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.
