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Researcher: Lorem Sit Amet

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Exploring the brain-gut-microbiota axis to characterize and predict outcome in pediatric diffuse intrinsic pontine glioma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Abstract

Diffuse intrinsic pontine gliomas (DIPGs), represent a group of malignancies with rapid onset of devastating neurologic symptoms associated with the local extension, poor response to adjuvant therapy and a very poor prognosis. Radiotherapy has remained the only modality of treatment with proven transient symptomatic improvement and represents the mainstay of any treatment in combination with any other drug.

It has been well known for decades that bidirectional signaling between the gastrointestinal tract and the brain is regulated at neural, hormonal, and immunological level. Due to the complex relationship between gut microorganisms and the host, a new concept has been proposed: the microbiota-gut-brain axis. The core hypothesis of the present proposal is that the microbiota may affect the CNS taking part in the regulation of nervous system function and affecting the pathogenesis and progression of diseases related to the nervous system. Thus, we plan to define non-invasive biomarkers by analysing stool specimens to predict patient response to therapy and the course of the disease. Since diet is the major factor driving the composition of the colonic microbiota, this project could identify potential microbiota profiles beneficial for radiotherapy and other therapeutic interventions and hence modulate disease using dietary regulation.

Impact

Cancer translational research and treatment is increasingly moving toward individualisation of tumour treatment (precision medicine) that relies on understanding the specific biological, genetic, and molecular changes driving the individual’s tumour growth. The last decade has witnessed the development of non-invasive methods that could have a significant impact in DIPG. The existence of the gut-brain axis consisting of the bidirectional communication between the central and the enteric (gut) nervous system has been known for decades; recent advances in research have described the importance of gut microbiota in influencing these interactions. Gut microbiota can be assessed by next-generation sequencing (NGS) approaches in fecal specimens and could be the ideal material for developing non-invasive biomarkers that can orient future personalised DIPG management programmes. We expect a relevant impact from this grant proposal paving the way to a new apprach for the disease. 

Objectives

The project aims at developing new treatment decision tools for DIPG patients exploiting information from  gut microbiota.

Aim 1) to develop models based on gut microbiota profiles at diagnosis to predict a patient's clinical course;

Aim 2) to monitor the course of disease in conjunction with a longitudinal series of gut microbiota specimens;

Aim 3) to investigate potential dietary intervention to shape microbiota profiles which could be beneficial for radiotherapy and other therapeutic interventions. 

Methodology

The project will collect material from an ongoing clinical trial activated at Fond. INT (Milan, Italy) and will exploit state-of-the-art of genomics technologies trought next generation sequencing (NGS). This data will be analysed in conjunction with detailed clinical data including the treatment and the disease course.

Executive Summary

Background

Diffuse intrinsic pontine glioma (DIPG) is a rare brain tumour of childhood whose abysmal prognosis has remained unchanged over at least the last four decades. Radiotherapy has remained the only intervention that has been able to modify the course of the disease albeit not in a curative way.  Without radiation, median survival is approximately 4 months. Even with radiation, subsequent tumor progression is almost universal, with a median overall survival between 8 and 11 months, and overall survival of approximately 30 % at 1 year and less than 10 % at 2 years.

Hypothesis

In the past 30 years, DIPG patients have participated in more than 250 clinical trials worldwide. These trials have involved a wide array of chemotherapeutic drugs and small-molecule targeted inhibitors. Unfortunately, none of these studies have shown substantial benefit in either the likelihood of survival or the median length of survival compared to radiotherapy alone. The reasons for lack of efficacy are multiple, and may include failure in choosing the right biological target in the tumour, selecting the right drug, adequately delivering the drug  into the tumour as well as the tumour developing resistance to drugs that have been used. The lack of suitable biological markers to target or to predict the disease trajectory also is an important factor to consider. Cancer translational research and treatment is increasingly moving toward individualisation of tumour treatment (precision medicine) that relies on understanding the specific biological, genetic, and molecular changes driving the individual’s tumour growth.

The last decade has witnessed the development of non-invasive methods that could have a significant impact in DIPG. The existence of the gut-brain axis consisting of the bidirectional communication between the central and the enteric (gut) nervous system has been known for decades; recent advances in research have described the importance of gut microbiota in influencing these interactions. Gut microbiota can be assessed by next-generation sequencing (NGS) approaches (sequencing the genetic code ) in fecal specimens and could be the ideal material for developing non-invasive biomarkers that can orient future personalised DIPG management programmes. Thus, we expect a potential high impact from this grant, laying the groundwork  for personalized treatments modalities.

Clinical significance

To improve the clinical outcome of DIPG patients, accurate detection and monitoring of disease is necessary. At present, surgical and/or biopsy specimens are generally used to detect tumour alterations and to build predictive treatment models. However, due to its invasive nature, the collection of this kind of material is not routinely feasible in children with DIPG. In addition, the tumour at baseline may fail to reflect the current tumour dynamics and drug sensitivity that may change during the therapeutic process. Therefore, non-invasive methods for assessing and monitoring the disease through the gut microbioma could be the ultimate way to define personalised DIPG management programs.

