ANG1005: Results of a phase I study in patients with advanced solid tumors and brain metastases.

Sarantopoulos, John; Gabrail, N.; Moulder, Stacy L.; Brenner, A. J.; Smith, C.; Bouchard, Danielle; Elian, Kelly; Lawrence, Ben; Castaigne, J.; Kurzrock, Razelle

doi:10.1200/jco.2010.28.15_suppl.2556

Cited by 10 publications

(7 citation statements)

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“…Ultimately, answering this question will require completion of large-scale controlled clinical trials. It is of interest to note, in this regard, that ANG1005 has been evaluated in two separate phase 1 multi-center, open-label, dose-escalation trials to identify the maximum tolerated dose and to obtain data on safety, tolerability, and preliminary efficacy in patients with either heavily pretreated advanced solid tumours with brain metastases or recurrent malignant glioma ( Drappatz et al , 2010 ; Sarantopoulos et al , 2010 ). Toxicities related to ANG1005 were similar to other taxanes, such as paclitaxel, with dose-limiting toxicity due to neutropenia.…”

Section: Discussionmentioning

confidence: 99%

“…The broad distribution pattern of LRP1, and its involvement in progression, suggests that ANG1005 may have broad applicability, especially in aggressive cancers, including non-brain cancers. Indeed, in patients with advanced solid tumours and brain metastases, ANG1005 therapy achieved important reductions in metastases located in a variety of organs, including the liver, lung, and lymph nodes ( Sarantopoulos et al , 2010 ). In combination, these studies continue to highlight the enormous potential of EPiC chemotherapeutics for the treatment of brain tumours that, until recently, have been refractory to most available therapies.…”

Section: Discussionmentioning

confidence: 99%

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Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

et al. 2011

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Background:ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood–brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells.Methods:Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines.Results:Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions.Conclusion:ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

et al. 2011

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“…Initial work in the phase I solid tumor study suggested clinical activity in CNS, including in patients with breast cancer (50). A phase II study in patients with breast cancer brain metastases was therefore launched.…”

Section: Brain Permeable Cytotoxic Chemotherapiesmentioning

confidence: 99%

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Lin

Amiri‐Kordestani

Palmieri

et al. 2013

Clinical Cancer Research

236

208

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Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities. Clin Cancer Res; 19(23); 6404-18. Ó2013 AACR. Disclosure of Potential Conflicts of InterestN.U. Lin has received commercial research grants from GlaxoSmithKline, Genentech, Array, and Novartis. N.U. Liu is a consultant/advisory board member for Novartis, GlaxoSmithKline, to-BBB, and Genentech. P.S. Steeg has received commercial research grants from GlaxoSmithKline and Sanofi. No potential conflicts of interest were disclosed by the other authors. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning Objective(s)Upon completion of this activity, the participant should have a better understanding of brain metastases in different subtypes of breast cancer, the development of preclinical models, and the novel systemic strategies for breast cancer brain metastasis.

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“…GRN1005 (a peptide-drug conjugate consisting of three molecules of paclitaxel conjugated to a 19-amino acid peptide) is known to penetrate the BBB by targeting low-density lipoprotein receptor-related protein 1 that is expressed on the surface of the BBB. Preclinical evidence indicated that the uptake of this agent in the brain was 54 times that of paclitaxel [84] and a phase I trial of 48 patients with heavily pretreated brain metastasesshowedanoverallobjectiveresponserateof71% [85].Unfortunately, preliminary results of the first 30 patients enrolled in an open-labelphaseIItrialexploringtheefficacyofthisagentamong patients with breast cancer and brain metastases did not reveal any confirmed intracranial responses [86]. Development of this drug in the setting of brain metastases has been halted.…”

Section: Systemic Therapies For Cns Metastasesmentioning

confidence: 99%

Progress in the Biological Understanding and Management of Breast Cancer-Associated Central Nervous System Metastases

Dawood

González-Angulo

2013

The Oncologist

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Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer-associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy.

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ANG1005: Results of a phase I study in patients with advanced solid tumors and brain metastases.

Cited by 10 publications

References 0 publications

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Progress in the Biological Understanding and Management of Breast Cancer-Associated Central Nervous System Metastases

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