Publications by authors named "Brittany C Parker Kerrigan"

13 Publications

  • Page 1 of 1

RNAi technology targeting the fusion breakpoint: an opportunity for precision medicine.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa132. Epub 2020 Oct 16.

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Fusion genes form as a result of abnormal chromosomal rearrangements linking previously separate genes into one transcript. The FGFR3-TACC3 fusion gene (F3-T3) has been shown to drive gliomagenesis in glioblastoma (GBM), a cancer that is notoriously resistant to therapy. However, successful targeting of F3-T3 via small molecular inhibitors has not revealed robust therapeutic responses, and specific targeting of F3-T3 has not been achieved heretofore. Here, we demonstrate that depleting F3-T3 using custom siRNA to the fusion breakpoint junction results in successful inhibition of F3-T3+ GBMs, and that exosomes can successfully deliver these siRNAs.

Methods: We engineered 10 unique siRNAs (iF3T3) that specifically spanned the most common F3-T3 breakpoint with varying degrees of overlap, and assayed depletion by qPCR and immunoblotting. Cell viability assays were performed. Mesenchymal stem cell-derived exosomes (UC-MSC) were electroporated with iF3T3, added to cells, and F3-T3 depletion measured by qPCR.

Results: We verified that depleting F3-T3 using shRNA to FGFR3 resulted in decreased cell viability and improved survival in glioma-bearing mice. We then demonstrated that 7/10 iF3T3 depleted F3-T3, and importantly, did not affect levels of wild-type (WT) FGFR3 or TACC3. iF3T3 decreased cell viability in both F3T3+ GBM and bladder cancer cell lines. UC-MSC exosomes successfully delivered iF3T3 in vitro, resulting in F3-T3 depletion.

Conclusion: Targeting F3-T3 using siRNAs specific to the fusion breakpoint is capable of eradicating F3T3+ cancers without toxicity related to inhibition of WT FGFR3 or TACC3, and UC-MSC exosomes may be a plausible vehicle to deliver iF3T3.
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http://dx.doi.org/10.1093/noajnl/vdaa132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680176PMC
October 2020

Endovascular Selective Intra-Arterial Infusion of Mesenchymal Stem Cells Loaded With Delta-24 in a Canine Model.

Neurosurgery 2020 12;88(1):E102-E113

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.

Background: Delta-24-RGD, an oncolytic adenovirus, shows promise against glioblastoma. To enhance virus delivery, we recently demonstrated that human bone marrow-derived mesenchymal stem cells loaded with Delta-24-RGD (hMSC-D24) can eradicate glioblastomas in mouse models. There are no studies examining the safety of endovascular selective intra-arterial (ESIA) infusions of MSC-D24 in large animals simulating human clinical situations.

Objective: To perform canine preclinical studies testing the feasibility and safety of delivering increasing doses of hMSCs-D24 via ESIA infusions.

Methods: ESIA infusions of hMSC-D24 were performed in the cerebral circulation of 10 normal canines in the target vessels (internal carotid artery [ICA]/P1) via transfemoral approach using commercially available microcatheters. Increasing concentrations of hMSC-D24 or particles (as a positive control) were injected into 1 hemisphere; saline (negative control) was infused contralaterally. Toxicity (particularly embolic stroke) was assessed on postinfusion angiography, diffusion-weighted magnetic resonance imaging, clinical exam, and necropsy.

Results: ESIA injections were performed in the ICA (n = 7) or P1 (n = 3). In 2 animals injected with particles (positive control), strokes were detected by all assays. Of 6 canines injected with hMSC-D24 through the anterior circulation, escalating dose from 2 × 106 cells/20 mL to 1 × 108 cells/10 mL resulted in no strokes. Two animals had ischemic and hemorrhagic strokes after posterior cerebral artery catheterization. A survival experiment of 2 subjects resulted in no complications detected for 24-h before euthanization.

Conclusion: This novel study simulating ESIA infusion demonstrates that MSCs-D24 can be infused safely at least up to doses of 1 × 108 cells/10 mL (107 cells/ml) in the canine anterior circulation using commercially available microcatheters. These findings support a clinical trial of ESIA infusion of hMSCs-D24.
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http://dx.doi.org/10.1093/neuros/nyaa470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735865PMC
December 2020

Targeting the Tumor Microenvironment in Brain Metastasis.

