Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children’s Oncology Group

Warren, Katherine E.; Jakacki, Regina I.; Widemann, Brigitte C.; Aikin, Alberta; Libucha, Madeleine; Packer, Roger J.; Vézina, Gilbert; Reaman, Gregory H.; Shaw, Dennis; Krailo, Mark; Osborne, C.; Cehelsky, Jeffrey; Caldwell, D.; Stanwood, John E.; Steinberg, S. M.; Balis, Frank M.

doi:10.1007/s00280-005-0172-7

Cited by 101 publications

(65 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although some problems were found in these animal models, including tachyphylaxis and a rapid restoration of the BBB within an hour, these studies were successful enough to pursue studies in humans in phase I and phase II clinical trials. Unfortunately, in two phase II trials testing this combination in childhood as well as recurrent adult primary CNS malignancies, activity was not observed (80,81). The researchers wondered whether a higher dose of RMP-7 may have been necessary to have the desired effect within the CNS.…”

Section: Disrupting the Bbbmentioning

confidence: 99%

The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

Deeken

Löscher

2007

Clinical Cancer Research

613

492

View full text Add to dashboard Cite

Despite scientific advances in understanding the causes and treatment of human malignancy, a persistent challenge facing basic and clinical investigators is how to adequately treat primary and metastatic brain tumors.The blood-brain barrier is a physiologic obstruction to the delivery of systemic chemotherapy to the brain parenchyma and central nervous system (CNS). A number of physiologic properties make the endothelium in the CNS distinct from the vasculature found in the periphery. Recent evidence has shown that a critical aspect of this barrier is composed of xenobiotic transporters which extrude substrates from the brain into the cerebrospinal fluid and systemic circulation. These transporters also extrude drugs and toxins if they gain entry into the cytoplasm of brain endothelial cells before they enter the brain. This review highlights the properties of the blood-brain barrier, including the location, function, and relative importance of the drug transporters that maintain this barrier. Primary and metastatic brain malignancy can compromise this barrier, allowing some access of chemotherapy treatment to reach the tumor.The responsiveness of brain tumors to systemic treatment found in past clinical research is discussed, as are possible explanations as to why CNS tumors are nonetheless able to evade therapy. Finally, strategies to overcome this barrier and better deliver chemotherapy into CNS tumors are presented.Despite the dramatic advances in understanding the molecular basis for carcinogenesis and the development of new targeting agents to treat malignancies, a critical challenge that continues to face cancer researchers is overcoming the sanctuary for primary and metastatic disease found within the central nervous system (CNS). Brain metastases occur in a significant percentage of patients with common malignancies, with 5-year cumulative incidence rates of 16% in lung cancer patients, 7% of breast cancer patients, and 5% of patients with colon cancer (1). In diseases such as melanoma, the incidence of brain metastatic disease is reported to be as high as 55% (2). Autopsy studies show that in patients who die from cancer, up to 25% of them develop brain metastases (3).The incidence of brain metastatic disease is on the rise (4). This could be due to a number of factors, including earlier brain screening for CNS disease in cancers known to spread to the brain; improved and more widely available radiological techniques such as magnetic resonance imaging; and improved therapies to treat systemic disease, which are prolonging survival and, in turn, increasing the risk of developing metastases to the brain. The irony is that as our therapies are improving clinical outcomes and prolonging survival, the incidence of CNS disease is on the rise. Furthermore, primary brain malignancies are intrinsically resistant to most chemotherapies for reasons that are poorly understood. These realities demand that we better understand, and learn how to treat, CNS malignancy.This CNS sanctuary for metastatic as well...

show abstract

Section: Disrupting the Bbbmentioning

confidence: 99%

The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

Deeken

Löscher

2007

Clinical Cancer Research

613

492

View full text Add to dashboard Cite

show abstract

“…The late toxicities of therapy are also equally important, and current approaches to this tumor treatment involve a balance between maximizing cures whereas limiting long-term sequelae of treatment. Another problem is the blood-brain barrier, which restricts the entry of hydrophilic and large lipophilic compounds into the brain (32). Trials have shown that craniospinal radiotherapy and reduced-dose or hyperfractionated craniospinal radiotherapy, together with chemotherapy, can improve overall survival and reduce the risk of radiotherapy-related cognitive and endocrine effects (33,34).…”

Section: Current Therapiesmentioning

confidence: 99%

Medulloblastoma: From Molecular Pathology to Therapy

Rossi

Caracciolo²,

Russo

et al. 2008

Clinical Cancer Research

156

134

View full text Add to dashboard Cite

Medulloblastoma is the most common malignant tumor of central nervous system in children.Patients affected by medulloblastoma may be categorized as high-risk and standard-risk patients, based on the clinical criteria and histologic features of the disease. Currently, multimodality treatment, including surgery, radiotherapy, and chemotherapy is considered as the most effective strategy against these malignant cerebellar tumors of the childhood. Despite the potential poor outcomes of these lesions, the 5-year survival stands, at present, at 70% to 80% for standard-risk patients, whereas high-risk patients have a 5-year survival of 55% to 76%. Attempts to further reduce the morbidity and mortality associated with medulloblastoma have been restricted by the toxicity of conventional treatments and the infiltrative nature of the disease. Over the past decade, new discoveries in molecular biology have revealed new insights in signaling pathways regulating medulloblastoma tumor formation. Recent advances in the molecular biology of medulloblastoma indicate that the classification of these embryonal tumors, solely based on histology and clinical criteria, may not be adequate enough. Better understanding of the growth control mechanisms involved in the development and progression of medulloblastoma will allow a better classification, leading to the improvement of the existing therapies, as well as to the development of new therapeutic approaches.

show abstract

“…Similar to the above agents, lobradimil, a bradykinin agonist, was tried with chemotherapy in a Phase II trial involving pediatric high-grade glioma, with a view to enhance the drug permeability of the chemotherapeutic agents. The fate was unfortunately no different (68).…”

Section: Molecular Targeted Therapymentioning

confidence: 99%

“…These include monoclonal antibodies like imatinib (anti-PDGFR) (65); erlotinib; gefitinib ( anti-EGFR) (66,67); and tipifarnib, a farnesyltransferase inhibitor (68). Most of these agents are in Stage I/II trials and have not really lived up to the expectations.…”

Section: Molecular Targeted Therapymentioning

confidence: 99%

Pediatric Glioblastoma

Das¹,

Kumar²

2017

Glioblastoma

View full text Add to dashboard Cite

Glioblastoma in children, when compared with adults, is relatively rare. Despite this rarity, it is apparent from the limited number of publications that pediatric glioblastoma is quite distinct from their adult counterparts. The differences pertain to the molecular genetics, effectiveness of the adjuvant therapies, and possibly the prognosis after treatment. With a plethora of path-breaking translational research coming through in recent times, a host of new information is now available on pediatric glioblastomas that holds great promise as far as the future treatment options are concerned. This chapter is an attempt to highlight the key clinical aspects of pediatric glioblastoma in the light of the emerging clinical and laboratory evidence.

show abstract

Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children’s Oncology Group

Abstract: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

Cited by 101 publications

References 12 publications

The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

Medulloblastoma: From Molecular Pathology to Therapy

Pediatric Glioblastoma

Contact Info

Product

Resources

About