Systemic high-dose intravenous methotrexate in patients with central nervous system metastatic breast cancer

Bazán, Fernando; Dobi, Erion; Royer, Bernard; Curtit, Elsa; Mansi, Laura; Menneveau, Nathalie; Paillard, Marie-Justine; Meynard, Guillaume; Villanueva, C.; Pivot, Xavier; Chaigneau, L.

doi:10.1186/s12885-019-6228-6

Cited by 13 publications

(4 citation statements)

References 22 publications

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“…Moreover, CBX2High cells were sensitive to methotrexate (Fig. 6B), a chemotherapeutic drug used in treatment of breast cancers [50]. However, effect of CBX7 on mTORC1 signaling did not correlate in terms of sensitivity to rapamycin as reflected in a [ Fig.…”

Section: Accepted Articlementioning

confidence: 99%

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

et al. 2021

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Striking similarity exists between metabolic changes associated with embryogenesis and tumorigenesis. Chromobox proteins‐CBX2/4/6/7/8, core components of canonical polycomb repressor complex 1, play essential roles in embryonic development and aberrantly expressed in breast cancer. Understanding how altered CBX expression relates to metabolic reprogramming in breast cancer may reveal vulnerabilities of therapeutic pertinence. Using transcriptomic and metabolomic data from breast cancer patients ( N > 3000 combined), we performed pathway‐based analysis and identified outstanding roles of CBX2 and CBX7 in positive and negative regulation of glucose metabolism, respectively. Genetic ablation experiments validated the contrasting roles of two isoforms in cancer metabolism and cell growth. Furthermore, we provide evidence for the role of mammalian target of rapamycin complex 1 signaling in mediating contrary effects of CBX2 and CBX7 on breast cancer metabolism. Underpinning the biological significance of metabolic roles, CBX2 and CBX7 were found to be the most up‐ and downregulated isoforms, respectively, in breast tumors compared with normal tissues. Moreover, CBX2 and CBX7 expression (not other isoforms) correlated strongly, but oppositely, with breast tumor subtype aggressiveness and the proliferation markers. Consistently, genomic data also showed higher amplification frequency of CBX2, not CBX7, in breast tumors. Highlighting the clinical significance of findings, disease‐specific survival and drug sensitivity analysis revealed that CBX2 and CBX7 predicted patient outcome and sensitivity to FDA‐approved/investigational drugs. In summary, this work identifies novel cross talk between CBX2/7 and breast tumor metabolism, and the results presented may have implications in strategies targeting breast cancer.

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Section: Accepted Articlementioning

confidence: 99%

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

et al. 2021

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“…Studies with metastatic breast cancer showed that patients tolerated i.v. administration of 3 g/m 2 to 3.5g/m 2 well and showed efficacy, claiming that MTX penetrates the blood-brain barrier if one administers such high doses, claiming that even higher doses of MTX could be administered [65,66]. Also, for Ara-C, studies with liposomal encapsulation of Ara-C demonstrated efficacy in patients with glioma and leptomeningeal metastasis [67].…”

Section: Discussionmentioning

confidence: 99%

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1

Zhao,

Braun,

Meyer

et al. 2024

Cells

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Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo® and Caspase-3 activity assays, we generated dose–response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10.000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

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“…It could impair ovarian reserve by targeting actively proliferating cells, including granulosa cells and oocytes 14 . While single low‐dose methotrexate used for the treatment of ectopic pregnancies had minimal impact on ovarian reserve, 15 the effects of higher doses at 3–16 g/m 2 , 16,17 or repeated doses, of methotrexate had not been well evaluated. Previous studies raised concerns about its gonadotoxicity, as iatrogenic menopause was reported in up to 68% of patients with breast cancers who received high‐dose methotrexate 18 .…”

Section: Discussionmentioning

confidence: 99%

Comparison of the multiples of the median of serum anti‐müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case–control study

Lai,

Lau,

Ngu

et al. 2024

Cancer Medicine

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IntroductionChemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear.Materials and MethodsThis case–control study included 57 GTN patients and 19 age‐matched patients with molar pregnancies (MP) in 2012–2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single‐agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared.ResultsThere was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single‐agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single‐agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = −2.69, p = 0.007) but not at 24 months (Z = −1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4‐year pregnancy rate and the livebirth rate between the single‐agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single‐agent group (2.88 vs. 1.88 years).ConclusionThis study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1–2 years after treatment or with other risk factors.

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Systemic high-dose intravenous methotrexate in patients with central nervous system metastatic breast cancer

Cited by 13 publications

References 22 publications

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1

Comparison of the multiples of the median of serum anti‐müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case–control study

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