Neurosurg Clin N Am 2020 Oct;31(4):641-649

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA. Electronic address:

Dynamic interplay between cancer cells and the surrounding microenvironment is a feature of the metastatic process. Successful metastatic brain colonization requires complex mechanisms that ultimately allow tumor cells to adapt to the unique microenvironment of the central nervous system, evade immune destruction, survive, and grow. Accumulating evidence suggests that components of the brain tumor microenvironment (TME) play a vital role in the metastatic cascade. In this review, the authors summarize the contribution of the TME to the development and progression of brain metastasis. They also highlight opportunities for TME-directed targeted therapy.
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http://dx.doi.org/10.1016/j.nec.2020.06.011DOI Listing
October 2020

Microcatheter delivery of neurotherapeutics: compatibility with mesenchymal stem cells.

J Neurosurg 2019 Sep 6:1-9. Epub 2019 Sep 6.

Departments of1Neurosurgery and.

Objective: Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have been used in clinical trials for the treatment of several neurological disorders. MSCs have been explored as a delivery modality for targeted viral therapeutic agents in the treatment of intracranial pathologies. Delta-24-RGD, a tumor-selective oncolytic adenovirus designed to target malignant glioma cells, has been shown to be effective in animal models and in a recent clinical trial. However, the most efficient strategy for delivering oncolytic therapies remains unclear. BM-hMSCs have been shown to home toward glioma xenografts after intracarotid delivery. The feasibility of selective intraarterial infusion of BM-hMSCs loaded with Delta-24-RGD (BM-hMSC-Delta-24) to deliver the virus to the tumor is being investigated. To evaluate the feasibility of endovascular intraarterial delivery, the authors tested in vitro the compatibility of BM-hMSC-Delta-24 with a variety of commercially available, clinically common microcatheters.

Methods: BM-hMSCs were cultured, transfected with Delta-24-RGD, and resuspended in 1% human serum albumin. The solution was then injected via 4 common neuroendovascular microcatheters of different inner diameters (Marathon, Echelon-14, Marksman, and SL-10). Cell count and viability after injection through the microcatheters were assessed, including tests of injection velocity and catheter configuration. Transwell assays were performed with the injected cells to test the efficacy of BM-hMSC-Delta-24 activity against U87 glioma cells. BM-hMSC-Delta-24 compatibility was also tested with common neuroendovascular medications: Omnipaque, verapamil, and heparin.

Results: The preinfusion BM-hMSC-Delta-24 cell count was 1.2 × 105 cells/ml, with 98.7% viability. There was no significant difference in postinfusion cell count or viability for any of the catheters. Increasing the injection velocity from 1.0 ml/min to 73.2 ml/min, or modifying the catheter shape from straight to tortuous, did not significantly reduce cell count or viability. Cell count and viability remained stable for up to 5 hours when the cell solution was stored on ice. Mixing BM-hMSC-Delta-24 with clinical concentrations of Omnipaque, verapamil, and heparin prior to infusion did not alter cell count or viability. Transwell experiments demonstrated that the antiglioma activity of BM-hMSC-Delta-24 was maintained after infusion.

Conclusions: BM-hMSC-Delta-24 is compatible with a wide variety of microcatheters and medications commonly used in neuroendovascular therapy. Stem cell viability and viral agent activity do not appear to be affected by catheter configuration or injection velocity. Commercially available microcatheters can be used to deliver stem cell neurotherapeutics via intraarterial routes.
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http://dx.doi.org/10.3171/2019.6.JNS19327DOI Listing
September 2019

Stem Cell Therapy of Gliomas.

Prog Neurol Surg 2018 10;32:124-151. Epub 2018 Jul 10.

Stem cells (SC) are the seeds of tissue repair and regeneration that have been extensively investigated as tumor-tropic vectors for gene delivery to solid cancers. SC have an inherent glioma tropism that supports their use as reliable vehicles to deliver therapeutic gene products to brain neoplasms. Several types of adult SC (ASC) have been used to carry antiglioma agents, and neural SC (NSC) and mesenchymal SC (MSC) are the most studied. The therapeutic cargoes that have been tested include secreted proteins, converting enzyme/prodrug suicide combinations, oncolytic viruses, antibodies, and nanoparticles. Some of these preclinical studies have advanced to phase I clinical trials. Use of SC as carriers to deliver various antitumor agents could become a valuable therapeutic option for glioma patients in the future.
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http://dx.doi.org/10.1159/000469686DOI Listing
October 2018

Linking inflammation and cancer: the unexpected SYK world.

Neuro Oncol 2018 04;20(5):582-583

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1093/neuonc/noy036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892156PMC
April 2018

Tumor Vaccines for Malignant Gliomas.

