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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Short-pulse ultrasound delivery of panobinostat for the treatment of diffuse intrinsic pontine gliomas in children
Informational
DIPG, Childhood (Brain Cancer)
Lay Summary

Children with diffuse intrinsic pontine gliomas (DIPGs) have a 2-year survival rate of less than 10%. Compared to other brain cancers, DIPG is particularly difficult to treat because it spreads behind an intact blood-brain barrier (BBB) affecting healthy developing paediatric brain tissue. There are currently no effective treatments for this disease. Although numerous novel mechanisms of biologically targeting these tumour cells are being identified in proof-of-concept studies in the laboratory, validation in living creatures and clinical application is hampered by the properties of the compounds, which are not optimised for penetration through the blood-brain barrier and into the central nervous system. We have invented an ultrasound technology – rapid short pulse (RaSP) sequencing – that delivers drugs to the developing brain with a low risk of side effects.  This will be the first demonstration of ultrasound delivery of chemotherapeutic agents to DIPG using this new technique, one that has been shown to have fewer side effects than existing ultrasound methods. The RaSP drug delivery method for DIPG has the potential to provide the urgently required improvements in the treatment of this disease in the developing brain.

The incidence of DIPG peaks at approximately 6-7 years of age, at a time of extensive myelination in the brainstem.  The ability to improve delivery of novel agents to DIPG cells, not only locally, but into cells spread through the brain, will open up a new wave of clinical trials in the disease using existing drugs without the need for further lengthy medicinal chemistry refinement.

Therapeutic ultrasound is currently engendering considerable interest because it has been shown in extensive studies that, when coupled with microbubble contrast agents commonly used for diagnostic ultrasound purposes, it can increase the spread of drugs out of blood vessels and into tumours.  This means that drugs may be infused into the blood stream, but uptake is only increased locally in the region exposed to ultrasound.  Commonly, the ultrasound beams used are focused, this allowing very selective exposure of tissue regions.  Of particular interest is the finding that ultrasound exposures can lead to a temporary opening of the blood-brain barrier (BBB), thus allowing therapeutic molecules to cross from vessels into the brain.  This is being investigated for a number of applications, including adult glioma treatments, and the first clinical trial involving Alzheimer’s drugs has just opened. The ultrasound exposure technique that we are proposing here provides the safest and most controlled changes in BBB permeability reported to date.  Compared to existing ultrasound methodology, RaSP reduces the time of blood brain barrier opening, thus reducing the risk of neuro-inflammation from blood-borne neurotoxic species such as albumin, and provides improved uniformity of drug distribution throughout the affected regions of the brain.

If this pilot study is successful we will apply for further funding to develop this technique for rapid clinical translation. Success in such a trial will further stimulate considerable interest in focused ultrasound as a technique for the treatment of brain cancers, amongst both clinicians and the general public.

Executive Summary

Scientific merit:

Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumour in children and a leading cause of paediatric brain tumour related deaths. Due to its location, surgical resection is not possible.  It is invariably fatal, with a mean overall survival of 9 to 12 months from the time of diagnosis.  Chemotherapy would normally be the preferred treatment option for such infiltrative disease, but such treatment of DIPG is complicated by its diffuse infiltration and co-habitation with healthy brain tissue, and the presence of an intact blood-brain barrier (BBB) throughout the majority of the tumour.

Drugs including panobinostat, a histone deacetylase inhibitor currently in clinical trial for this disease [3], and EPZ6438, an inhibitor of the histone methyl transferase subunit of the PRC2 complex, EZH2 [4] have demonstrated potent in vitro efficacy, but local delivery, required to cause a survival benefit in vivo, has not be achieved, most likely due to poor CNS penetration of the compounds.

