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Grants Awarded to Date

The Foundation is pleased to announce that a grant has been awarded to Glasgow-based charity Funding Neuro to support a UK based clinical trial, lead by Professor Steven Gill, to treat children with DIPG brain tumours using a unique and pioneering form of Convection Enhanced Delivery. (CED). The Foundation has granted £244,000 to provide the funding needed to ensure the trial started last autumn.

The Foundation chose to fund this study after careful review by our scientific advisory board and considerable discussions with Professor Gill and his team. The results achieved, thus far, have been promising and show potential for the development of an effective form of treatment for DIPG.

Funding Neuro Chief Executive Sharon Kane said: “The Lyla Nsouli Foundation has been leading the way in finding a cure for brain cancers which affect children for the last five years, so we are incredibly grateful the organisation has chosen to make such a significant contribution to ensure we could secure the total amount needed.”

British neurosurgeon Professor Steven Gill and his medical team in Harley Street Clinic, London, will carry out the trial, the only one of its kind in the world.

It will see 18 children diagnosed with deadly DIPG brain tumours treated using a pioneering robotic procedure, which requires the installation of a titanium port in the skull linked to a series of micro-catheters targeting specific parts of the brain.

This procedure allows Bristol-based Professor Gill to bypass the protective brain blood barrier membrane, which makes it almost impossible to administer neurological treatment drugs using conventional oral or intravenous methods.

By administering treatment drugs directly into the brain through a series of pain-free infusions, the membrane then works to the professor's advantage by acting as a protective barrier to the rest of the body. This allows Professor Gill to deliver far greater drug doses such as chemotherapy to a tumour without the usual side effects such as hair and weight loss and nausea. Sharon Kane added: “That an organisation such as The Lyla Nsouli Foundation is willing to invest so much money is testament to their confidence in the pioneering work currently being carried out by Professor Steven Gill and his team in Bristol.

Each year in the UK, DIPG brain tumours, very sadly, claim the lives of between 30 and 40 children just like Lyla. Up until this point, treatment methods have proved ineffective, but the professor and his team are on the verge of making a major breakthrough in the way we treat DIPG tumours.

They have made great strides already by both extending and improving the lives of the children currently being treated by the team, but the ultimate goal is to find a lasting cure.  The team learns more each time they treat a child, so having the funding in place to get the trial underway is extremely important.”

Speaking on behalf of The Lyla Nsouli Foundation, Director Nadim Nsouli said: “We decided to support this study as we believe that the results thus far have been very promising and the team leading this study have demonstrated great commitment to using their CED expertise and technology to treat DIPG. We believe that CED (Convection Enhanced Delivery; see image below) has the potential to become an effective method of targeting and treating DIPG tumours and we continue to show our support for this field of DIPG research with this latest grant.”


Unique CED catheter system comprises implantable microcatheters and a skull anchored port, which allows drugs to be repeatedly administered without the need for further surgery.

The Foundation awarded $130,000 to the Paediatric Brain Tumour Consortium for a Phase 1 Clinical Trial of Panobinostat in Children with Diffuse Intrinsic Pontine Glioma

In February the Foundation made a final stage grant of $130,000 for a Phase 1 Clinical trial of Panobinostat, a deacetylase inhibitor that has shown anti-tumour activity in pre-clinical models and cancer patients.

Many clinical trials over the past three decades have explored the use of various chemotherapeutic agents for DIPG but none have ever shown significant efficacy. Pre-clinical evidence for panobinostat effects against DIPG cell lines to histone deacetylase inhibitors in in vitro  cell culture studies, and tumour inhibitory effect of panobinostat in in vivo  efficacy studies performed using orthotopic xenograft models of DIPG. Panobinostat has yet to be tested against DIPG in humans.

This trial will use panobinostat to assess safety, tolerability and pharmacokinetics as well as initial observations of any clinical effect in paediatric patients with DIPG.

The trial is multi-institutional. Panobinostat will be supplied by Novartis who have given final approval. We expect results to be available after 24 months.

