Improving CNS Delivery to Brain Metastases by Blood–Tumor Barrier Disruption

Sprowls, Samuel A.; Arsiwala, Tasneem; Bumgarner, Jacob R.; Shah, Neal; Lateef, Sundus S.; Kielkowski, Brooke N; Lockman, Paul R.

doi:10.1016/j.trecan.2019.06.003

Cited by 77 publications

(62 citation statements)

References 84 publications

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“…Additionally, at a cerebral blood ow rate of 2 mL/min/g (67), immune cells traversing the cerebrovascular network will be exposed to a substantial dose of radiation, more than likely perturbing an in ammatory response. The damage associated molecular patterns released and innate immune cell cytokine production following radiation therapy could potentially amplify this immune response (10,68,69). All of the underlying in ammatory events following radiation treatments may result in a potential mechanism for BBB disruption in immune competent subjects.…”

Section: Discussionmentioning

confidence: 99%

“…One reason for the overall treatment failure in patients with brain lesions is the presence of the bloodbrain barrier (BBB) (10)(11)(12). The BBB is an anatomically unique, physicochemical vascular barrier which forms the interface between blood system and brain (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…While these therapies provide e cacy and may reduce central tumor progression, it has been reported that it may also increase the permeability of the BBB (10,29). However, the timing and magnitude of the BBB and BTB permeability changes are not de ned well and remain in some debate in the current literature (10,29). Several groups have reported permeability changes up to 24hrs following radiation therapy, while others suggest that any changes occur at later time points.…”

Section: Introductionmentioning

confidence: 99%

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Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Sprowls

Arsiwala

Kielkowski

et al. 2020

Preprint

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Background Brain metastasis is a devastating stage of cancer progression, occurring in ~30% of metastatic breast cancer patients. Two-year survival rates for these patients is low, and most typically survive less than one year. Treatments for these women are limited by the blood-brain barrier, but include cytotoxic chemotherapy, surgical resection, and radiation therapy (whole-brain radiotherapy or stereotactic radiosurgery). Radiotherapy is considered to be capable of inducing disruption of the blood-brain barrier and eliciting an abscopal response to extracranial tumors. Methods A combination of ionization chamber and Gafchromic film dosimetry was used to commission and determine dose outputs for our experimental design. Dose deposition in-vivo was verified by immunohistochemistry. To evaluate the effects of ionizing radiation at the normal blood-brain barrier and the blood-tumor barrier, athymic nude and FVB mice were used. Athymic nude mice were injected with MDA-MB-231Br cells. Lesions were allowed to develop for ~28 days. Mice were then irradiated at the prescribed dose. Prior to tissue collection, mice were injected with Texas red, followed by a vascular washout with physiological buffer. Fluorescence in normal and diseased brain was quantified by fluorescent microscopy. Results Using a 10mmx10mm collimator, determined to have adequate field homogeneity as determined by Gafchromic film analysis, we were able to successfully treat a single hemisphere in mice. The blood-brain-barrier remained undisrupted in athymic nude mice at doses up to 12Gy compared to untreated brain and radiation naïve controls. Immune competent FVB mice treated with radiation showed significant blood-brain barrier disruption at a dose of 12Gy only. The blood-tumor barrier showed significant disruption at 24hrs following radiation treatment (6 or 12Gy). Conclusion Our study demonstrated that radiation therapy disrupts the blood-tumor barrier, but fails to disrupt the normal blood-brain barrier in athymic nude mice. However, in FVB immune competent mice, the blood-brain barrier was disrupted at a dose of 12Gy, suggesting an abscopal-like response impacts extent of barrier leakage.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Sprowls

Arsiwala

Kielkowski

et al. 2020

Preprint

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“…Patients had a mean OS of 4.4 months (range 1-10) from diagnosis following either WBRT or resection with adjuvant WBRT [33]. CNS failures following MVAC are believed to be related to improved extracranial disease control and reduced penetration of the bloodbrain barrier by systemic therapy [18,19,33,34].…”

Section: Incidence Of Bladder Cancer Brain Metastasesmentioning

confidence: 99%

“…Brain metastases are uncommon, though incidence is higher following first-line platinum-based systemic therapy, which improves extracranial disease control and OS [17]. Responding BC patients live longer and are at higher risk for developing intracranial failure, likely secondary to reduced penetration of systemic agents across the blood-brain barrier [18][19][20]. Recent approval of ICB monoclonal antibodies (mAbs) as first-or second-line therapy for metastatic urothelial carcinoma (mUC) may offer alternatives to treat or prevent intracranial failures; however, their efficacy for prophylaxis or treatment of BC brain metastases is currently unknown [21,22].…”

Section: Introductionmentioning

confidence: 99%

Review: Brain Metastases in Bladder Cancer

Brenneman

Christodouleas

Sargos

et al. 2020

BLC

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Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

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The current knowledge concerning solid cancer and therapy

Najafi

Majidpoor

Toolee

et al. 2021

J Biochem & Molecular Tox

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Solid cancers comprise a large number of new cases and deaths from cancer each year globally. There are a number of strategies for addressing tumors raised from solid organs including surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, combinational therapy, and stem cell and extracellular vesicle (EV) therapy. Surgery, radiotherapy, and chemotherapy are the dominant cures, but are not always effective, in which even in a localized tumor there is a possibility of tumor relapse after surgical resection. Over half of the cancer patients will receive radiotherapy as a part of their therapeutic schedule. Radiotherapy can cause an abscopal response for boosting the activity of the immune system outside the local field of radiation, but it may also cause an unwanted bystander effect, predisposing nonradiated cells into carcinogenesis. In the context of immunotherapy, immune checkpoint inhibition is known as the standard‐of‐care, but the major concern is in regard with cold cancers that show low responses to such therapy. Stem‐cell therapy can be used to send prodrugs toward the tumor area; this strategy, however, has its own predicaments, such as unwanted attraction toward the other sites including healthy tissues and its instability. A substitute to such therapy and quite a novel strategy is to use EVs, by virtue of their stability and potential to cross biological barriers and long‐term storage of contents. Combination therapy is the current focus. Despite advances in the field, there are still unmet concerns in the area of effective cancer therapy, raising challenges and opportunities for future investigations.

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Improving CNS Delivery to Brain Metastases by Blood–Tumor Barrier Disruption

Cited by 77 publications

References 84 publications

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Radiation increases BTB permeability in a preclinical model of breast cancer brain metastasis.

Review: Brain Metastases in Bladder Cancer

The current knowledge concerning solid cancer and therapy

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