that regulates the runaway growth, leukemia is often the result.

The study, "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia," began nearly a decade ago when Dr. Rajpurkar treated a child at the Children's Hospital of Michigan for low blood platelets, known medically as "congenital thrombocytopenia." When both the child and an aunt later developed ALL - even as several other family members were diagnosed with thrombocytopenia - Dr. Rajpurkar began to suspect that there might be a genetic mutation at work in the family.

What followed was a 10-year journey through the labyrinth of the Human Genome, as the researchers worked with a growing number of genetic investigators to isolate and identify the mutation in a gene (ETV6) that regulates growth rates in bone marrow.

A key breakthrough in the quest for the genetic culprit took place when a nationally recognized expert in gene mutation - University of Colorado physician-researcher Jorge DiPaola, M.D. - joined Drs. Rajpurkar and Callaghan, and other investigators from Italy and Canada, in the effort to solve the DNA puzzle by uncovering the flaw in ETV6. The mutation discovery occurred in a core facility where the gene-sequencing took place.

While noting that "our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition," the study's authors concluded that the mutation occurs through "aberrant cellular localization" of the gene, which can result in "decreased transcriptional repression" during white blood cell formation.

"What we think that means," Dr. Callaghan said, "is that ETV6's job is to 'turn off' growth, but when you have this mutation, it can't turn it off because it's in the wrong place. It's usually supposed to sit on the DNA and keep things (including cancer) from getting made, but when you have this mutation, instead of sitting on the DNA it's sitting in a different part of the cell.... And that predisposes you to getting a (blood) cancer."

Dr. Rajpurkar, who is also the division chief of Hematology at the Children's Hospital of Michigan and an associate professor of Pediatrics at the Wayne State University School of Medicine, said she was "greatly pleased" that her decade of treating the Detroit family with the mutation eventually led to the breakthrough. "I told them that I didn't know what the family had," she said, "but that I would do my best to find out. Sometimes one has to accept uncertainty in the field of medicine, but (persistence in clinical research) pays off!"

The Children's Hospital of Michigan Pediatrician-in-Chief and chair of the Wayne State University School of Medicine Department of Pediatrics Steven E. Lipshultz, M.D., said the breakthrough was "hugely important" because it resulted in "a new association (between a genetic mutation and leukemia) that can now be scanned for.

"Because of this finding," he added, "families will eventually be counseled regarding their risk for some kinds of cancer and targeted interventions will be devised and tested."

Dr. Lipshultz also noted that the new findings in "what many physicians and researchers regard as the leading journal in the world on the molecular genetic basis of human disease" also provide "an exciting and extremely encouraging example of how research that takes place in the clinical setting can greatly improve care for patients.

"Our goal at the Children's Hospital of Michigan is to do everything we can to help achieve better outcomes for the patients we serve. This latest publication by two CHM physician-researchers and their colleagues underlines the vitally important links between treatment and research, and to see them demonstrated so compellingly inNature Genetics is quite thrilling for all of us who spend our days trying to help kids at the Children's Hospital of Michigan!"

Source:

Wayne State University - Office of the Vice President for Research

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por cyto às 11:49


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