Update from Dr. Chris Jones' study "The Role of ACVR1 / ALK2"

The Foundation awards Dr. Chris Jones a further £90,000

In February, The Foundation met with Dr. Chris Jones of the Institute of Cancer Research in February to discuss the progress of his study, "The role of ACVR1/ALK2 mutations in Diffuse Intrinsic Pontine Glioma (DIPG)".
The Foundation first funded Dr. Jones in 2013 and his study is progressing well. He is currently in the process of creating various different mouse models of the ACVR1/ALK2 mutation in order to develop a better understanding of how tumours with this mutation behave and develop drugs that target this mutation. In 2014, Dr. Jones and his team identified that these mutations found in DIPG are also shared by patients with a rare genetic condition known as fibrodysplasia ossificans progressiva (FOP) – sometimes referred to as Stone Man Syndrome – that locks people in a second skeleton as they age. As a result of this finding, they have been working closely with FOP researchers who already have developed potential drug leads for targeting these mutations. The Foundation extended a second grant to Dr. Jones in July 2014, following a review of his research update and progress by our scientific advisory board. More recently, in June 2015, a further extension was awarded. This new funding will enable Dr. Jones and his team to develop further mice models with ACVR1 and PI3 Kinase mutations, based on the prediction that DIPG tumours are more likely to grow in these mice with more than one DIPG mutation, and also due to the synergy observed between ACVR1 and PI3 Kinase inhibitors. Therefore, it is critical to have the appropriate mouse models for testing drug combinations that act on this inhibitors.

https://instituteofcancerresearch.wordpress.com/2014/04/07/stone-man-syndrome-and-its-mysterious-link-to-childhood-brain-cancer/

The Foundation has approved a grant to Dr. Mark Souweidane of Memorial Sloan Kettering Cancer Center in New York in the amount of $266,400.

The funding is to allow for the extension of a Phase One Clinical Trial currently taking place. This is a therapeutic Phase 1 study with a standard “3+3” design intended to assess the safety of convection enhanced delivery (CED) of a radio-antibody in the treatment of children with DIPG.
Diffuse intrinsic pontine glioma (DIPG) in childhood is currently a consistently lethal condition. Ineffective drug delivery has been postulated as a dominant reason for poor tumor response in children with DIPG.
One means for overcoming this limitation is to use convection enhanced delivery (CED),a form of local drug delivery that bypasses the blood brain barrier (BBB). Using this strategy in the brain stem has until recently been only theoretical and experimental.
Based on preliminary success, the funding is for an extension of a phase one clinical trial defining the tolerated infusion dose (MTiD) and/or an infusion volume (T2-weighted images) that best approximates the intended treatment (tumor) volume.

This is the second grant awarded to Dr. Souweidane. The first one in the amount of $114,670 was awarded in September 2012 for “Assessing Regional Tumor Response After Convection Enhanced Delivery (CED) for Diffuse Intrinsic Pontine Glioma”.

A grant has been awarded to Dr. Viola Caretti from the lab of Dr. Michelle Monje at Stanford University. The Foundation awarded Dr. Caretti $75,000 for funding a study entitled ‘Non-cell Autonomous Effects in Pediatric Pontine Gliomas'

Hypothesis: DIPG cells secrete soluble factors that recruit healthy Neural Precursor Cells (“NPCs”) in the developing brain and this interaction can be targeted therapeutically. The present proposal seeks to understand the mechanism of DIPG non-cell autonomous effects on neighboring cells and ultimately therapeutically target DIPG cell:NPC interactions in the developing brain.

Problem & Solution: Despite numerous clinical trials based on conventional chemotherapy and targeted molecular therapy, the prognosis of children affected by DIPG remains universally dismal. Effective treatment options are urgently needed. To develop new treatment strategies, scientists and physicians have historically focused on targeting the cancer cells themselves. Instead, the present proposal seeks to understand the mechanism of DIPG non-cell autonomous effects on neighboring normal cells and ultimately therapeutically target putative DIPG cell:NPC interactions in the developing brain to mitigate tumor growth and offer new potential effective therapies for these children.

