Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer

Taskar, Kunal S.; Rudraraju, Vinay; Mittapalli, Rajendar K.; Samala, Ramakrishna; Thorsheim, Helen R.; Lockman, Julie A.; Gril, Brunilde; Hua, Emily; Palmieri, Diane; Polli, Joseph W.; Castellino, Stephen; Rubin, Stephen D.; Lockman, Paul R.; Steeg, Patricia S.; Smith, Quentin R.

doi:10.1007/s11095-011-0601-8

Cited by 182 publications

(157 citation statements)

References 43 publications

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“…Thus, optimal compound concentrations may not be achieved throughout the tumor, which is likely to limit efficacy. This finding is consistent with the variability observed with radiolabeled paclitaxel, doxorubicin (Lockman et al, 2010), and lapatinib (Taskar et al, 2012) in a model of brain metastasis of breast cancer, with up to a 10-fold range in concentrations between and within the tumor metastases. The U87 model, with its compromised BBB, represents what may occur in the contrastenhancing region(s) of a human brain tumor.…”

Section: Resultssupporting

confidence: 87%

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

Salphati¹,

Shahidi-Latham²,

Quiason³

et al. 2014

Drug Metab Dispos

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Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d] pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing bloodbrain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrastenhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6-fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain-to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM.

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Section: Resultssupporting

confidence: 87%

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

Salphati¹,

Shahidi-Latham²,

Quiason³

et al. 2014

Drug Metab Dispos

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“…However, most of them have been showed to be substrates of Pgp and/ or BCRP (29)(30)(31)(32)(33)(34), and are likely to exert their effects only in areas where the BBB or blood-tumor barrier is permeable, as described by Taskar and colleagues with lapatinib (35).…”

Section: Discussionmentioning

confidence: 99%

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Salphati

Heffron²,

Alicke³

et al. 2012

Clinical Cancer Research

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Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM.Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM.Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively.Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

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“…The metastatic spread of breast cancer is a major cause of patient morbidity; spread from the breast to the lungs, bones, and brain is frequently observed (Taskar et al, 2012). To assess whether lapatinib/obatoclax treatment could affect the growth of breast cancer cells in tissues other than the breast/mammary fat pad, we infused BT474 tumor cells into the brains of athymic mice, allowed tumors to form, and then treated the animals with the drug combination.…”

mentioning

confidence: 99%

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

et al. 2012

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Previous studies showed that lapatinib and obatoclax interact in a greater-than-additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses. Lapatinib and obatoclax killed multiple tumor cell types, and cells lacking phosphatase and tensin homolog (PTEN) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null breast cancer cells restored drug sensitivity. Coadministration of lapatinib with obatoclax elicited autophagic cell death that was attributable to the actions of mitochondrial reactive oxygen species. Wild-type cells but not mitochondria-deficient rho-zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase 1/2 (JNK1/2) by the drug combination was enhanced by radiation, and signaling by p38 MAPK and JNK1/2 promoted cell killing. In immunohistochemical analyses, the autophagosome protein p62 was determined to be associated with protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1, as well as with binding immunoglobulin protein/78-kDa glucose-regulated protein, in drug combination-treated cells. Knockdown of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knockdown of PERK suppressed the reduction in Mcl-1 expression after drug combination exposure, and overexpression of Mcl-1 protected cells. Our data indicate that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax, as well as radiosensitization by this drug combination.

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Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer

Cited by 182 publications

References 43 publications

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

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