Neurotherapeutics 2017 04;14(2):345-357

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Despite continued research efforts, glioblastoma multiforme (GBM) remains the deadliest brain tumor. Immunotherapy offers a novel way to treat this disease, the genetic signature of which is not completely elucidated. Additionally, these tumors are known to induce immunosuppression in the surrounding tumor microenvironment via an array of mechanisms, making effective treatment all the more difficult. The immunotherapeutic strategy of using tumor vaccines offers a way to harness the activity of the host immune system to potentially control tumor progression. GBM vaccines can react to a variety of tumor-specific antigens, which can be harvested from the patient's unique pathological condition using selected immunotherapy techniques. This article reviews the rationale behind and development of GBM vaccines, the relevant clinical trials, and the challenges involved in this treatment strategy.
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http://dx.doi.org/10.1007/s13311-017-0522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398993PMC
April 2017

Ionizing radiation augments glioma tropism of mesenchymal stem cells.

J Neurosurg 2018 01 31;128(1):287-295. Epub 2017 Mar 31.

Departments of1Neurosurgery and.

OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.
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http://dx.doi.org/10.3171/2016.9.JNS16278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008155PMC
January 2018

Mesenchymal stromal cells for the delivery of oncolytic viruses in gliomas.

Cytotherapy 2017 04 21;19(4):445-457. Epub 2017 Feb 21.

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Mesenchymal stromal cells (MSCs) are a type of adult stem cell that has been exploited for the treatment of a variety of diseases, including cancer. In particular, MSCs have been studied extensively for their ability to treat glioblastoma (GBM), the most common and deadly form of brain cancer in adults. MSCs are attractive therapeutics because they can be obtained relatively easily from patients, are capable of being expanded numerically in vitro, can be easily engineered and are inherently capable of homing to tumors, making them ideal vehicles for delivering biological antitumoral agents. Oncolytic viruses are promising biological therapeutic agents that have been used in the treatment of GBMs, and MSCs are currently being explored as a means of delivering these viruses. Here we review the role of MSCs in the treatment of GBMs, focusing on the intersection of MSCs and oncolytic viruses.
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http://dx.doi.org/10.1016/j.jcyt.2017.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410175PMC
April 2017

Immune modulatory nanoparticle therapeutics for intracerebral glioma.

Neuro Oncol 2017 03;19(3):372-382

Departments of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases.

Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects.

Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable.

Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.
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http://dx.doi.org/10.1093/neuonc/now198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464307PMC
March 2017

Retinal pigment epithelial cell death by the alternative complement cascade: role of membrane regulatory proteins, calcium, PKC, and oxidative stress.

Invest Ophthalmol Vis Sci 2014 May 6;55(5):3012-21. Epub 2014 May 6.

Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.

Purpose: Retinal pigment epithelial (RPE) cell death is an important feature of the advanced forms of AMD. Complement alternative pathway (AP) activation is associated with RPE cell death in AMD. In this study, we developed a new model to initiate AP activation on RPE cells and investigated the cellular mechanisms modulating AP activation-mediated RPE cell death.

Methods: An anti-RPE antibody was developed. A spontaneously arising human RPE cell line (ARPE-19) and donor RPE cells were primed with this antibody followed by stimulation with 6% C1q-depleted human serum (C1q-Dep) to activate AP. Complement activation was evaluated by flow cytometry and immunofluorescent staining. Cellular response to complement activation was examined by measurement of intracellular calcium and adenosine triphosphate (ATP) release. Cell viability was assessed by Sytox orange, tetrazolium salt, and lactate dehydrogenase release assays.

Results: Alternative pathway complement-mediated RPE cell death was associated with membrane attack complex formation and a rapid rise in intracellular calcium followed by release of ATP. Downregulation of membrane complement regulatory proteins and protein kinase C (PKC) inhibition increased cell susceptibility to complement attack. Pretreatment of RPE cells with either hydrogen peroxide or hydroquinone enhanced cell death. Chronic repetitive treatment of RPE cells with low levels of oxidants also enhanced complement-mediated cell death.

Conclusions: Activation of complement through the alternative pathway induces sublytic and lytic phases of complement attack on RPE cells, leading to cell death modulated by extracellular calcium, membrane complement regulatory proteins, and intracellular signaling mechanisms. Single-dose oxidant exposure and low-dose repetitive oxidant exposure rendered RPE cells more susceptible to complement-mediated death.
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http://dx.doi.org/10.1167/iovs.13-13554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581691PMC
May 2014

MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer.

J Pathol 2014 Jul 21;233(3):308-18. Epub 2014 May 21.

Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, People's Republic of China.

Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has anti-tumour activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over-expression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that CDK4 and CDK6 are direct targets of miR-506, and that miR-506 can inhibit CDK4/6-FOXM1 signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506-CDK4/6-FOXM1 axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent.
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http://dx.doi.org/10.1002/path.4348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144705PMC
July 2014

Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions.

J Hematol Oncol 2014 Mar 5;7:19. Epub 2014 Mar 5.

Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease.
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http://dx.doi.org/10.1186/1756-8722-7-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973872PMC
March 2014