This is the second grant awarded to Dr. Michelle Monje's lab. The first one in the amount of $180,000 was awarded in March 2013 for funding a study entitled “A Combinatorial Approach to Target Cellular Subpopulations in Diffuse Intrinsic Pontine Glioma”.

The Foundation has extended an offer of US$85,000 to an international consortium of DIPG researchers (July 2014)

The Foundation has extended a second £90,000 grant to Dr. Chris Jones at The Institute of Cancer Research for the study entitled ‘The role of ACVR1/ALK2 mutations in Diffuse Intrinsic Pontine Glioma' (July 2014)

The Foundation has approved a second grant of US$300,000 to an international consortium of DIPG researchers. The press release is published below.

International group of pediatric brain cancer researchers receives $300K toward a cure

Parents of children who died from rare cancer believe greater investment in quality research is critical

PORTLAND, Ore. – An international consortium of researchers focused on identifying new molecularly targeted drugs to treat the most fatal form of childhood brain tumor, diffuse intrinsic pontine glioma, or DIPG, has been awarded nearly $300,000 by The Lyla Nsouli Foundation for Children's Brain Cancer Research, based in London, England. The foundation was established in memory of 3-year-old Lyla Nsouli, who died in January 2012 after a devastating five-month battle with DIPG.

Lyla's parents, Nadim and Simone Nsouli, are hopeful their contribution will help bring researchers closer to a cure: "Facing her sudden, brutal diagnosis without any real option for treatment or survival is not an experience any child or their family should ever have to bear. Significantly greater investment in quality research is vital to improving the prognosis for children like Lyla. We are determined that research can provide treatments and eventually a cure for this cruel childhood cancer."

To date, no treatment does more than incrementally increase survival of children with DIPG. One day a child may have a headache or unsteadiness, but the next day a family's life and plans are tragically changed. A group of international researchers called the DIPG Preclinical Consortium hopes to change this.

"Our first phase of drug screening and tumor DNA sequencing couldn't have been possible without the support of the Lyla Nsouli Foundation, the Cure Starts Now, Accelerate Brain Cancer Cures and CureSearch Foundations. Now that we have drug leads, the hard work of validating these begins. The Lyla Nsouli Foundation has been with us every step of the way, both in terms of support and accountability — both matter," said consortium coordinator Charles Keller, M.D., associate professor of pediatrics at Oregon Health & Science University Doernbecher Children's Hospital and the OHSU Knight Cancer Institute.

"The members of the Children's Oncology Group CNS committee express a deep sense of gratitude to the Lyla Nsouli Foundation for funding the DIPG Preclinical Consortium," said Amar Gajjar, M.D., chair of the brain tumor committee for the National Cancer Institute-supported Children's Oncology Group (COG). "The grant from the foundation has sparked a global effort to find new and effective therapies using the latest technologies currently available against diffuse intrinsic pontine glioma. The rapid translation of information from research laboratories to a clinical protocol is an often sought aim for advancing cancer cure rates – the grant from the Lyla Nsouli Foundation has made this dream a reality."

Gajjar and Maryam Fouladi, M.D., co-chair of the COG brain tumor new agents committee and leader of its Pediatric Brain Tumor Consortium, conceived the DIPG Preclinical Consortium with Keller: "Real-time science in partnership with the community for a shared goal of finding a two-drug combination to put into international clinical trials for DIPG."

Consortium member Jacques Grill, M.D., Ph.D., Institut Gustave-Roussy, Villejuif, France, innovates by creating living cell cultures not from autopsy-derived tumor samples, but from biopsies from the brainstem. This novel approach was initially controversial but is winning acceptance, Keller noted.

"Grill and his colleague, Dr. Darren Hargrave at Great Ormond Street Hospital, London, keep a clear line of communication so that the consortium's results are reported in real time to the European clinical trial groups to inform on that side of the Atlantic," said Keller. "The scientific teams are diverse due to the pressing nature of the need to understand and treat DIPG."

