Objective:
To increase plasma ctDNA and thereby improve the identification of ctDNA-based genomic
and epigenomic biomarkers, magnetic resonance-guided focused ultrasound (MRgFUS) will be
utilized in brain tumor patients to enhance the release of tumour DNA into blood
circulation and CSF.
Study type:
Single-center, prospective, single-blinded, single arm, controlled clinical trial.
Experimental Approach:
Aim 1: To assess the utility of MRgFUS in enhancing the abundance of brain tumor ctDNA.
Non-invasive brain tumor diagnosis and treatment has the potential to transform patient
care but necessitates improved sensitivity for epigenomic and genomic biomarker detection
than is possible with current approaches. It has been shown that MRgFUS can enhance
circulating biomarker presence in animal models and that it can be safely utilized
intracranially in humans. Accordingly, this Aim expands on existing literature to utilize
MRgFUS to improve the abundance of circulating tumour DNA in brain tumor patients as the
first step in the transformation to non-invasive diagnosis and monitoring. The results of
this aim will inform on the optimal timepoint of plasma sampling after MRgFUS to obtain
the highest quantity of ctDNA for use in molecular analyses.
Aim 2: To evaluate the utility of MRgFUS in enhancing the non-invasive detection of brain
tumor methylation signatures. Published work from our lab has shown that gliomas can be
distinguished from other brain tumours accurately using the sensitive detection of plasma
methylation alterations (mean AUC 0.99). Unfortunately, the identification of glioma
subtype is more limited, and the models developed to distinguish glioblastomas have a
mean AUC of 0.71 (only for IDH). Given that glioblastomas have a distinct biology and are
typically managed differently than lower grade gliomas, the ability to non-invasively
determine glioma subtype is clinically very important. The use of MRgFUS to improve the
sensitivity of non-invasive plasma methylation signature detection of brain tumors in
this aim has the potential to change care for these patients by allowing for either
avoidance of surgery in patients who are not amenable to resection, improved surgical
planning for those that are, and longitudinal repeat sampling to identify clonal
evolution and acquisition of new clinically-relevant molecular alterations.
Aim 3: To improve the non-invasive detection of brain tumor genomic alterations using
MRgFUS. Attempts to identify tumour genomic alterations non-invasively through blood
samples has largely been ineffective due to the low ctDNA abundance and its short
half-life. The identification of tumoral mutations is important for prognostication at
the time of diagnosis and to identify alterations with available targeted treatments.
This aim utilizes MRgFUS to improve ctDNA abundance in order to allow for non-invasive
detection of clinically-relevant genomic alterations such as IDH1/2, TERT promoter,
CDKN2A/B, PTEN, EGFR, TP53, BRAF, and PDGFRA mutations in glioblastoma patients.
Significance:
Overall, this work will support the use of a MRgFUS-enhanced liquid biopsy approach that
avoids the risks of intracranial biopsy and identifies genomic and epigenomic alterations
of brain tumors with higher sensitives and specificities than can be achieved with
current plasma-based approaches which approach the accuracy of tissue-based approaches.
This non-invasive identification of brain tumor methylation signatures will allow for
diagnosis without the need for invasive intracranial biopsy. Additionally, non-invasive
identification of and monitoring for genomic alterations in brain tumors will be
important for treatment decision, particularly for targeted treatments typically offered
at the time of recurrence which depend on mutations found in the tumor.
The overarching goal of this project is to shift the paradigm of ascertaining brain tumor
diagnosis from high-risk invasive procedures to a non-invasive diagnostic approach with
potentially additional advantages, such as reaching surgically inaccessible brain
regions, capturing the tumoral heterogeneity, serial monitoring of the tumor, early
detection of progressive disease and distinguishing tumor from
pseudoprogression/radiation necrosis.
Impact Statement Liquid biopsies in brain tumor patients are limited to date by low or
even undetectable levels of tumor biomarkers. We hypothesize that this limitation can be
overcome by a novel approach using high intensity focused ultrasound to significantly
increase the release tumor biomarker into the blood and thereby improve the sensitivity
of liquid biopsy. This work is expected to lead to a paradigm shift in the way we
approach brain tumour diagnosis and treatment, allowing for non-invasive patient
prognostication and treatment target identification to optimize approach to prevent
glioblastoma progression. We expect many changes to neuro-oncology care to follow as
approaches to improve liquid biopsy improve as outlined below.
Firstly, a common indication for surgery in brain tumour patients is for a tumour biopsy,
as treatment decisions for other cancer therapies like radiotherapy and systemic
therapies depend on tumour diagnosis and specific tumour mutations which cannot be made
based on imaging alone. For these patients, it is expected that non-invasive diagnosis
would replace the need for neurosurgical biopsy and avoid associated risks including
hemorrhage and death. Additionally, for patients who require surgery for tumour removal
together with diagnosis, the ability to diagnose tumour prior to surgery will inform
preoperative and intraoperative decision making regarding the aggressiveness of tumour
resection undertaken.
Additionally, the median time to glioblastoma recurrence is 7-8 months and treatment
decision making at the time of recurrence typically leads to the use of targeted
treatments, often in the context of clinical trials, which requires repeat tumour
biopsies. Not only will this technology avoid the need for repeat biopsies at the time of
recurrence in these patients and associated risks, but this technology also allows for
the entirety of tumoral heterogeneity to be assessed for genomic/epigenomic alterations
and not only the small portion of tumour biopsied neurosurgically which may not be
representative to the overall tumour heterogeneity.
Not only does this approach avoid the need for tumour re-biopsy at the time of
recurrence, but it would allow for ongoing longitudinal tumour sampling during routine
clinical follow-up which is not possible with neurosurgical biopsies but is possible
using non-invasive technology alone as is done here. This can be used to model tumour
response to treatment, allowing for early identification of resistance mechanisms, while
also tracking clonal evolution over time and outside of when surgical biopsies are
indicated. Longitudinal MRgFUS-enhanced liquid biopsy is also expected to allow for the
early diagnosis of tumor progression by distinguishing it from
pseudoprogression/radiation necrosis, which is an important differential diagnosis.
In addition to the diagnostic benefits, spatially partial thermocoagulation necrosis of
the tumor after MRgFUS procedure may contribute to the treatment of the patients by
cytoreduction of the viable tumor cells and a decrease in their invasion capacity. This
is particularly of concern to patients with surgically unresectable tumors in eloquent
areas and will benefit these patients significantly. It is also expected that
MRgFUS-induced hyperthermia in tumours may enhance the efficacy of radiation treatment.
We may potentially simultaneously radiosensitize tumor while obtaining liquid biopsies to
monitor treatment response and track of clonal evolution over time.
In summary, this study is unique in pairing experts with both MRgFUS experience and
non-invasive liquid tumour biopsy expertise, in order to apply the benefits of MRgFUS to
a new clinical problem that has the potential to change the way we diagnose and monitor
glioblastoma patients. Currently, patients require invasive neurosurgical procedures to
diagnose glioblastoma that have associated risks and complications. Our lab has shown
that liquid biopsy techniques can be utilized in brain tumour diagnostics but low
abundance of circulating tumour DNA limits our ability to determine tumour subtypes and
mutations non-invasively. The enhancement of circulating tumour DNA after MRgFUS is a
unique approach to improving the sensitivity and specificity of non-invasive approaches
to identify glioblastoma epigenomic and genomic alterations. The results of this work may
lead change in the way we manage glioblastoma patients, moving away from invasive
diagnostic procedures and towards non-invasive tumour diagnosis and monitoring to guide
treatment decisions.
