a-murine-ommaya-xenograft-model-to-study-direct-targeted-therapy

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers ...

ex-vivo-culture-circulating-tumor-cells-cerebral-spinal-fluid-from

<i>Ex Vivo</i> Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma&#45;Associated Leptomeningeal Disease

Melanoma-associated leptomeningeal disease (M-LMD) occurs when circulating tumor cells (CTCs) enter into the cerebral spinal fluid (CSF) and colonize the ...

H. Lee Moffitt Cancer Center & Research Institute

University of South Florida, H. Lee Moffitt Cancer Center & Research Institute

The development of brain metastases is common in patients with melanoma and is associated with a poor prognosis. Treating patients with melanoma brain metastases (MBMs) is a major therapeutic challenge. Standard approaches with conventional chemotherapy are disappointing, while surgery and radiotherapy have improved outcomes.

Novel treatments for melanoma brain metastases.

Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.

Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus.

Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.

Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.

BRAF-MEK inhibition in melanoma brain metastases: a new hope.

Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease.

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

Leptomeningeal disease is a rare presentation of advanced metastatic breast cancer. The purpose of this study was to evaluate craniospinal progression between intrathecal (IT) trastuzumab, IT chemotherapy, and whole brain radiation therapy (WBRT) in leptomeningeal disease.

Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy.

Leptomeningeal disease (LMD) is an advanced metastatic disease presentation portending a poor prognosis with minimal treatment options. The advent and widespread use of new systemic therapies for metastatic breast cancer has improved systemic disease control and extended survival; however, as patients live longer, the rates of breast cancer LMD are increasing.

Breast leptomeningeal disease: a review of current practices and updates on management.

The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the cerebrospinal fluid (CSF) from patients with LMM to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells.

Proteomic Analysis of CSF from Patients with Leptomeningeal Melanoma Metastases Identifies Signatures Associated with Disease Progression and Therapeutic Resistance.

ArticleTotal : 2	Year
Publication title Cited by 10	2021
Publication title	2024

Article	Year
Novel treatments for melanoma brain metastases. Cancer control : journal of the Moffitt Cancer Center\| PubMed ID: 24077406	2013
Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus. Cancer research\| PubMed ID: 25336188	2014
Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells. The Journal of biological chemistry\| PubMed ID: 25538243	2015
BRAF-MEK inhibition in melanoma brain metastases: a new hope. The Lancet. Oncology\| PubMed ID: 28677560	2017
Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience. Breast cancer research and treatment\| PubMed ID: 29392582	2018
Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy. Breast cancer research and treatment\| PubMed ID: 30859348	2019
Breast leptomeningeal disease: a review of current practices and updates on management. Breast cancer research and treatment\| PubMed ID: 31209686	2019
Proteomic Analysis of CSF from Patients with Leptomeningeal Melanoma Metastases Identifies Signatures Associated with Disease Progression and Therapeutic Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 31924735	2020

Peter A. Forsyth

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