Non-invasive focused ultrasound combined with systemic delivery of microbubbles (clinically approved for diagnostic ultrasound imaging) has the potential to deliver such drugs to the brain [2]. To achieve drug delivery, a focused ultrasound beam, generated using an externally placed source, travels through the intact skin and skull and into brain tissue. Microbubbles, administered systemically into the vasculature, are mechanically stimulated by the ultrasound beam only at the target site. One of the biological outcomes of this ultrasound-microbubble interaction is an increase in the permeability of blood vessels to therapeutic molecules. Where the target site is the brain, the changes in BBB permeability results in increased presence of drugs within the brain parenchyma [2, 3].

Current ultrasound methodology (see Fig. 1 in the attached Figure file) uses standard long-pulse sequences (10,000 cycles delivered at a slow rate (1 Hz)), which can result in adverse biological responses unrelated to the desired blood-to-brain-parenchymal drug delivery. These include: long BBB disruption times (up to 24 hours), release of neurotoxic species (e.g. albumin) into the brain, drug delivery to untargeted vessels and, occasionally, haemorrhage. These are particularly undesirable in the young, developing brain that is characteristic of the DIPG affected population. The delivery efficiency also varies, hence dose distribution heterogeneity is also an issue with long-pulse sequences.

We have developed a new rapid short-pulse (RaSP) ultrasound method (5 cycles) with significant safety and performance advantages. In our proposed research, we will optimize this new technology to deliver drugs to reduce DIPG progression in an orthotopic, patient-derived xenograft model of DIPG.

This new sequence enables a homogeneous dose delivery throughout the parenchyma. The safety concerns are also reduced, with a short duration BBB permeability change (<10 minutes) and reduced albumin and immunoglobulin release into the brain.

In this project, we aim to assess the efficacy and safety profile of RaSP drug delivery in a DIPG animal model, using panobinostat. This is a necessary step before Phase I clinical implementation. This approach has the potential to provide the urgently required improvements in the safetreatment of this disease in the developing brain.

 

Feasibility:

The breakthroughs in ultrasound delivery described above have been made possible with core technological advances made at ICL. The regime used in all current clinical trials of ultrasound enhanced drug delivery to the brain involves long-pulse sequences (10,000 cycles) [2, 3, 7-18] (Fig. 1, attached).  . Choi et al have shown that surprisingly short pulses can also deliver drugs [6] and when incorporated into a rapid emission sequence can deliver a higher dose and more homogeneous distribution of drugs, as reported in PNAS [19].  We now have a better understanding of how ultrasound stimulates microbubbles in vascular flow conditions. Long pulses have been shown to produce a diverse and chaotic array of microbubble stimuli that could last as long as the full pulse duration (10,000 cycles) [20, 21] while short pulses produce less microbubble stimulus for a very short duration (5 cycles) [22, 23]. Furthermore, short pulses have been demonstrated to distribute the microbubble-mediated stimuli more uniformly throughout the acoustic field [22, 23].  

We are now in a position to capitalize on these technological advances by combining the ultrasound engineering expertise available at ICL, with the pre-clinical facilities for DIPG studies available at ICR.  Apart from the expertise listed below, we have in place all the necessary facilities for growing the DIPG model in mice, pre-clinical imaging and immunohistochemical analysis at ICR. 

 

Expertise:

The proposed study is a joint effort between Imperial College London (ICL) and the Institute of Cancer Research (ICR). The project will begin at ICL where the technology will be optimised, and as the study progresses, the project will be increasingly conducted at ICR where the new technology will be tested on DIPG. This project will strengthen the link between ICL and ICR, which have recently jointly been awarded CRUK Major Cancer Centre status. Ultrasound pulse sequencing techniques under development at ICL (Dr. James Choi, co-I) will be made available for pre-clinical testing to world-leading cancer research groups in therapeutic ultrasound (Prof. Gail ter Haar, PI), cancer imaging using MRI (Dr. Simon Robinson, co-I), DIPG tumour models & histopathology (Dr Jessica Boult, co-I) and DIPG biology (Prof. Chris Jones, co-I).

Description of Research Proposal

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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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