Chemotherapy for Breast Cancer Brain Metastases

Fenner, Martin; Possinger, K.

doi:10.1159/000067443

Cited by 26 publications

(14 citation statements)

References 54 publications

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“…Unfortunately, brain metastases shows a poor response to chemotherapeutic agents that are active in the primary tumor site (21). The unexpected characteristics of tumor cells growing in the brain elucidated by our experimental approach may help to explain the mechanisms underlying the chemoresistance of these tumors.…”

Section: Discussionmentioning

confidence: 88%

Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis

Park¹,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

100

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Although the importance of the cellular microenvironment (soil) during invasion and metastasis of cancer cells (seed) has been well-recognized, technical challenges have limited the ability to assess the influence of the microenvironment on cancer cells at the molecular level. Here, we show that an experimental strategy, competitive cross-species hybridization of microarray experiments, can characterize the influence of different microenvironments on cancer cells by independently extracting gene expression data of cancer and host cells when human cancer cells were xenografted into different organ sites of immunocompromised mice. Surprisingly, the analysis of gene expression data showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells, resulting in a gain of neuronal cell characteristics and mimicking neurogenesis during development. We also show that epigenetic changes coincide with transcriptional reprogramming in cancer cells. These observations provide proof of principle for competitive cross-species hybridization of microarray experiments to characterize the effect of the microenvironment on tumor cell behavior.genomics | tumor microenvironment | stromal cells | DNA methylation D uring tumorgenesis, the changes in the local microenvironment play major roles in each step in metastasis from dissemination to colonization of distant organ sites (1-4). Therefore, inhibition of the cross-talk between invasive cancer cells and stromal cells might delay or completely block tumor invasion and subsequent colonization of cancer cells. However, a lack of understanding of the bidirectional communication between cancer cells and stromal cells at the molecular level hampers the ability to develop and implement useful targeted therapies.Despite the potential to obtain stromal-and cancer-specific signatures using laser-captured microdissection (5), segregating cancer cells from stromal cells and vice versa remain a timeconsuming and labor-intensive procedure that is technically challenging. There is also a high risk of failure because of instability of RNA during cell isolation as well as the potential systemic bias of gene expression during amplification of partially degraded RNA (6, 7). Thus, there is an urgent need for the development of new experimental strategies that can delineate cancer cell-specific gene expression signatures from stromal cell signatures or vice versa.In vivo xenografting of human cancer cells to different mouse organs has the potential to elucidate the influence of the tumor microenvironment on gene expression in cancer cells by mimicking the conditions that human metastases undergo at different organ sites. Characterization of these in vivo models might provide clues for the specific role of each unique tumor microenvironment in determining the propensity of particular tumors to metastasize to different sites as well as the sensitivity and resistance to therapy at different sites. In the current study, we have devised and performed proof of concept studies...

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Section: Discussionmentioning

confidence: 88%

Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis

Park¹,

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

100

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“…However, standard agents used to treat breast cancer, such as taxanes and anthracy-clines, have demonstrated limited efficacy in the treatment of brain metastases. 7 Therefore, new active regimens are needed. Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) is an orally administered alkylating agent that penetrates the bloodbrain barrier and has minimal toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…3,7 Controlled trials comparing chemotherapy with either supportive care or WBRT have not been performed. The bulk of the clinical experience is with cyclophosphamide and 5-FU-based regimens (e.g., cyclophosphamide, methotrexate, 5-fluorouracil [CMF] or cisplatin and etoposide [PE]), which have been shown to produce response rates ranging from 20% to 60%, including some durable complete responses.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma

Rivera

Meyers

Groves

et al. 2006

Cancer

141

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BACKGROUND A single‐institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer. METHODS Patients were eligible if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients could have received up to 3 prior chemotherapy regimens. Temozolomide and capecitabine were administered concomitantly to 4 sequential cohorts at different dosing levels on Days 1–5 and Days 8–12, with cycles repeated every 21 days until disease progression. RESULTS Twenty‐four patients with multiple brain lesions were treated, including 14 patients with newly diagnosed brain metastases and 10 patients with recurrent brain metastases. Only 1 patient was chemotherapy‐naive. Fatigue and nausea were the most commonly observed toxicities observed at any dose levels. Significant antitumor activity was observed, with a total of 1 complete and 3 partial responses (18% objective response rate) in the brain. The median response duration was 8 weeks (range, 6–64 weeks) and the median time to progression in the brain was 12 weeks (range, 3–70 weeks). Neurocognitive function improved or remained stable in patients with a response or stable disease. CONCLUSIONS The combination of temozolomide and capecitabine is an active, well‐tolerated regimen. The observed antitumor activity warrants further evaluation of this combination as an alternative to or in combination with whole‐brain radiation therapy for the treatment of multiple brain metastases. Cancer 2006. © 2006 American Cancer Society.

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“…The strong cytotoxic effect of paclitaxel results from mitotic arrest followed by apoptotic cell death (5). However, the therapeutic use of taxanes is limited by an intrinsic or acquired resistance phenomena and poor solubility, which requires Cremophor EL formulations (6,7). Among the multiple reasons accounting for taxane resistance, two mechanisms seem particularly important, namely overexpression of P-glycoprotein (P-gp) efflux pumps (8) and h-tubulin mutations (9,10).…”

Section: Introductionmentioning

confidence: 99%

Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone

et al. 2008

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Sagopilone (ZK-EPO) is the first fully synthetic epothilone undergoing clinical trials for the treatment of human tumors. Here, we investigate the cellular pathways by which sagopilone blocks tumor cell proliferation and compare the intracellular pharmacokinetics and the in vivo pharmacodynamics of sagopilone with other microtubule-stabilizing (or tubulinpolymerizing) agents. Cellular uptake and fractionation/ localization studies revealed that sagopilone enters cells more efficiently, associates more tightly with the cytoskeleton, and polymerizes tubulin more potently than paclitaxel. Moreover, in contrast to paclitaxel and other epothilones [such as the natural product epothilone B (patupilone) or its partially synthetic analogue ixabepilone], sagopilone is not a substrate of the P-glycoprotein efflux pumps. Microtubule stabilization by sagopilone caused mitotic arrest, followed by transient multinucleation and activation of the mitochondrial apoptotic pathway. Profiling of the proapoptotic signal transduction pathway induced by sagopilone with a panel of small interfering RNAs revealed that sagopilone acts similarly to paclitaxel. In HCT 116 colon carcinoma cells, sagopilone-induced apoptosis was partly antagonized by the knockdown of proapoptotic members of the Bcl-2 family, including Bax, Bak, and Puma, whereas knockdown of Bcl-2, Bcl-X L , or Chk1 sensitized cells to sagopilone-induced cell death. Related to its improved subcellular pharmacokinetics, however, sagopilone is more cytotoxic than other epothilones in a large panel of human cancer cell lines in vitro and in vivo. In particular, sagopilone is highly effective in reducing the growth of paclitaxel-resistant cancer cells. These results underline the processes behind the therapeutic efficacy of sagopilone, which is now evaluated in a broad phase II program. [Cancer Res 2008;68(13):5301-8]

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Chemotherapy for Breast Cancer Brain Metastases

Cited by 26 publications

References 54 publications

Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis

Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma

Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone

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