Focused ultrasound-mediated blood-brain barrier opening for diffuse midline glioma
Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), represent a formidable challenge in pediatric oncology, with a dismal prognosis despite advancements in therapeutic approaches. The intact blood-brain barrier (BBB) in DMG tumors restricts the delivery of therapeutic agents, limiting treatment options and contributing to the poor outcomes observed. Current standard-of-care treatment involves radiotherapy (RT), often combined with temozolomide, but remains palliative, emphasizing the urgent need for novel therapeutic strategies.
Radiosensitization through the inhibition of poly (ADP-ribose) polymerase 1 (PARP1) with olaparib presents a promising approach to enhance the efficacy of RT in DMG treatment. In a study by 't Hart et al., the authors investigated the potential of PARP1 inhibition to augment radiosensitivity in vitro and in vivo following focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO). Their findings demonstrated that olaparib treatment in combination with radiation delayed tumor cell proliferation in vitro by reducing poly (ADP-ribose) (PAR) levels. Additionally, FUS-BBBO significantly increased olaparib bioavailability in the brainstem without adverse effects, highlighting its potential as a non-invasive method to enhance drug delivery to DMG tumors.
However, despite the promising effects observed in vitro and the improved olaparib delivery facilitated by FUS-BBBO, the study did not observe survival benefits in an in vivo DMG patient-derived xenograft (PDX) mouse model. Further investigations are warranted to explore the therapeutic potential of olaparib in suitable preclinical models and to optimize treatment strategies for DMG.
Moreover, the BBB poses a significant challenge for the delivery of molecular therapies to the brain parenchyma. Focused ultrasound (FUS) with microbubbles has emerged as a promising technology to transiently permeabilize the BBB, allowing for enhanced drug delivery to brain tumors. Martinez et al. discuss the recent advancements in FUS-mediated BBB opening and its potential application in treating DMGs, highlighting the need for further research in optimizing ultrasound parameters and evaluating its efficacy in DMG treatment.
Furthermore, Tazhibi et al. investigate the feasibility of combining FUS-mediated BBB opening with clinical doses of RT in a brainstem DMG murine model. Their results demonstrate the safety and feasibility of repeated FUS-mediated BBB opening concurrent with RT, providing valuable insights for future combination therapies in DMG treatment.
In conclusion, while significant progress has been made in understanding and treating DMGs, including the exploration of radiosensitization strategies and innovative approaches to overcome the BBB, continued research efforts are essential to improve outcomes for patients with this devastating disease.
Review
Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma, have among the highest mortality rates of all childhood cancers, despite recent advancements in cancer therapeutics. This is partly because, unlike some central nervous system tumors, the blood-brain barrier (BBB) of DMG tumor vessels remains intact. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitization by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. 't Hart et al. assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO).
Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo, olaparib extravasation and pharmacokinetic profiling following FUS-BBBO were measured by LC-MS/MS. The survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model.
Treatment with olaparib in combination with radiation delayed tumor cell proliferation in vitro through the reduction of PAR. Prolonged exposure to low olaparib concentration was more efficient in delaying cell growth than short exposure to high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO-mediated olaparib extravasation delayed local tumor growth, survival benefits were not observed in an in vivo DMG PDX model.
Olaparib effectively radiosensitizes DMG cells in vitro and reduces primary tumor growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models 1)
The BBB prevents the permeation of many molecular therapies into the brain parenchyma, where the cancer cells reside. Focused ultrasound (FUS) with microbubbles has recently emerged as an innovative and exciting technology that non-invasively permeabilizes the BBB in a small focal region with millimeter precision. State-of-the-art FUS-mediated BBB opening is then examined, with a focus on the effects of various ultrasound parameters and the treatment of DMGs 2).
A study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. Tazhibi et al. hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT.
To establish a safety timeline, they administered FUS to the brainstem of non-tumor-bearing mice concurrent with or adjuvant to RT; the findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53-/-). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI).
FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor-bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT.
Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In the syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery 3)