Each member will take a different but complementary role to ensure the results of the robotic drug screen of 17 autopsy- or biopsy-derived DIPG cultures can be validated in mouse models.

"This collaboration has been a wonderful opportunity to work together as a community to move the field closer to an effective therapy for this terrible disease. I am hopeful that, together and with the immense support from Lyla Nsouli Foundation, we will make real strides forward now," said Michelle Monje, M.D., Ph.D., Stanford University Beirne Faculty Scholar in Pediatric Neuro-Oncology, Stanford Cancer Institute, Lucile Packard Children's Hospital.

"The DIPG Preclinical Consortium offers hope where once there was very little. When my son, Andrew, was diagnosed with DIPG in October 2007, I never imagined that such a collaboration would exist a few short years later — a collaboration where exceptional science and a remarkable patient community meet in partnership to change the future for children like Andrew and Lyla," said DIPG parent Sandy Smith.

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Consortium members include: Keller, Kellie Nazemi, M.D., Nathan Selden, M.D., Ph.D., Doernbecher Children's Hospital, Oregon Health & Science University; Monje, Stanford University; Grill, Institut Gustave-Roussy; Oren Becher, M.D., Duke University Medical Center; Cynthia Hawkins, M.D., Ph.D., University of Toronto; Xiao-Nan Li, M.D., Ph.D., Baylor College of Medicine; Esther Hulleman, VU Cancer Center Amsterdam; Eric H. Raabe, Johns Hopkins University; Katherine Warren, Paul Meltzer and Martha Quezado, NIH; and Marta Alonso, University of Navarra, Madrid, Spain.

The Foundation has approved its first UK research grant.

The role of ACVR1/ALK2 mutations in Diffuse Intrinsic Pontine Glioma (UK£90,000 Grant)-Dr. Chris Jones, The Institute of Cancer Research

Summary

Diffuse intrinsic pontine glioma (DIPG) have a universally dismal prognosis (median 9-12 months), with neither chemotherapeutic nor targeted agents showing any substantial survival benefit in clinical trials in children with these tumours. We recently identified recurrent activating mutations in the ACVR1/ALK2 gene, which encodes a type I activin receptor serine/threonine kinase, in nearly 20% of DIPG samples [Taylor et al., submitted; Buczkowicz et al., submitted]. Strikingly, these somatic mutations (R206H, Q207E, R258G, G328E/V/W, G356D) have not been reported previously in cancer, but are identical to those found in the germline of patients with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP), and have been shown to constitutively activate the BMP/TGF-b signalling pathway. ACVR1/ALK2 mutations represent novel targets for therapeutic intervention in this otherwise incurable disease, and we aim to exploit these findings to investigate the role of ACVR1/ALK2 mutations and activation in DIPG. Specifically, we wish to evaluate the therapeutic potential of targeting the mutant receptor through genetic and pharmacological inhibition, both in vitro and in vivo, and to better understand the mechanism by which these mutations promote gliomagenesis by generating genetically engineered mouse models of the disease. This data has the potential to be rapidly translated to the clinical setting given the poor clinical outcome of these patients and the lack of currently open trials in the UK.

A Combinatorial Approach to Target Cellular Subpopulations in Diffuse Intrinsic Pontine Glioma-US$180,000 (March 2013)

The Foundation has approved its largest grant to date to Michelle Monje, MD, PhD, Assistant Professor of Neurology and Neuro- Oncology, Stanford University. The Lyla Nsouli Foundation funded 80% of the grant and the remainder was funded by The DIPG Collaborative and The Cure Starts Now.

Specific Aims
Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating childhood cancer. We have recently developed the first available cell culture and orthotopic xenograft models of DIPG . These invaluable resources, together with our parallel studies of normal brainstem development, have led to the discovery of a DIPG tumor-initiating cell type. The tumor-initiating cell, or "cancer stem cell (CSC)", of DIPG is a small subpopulation that is responsive to the powerful signaling pathway Hedgehog. The classic cancer stem cell hypothesis posits that the cancer stem cell is solely responsible for tumor propagation, as though the CSC population is like the tumor's "engine", giving rise to a rapidly proliferating transit amplifying cell type and more "differentiated" cell types downstream in the cellular hierarchy. Without the CSC, all daughter cell types would be expected to burn out and the tumor to become indolent.