The project will offer solutions to clinical needs in DIPG care by:

1) predicting the patient’s outcome at diagnosis without any invasive procedure

2) developing a tool to monitor the course of the disease and treatment efficacy using a non-invasive methodology

3) improving our understanding  of gut microbiota in order to modify this through diet variation or other  tools such as Bacillaceae medication.

In the context of a still incurable disease, the tumour in children currently with the worst prognosis, the realisation of any one of these aims will result in an important step forward in the management of this disease.

 

Goals

The project aims at  developing new treatment decision tools for DIPG patients exploiting information from  gut microbiota.

AIM 1) to develop models based on gut microbiota profiles at diagnosis to predict a patient's clinical course;

AIM 2) to monitor the course of disease in conjunction with a longitudinal series of gut microbiota specimens;

AIM 3) to investigate potential dietary intervention to shape microbiota profiles which could be beneficial for radiotherapy and other therapeutic interventions. 

 

Methodology

The present proposal is a translational research to define non-invasive biomarkers associated to the following clinical trial “phase II open label randomized study of radiotherapy, concomitant nimotuzumab and vinorelbine and re-irradiation at relapse versus radiotherapy and multiple elective radiotherapy courses with concomitant nimotuzumab and vinorelbine for newly diagnosed childhood and adolescence DIPG” activated at Fond. INT (Milan, Italy).

The project will exploit state-of-the-art in metagenomic profiling which will be able to identify not only bacterial but also viral/fungal genetic material. This data will be analysed in conjunction with detailed clinical data including the treatment and the disease course.

 

Feasibility

The feasibility is ensured by the expertise of the team ans collaborators involved in the research project. 

Dr. Maura Massimino’s research is particularly focused at the study of brain tumors in pediatric age. She has been the PI of two protocols for the diagnosis and treatment of pediatric ependymoma for the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP)  and she is particularly involved in the activities of the Brain Tumor Subcommittee. Since November 2015 she has been coordinator of the AIEOP Working Group for Childhood Central Nervous System Tumors. She designed and coordinated a study for DIPG patients whose results are, to date, the best published in the field. Together with Dr Biassoni, she is on the Executive Committee of the SIOP DIPG Registry.

The experimental activities will be overseen by Dr, Loris De Cecco, PhD who has scientific and appropriate background, knowledge and skills in the specific field of interest. To manage the multidisciplinarity of the project, a hierarchical organisation scheme will be structured, assigning responsibilities at the different levels of decision and operational intervention.

The PI will ensure the proper functioning of the project to achieve the objectives and ensure the timely realisation of its milestones and deliverables. She will define, implement and monitor the strategy for the dissemination and communication of the project and establish a governance structure with appropriate participation of all the project members.

 

The team also includes L.Boschetti, PhD, will manage grants, and legal and ethical issues. 

The project will be supported by Dr. F. Iannò (Biologist) for the experimental activities; Dr. A. Carenzo (Bioinformatician) for data processing and analysis; E. Schiavello, MD - oncologist – that will manage clinical treatments and appropriate sample collection.

The feasibility of the project is ensured by preliminary data that proves the microbiome 16S analysis starting from stool specimens of DIPG patients (see Supporting Documentation) 

Expertise

Fondazione IRCCS Istituto Nazionale dei Tumori and, particularly, the Paediatric Oncology and the Radiotherapy Units have a long standing experience in the care of paediatric brain tumors. Every year, about 70-80 new patients are submitted to adjuvant treatment, consisting of radiotherapy and chemotherapy depending on histological diagnoses, the extent of the disease and the patients' age. Around 400 patients cured for brain tumors are undergoing an active follow-up consisting of clinical, MRI, neurological and endocrinological examinations, in parallel to psychiatric and psychological counseling when requested. 12 to 15 children affected with DIPG and midline glioma are diagnosed and treated annually.

Platform of Integrated Biology (PBI) - the activities are based on the availability of instruments/equipments for: nucleic acid extraction and purification, such as QIAsymphony SP and QIAcube; quantity and quality controls of nucleic acids, such as Agilent Bioanalyzer, Nanodrop, Qubit, TapeStation; microarray analysis of mRNA expression, miRNA and lncRNA expression, DNA methylation, CGH and CNV, SNPs such as Illumina (iScan), Affymetrix (GeneChip 3000) and Agilent platforms; quantitative real-time PCR such as Quantstudio 12K with Open Array Block and Accufil; Next Generation Sequencing, such as IonS5XL, Personal Genome Machine (ION TORRENT technology) and NextSeq500 (Illumina); dedicated servers, workstations and up-to-date software, hardware and web-based databases. The samples and all the experimental and bioinformatic activities are tracked using dedicated software provided by TwinHelix and IBM. The scientific and technical staffs of the PBI have the appropriate background, knowledge and skill in the specific field of interest.

 

Description of Research Proposal

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Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

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