We have targeted the DIPG tumor initiating cell population using pharmacological Hedgehog pathway inhibition. We have now shown that while Hedgehog pathway inhibition has dramatic effects on tumor cell self-renewal in vitro, and does slow tumor growth for about a month in vivo, it does not change the ultimate size of the tumors that diffusely infiltrate the brainstem in our DIPG orthotopic xenograft model nor does it significantly alter survival. Hedgehog inhibitor therapy does, however, appear to deplete or eliminate the tumor-initiating cell population in vivo. In other words, the "cancer stem cell" is gone, but the tumor still grows enough to kill the mouse. It may be that DIPG tumor cell behavior does not conform precisely to the cancer stem cell hypothesis, or it may be that in DIPG the time required for transit amplifying cell "burn out" is not tolerated by the functionally critical, relatively small and confined brainstem. Either way, these findings point to a paradigm shift from the classic cancer stem cell hypothesis, and so a novel strategy is needed. We thus propose to test the hypothesis that it is necessary to target multiple cellular subpopulations to achieve a survival benefit in DIPG.

AIM I Define the cellular heterogeneity of primary DIPG tumor samples using single cell molecular analyses

AIM II High throughput in vitro drug screening of each cellular subpopulation

AIM III in vivo preclinical testing and development of a combinatorial strategy to target the functional cellular compartments in DIPG

Assessing Regional Tumor Response After Convection Enhanced Delivery (CED) for Diffuse Intrinsic Pontine Glioma-$114,670 Grant (September 2012)

The Lyla Nsouli Foundation is proud to announce the award of a US$114,670 grant to Dr. Mark Souweidane at the Joan & Sanford Weill Medical College of Cornell University.

In clinical trials for children with DIPG, length of survival has served as the only measure of therapeutic benefit. This outcome measure is reasonable assuming the entire tumor is equally affected by drug delivery. However, distribution of a therapeutic compound delivered by CED is expected to have some variability within a defined volume. The study's hypothesis is that DIPG tumor response will occur on a regional and variable basis after being treated with CED. To test this hypothesis a reliable method must be devised that offers an objective measurement of response within different zones of each individual tumor. Measuring DIPG response has thus far been problematic since these tumors do not typically exhibit contrast enhancement and tumor volume is difficult to define, two parameters commonly used for other brain tumor response assessments. Without a means for assessing early therapeutic response, potential beneficial strategies that employ local delivery may be masked and inaccurately be abandoned. To date, no method has been developed to measure regional tumor responses as a function of local therapeutic delivery. Assessing intratumoral response will play a critical role in defining future CED parameters, including anatomic targets, infusion rates, durations, and volumes. The intent of this proposal is to design a reliable method by which tumor response can be measured on a regional intratumoral basis and to merge this response information with an assessment of drug distribution.

Oregon Health & Science University (and other institutions globally) - $8,800 Supplement (August 2012)

An additional $8,800 was granted to Oregon Health & Science University to include John Hopkins University in this DIPG Preclinical study.

You can monitor the progress of this study on http://pptiohsu.blogspot.co.uk/

Pharma Partner/Oregon Health & Science University Pilot Study - $67,000 (May 2012)

Examination of a new set of cell surface receptors in DIPG to determine whether their co-expression matches a profile consistent with novel biologic targets being developed by a potential pharmaceutical partner

Press Release to Follow

DIPG Collaborative - $50,000 (April 2012)

Foundational Leadership Partner

Press Release

Oregon Health & Science University (and other institutions globally) - $28,000 (November 2011)

Rapid Preclinical Development of a Targeted Therapy Combination for DIPG

Pediatric Preclinical Testing Initiative
The Keller Laboratory at OHSU

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