Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer

Turner, Tia H.; Alzubi, Mohammad A.; Sohal, Sahib S.; Olex, Amy L.; Dozmorov, Mikhail G.; Harrell, J. Chuck

doi:10.1007/s10549-018-4748-4

Cited by 30 publications

(32 citation statements)

References 61 publications

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“…Cell lines have been shown to undergo considerable changes while in culture that can affect drug response, whereas three-dimensional PDX cultures have been shown to more faithfully maintain tumor cell morphology, gene expression, and drug response profiles [55][56][57] . Indeed, we have previously found that two of the breast cancer PDXs employed in the present studies maintain the gene expression profiles of their in vivo counterparts after seven days in cell culture 36 . Therefore, preclinical drug screening studies using PDXs are more likely than those using cell lines to be indicative of in vivo efficacy, and in vivo PDX drug studies are more likely to predict clinical potential 37 .…”

Section: Discussionmentioning

confidence: 50%

“…For PDX cell viability assays, PDX cells were plated in 96-well plates at 25,000 cells per well in M87 medium 33 and treated with drugs for 72 h, followed by imaging and measurement of luciferase activity (total photon flux per second) two minutes after the addition of D-luciferin (15 mg/ml; GoldBio) to each well (1/10 of total volume per well), using the IVIS Spectrum In Vivo Imaging System (Xenogen IVIS-200) and living image software (PerkinElmer), as described in our previous work 36 . For cell line viability assays, MDA468, HCC1143, or HCC1937 cells were plated in 96-well plates at 5,000 cells per well in complete RPMI-1640 GlutaMAX medium, cultured overnight to allow for adherence, and subsequently treated with drugs for 72 h. Viability of cell lines was measured using the CellTiter-Glo Luminescent Viability Assay (Promega), according to the provided protocol.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

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Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Turner

Alzubi

Harrell

2020

Sci Rep

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Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basallike PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC. therefore suitable models for studying tumor biology and drug response, both in vivo and ex vivo/in vitro [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Using this approach, we have generated a dataset that can be used to quickly assess and compare responses of breast cancer PDXs of varying subtypes to many different drugs, most of which are approved by the U.S. Food and Drug Administration (FDA) for various cancer or non-cancer indications. From these data, we identified 176 drugs that were consistently effective across four basal-like TNBC PDXs, encompassing a wide variety of molecular targets and mechanisms of action. Several of these drugs have shown promising efficacy in TNBC and other solid tumors, however it is likely that incorporation into combination regimens is needed to maximize their efficacy and thus their likelihood of clinical success. Through a series of in vitro drug response assays, we selected four drugs to test in various two-drug combinations: carfilzomib (proteasome inhibitor), afatinib (epidermal growth factor receptor (EGFR) inhibitor), and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression), along with carboplatin, a chemotherapeutic that is part of the current standard-of-care for TNBC and that we have previously tested in several PDXs 36 . Of the six drug combinations tested, we found that the combination of afatinib and YM155 was synergistically cytotoxic across four basal-like TNBC PDXs, and this drug combination significantly reduced PDX mammary tumor growth in vivo, without observable toxicity. Notably, the genes encoding the targets of ...

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Section: Discussionmentioning

confidence: 50%

Section: Cell Viability Assaysmentioning

confidence: 99%

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Turner

Alzubi

Harrell

2020

Sci Rep

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“…five-fold the concentration used in the present study. Bortezomib partially reduced tumor growth in TNBC patient-derived xenografts at 0.75 mg/kg [ 51 ], i.e. three-fold the dosage used in our in vivo protocol.…”

Section: Discussionmentioning

confidence: 99%

Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer

Salaroglio

Gazzano

Abdullrahman

et al. 2018

J Exp Clin Cancer Res

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BackgroundTriple negative breast cancer (TNBC) easily develops resistance to the first-line drug doxorubicin, because of the high levels of the drug efflux transporter P-glycoprotein (Pgp) and the activation of pro-survival pathways dependent on endoplasmic reticulum (ER). Interfering with these mechanisms may overcome the resistance to doxorubicin, a still unmet need in TNBC.MethodsWe analyzed a panel of human and murine breast cancer cells for their resistance to doxorubicin, Pgp expression, lysosome and proteasome activity, nitrite production, ER-dependent cell death and immunogenic cell death parameters. We evaluated the efficacy of genetic (C/EBP-β LIP induction) and pharmacological strategies (lysosome and proteasome inhibitors), in restoring the ER-dependent and immunogenic-dependent cell death induced by doxorubicin, in vitro and in syngeneic mice bearing chemoresistant TNBC. The results were analyzed by one-way analysis of variance test.ResultsWe found that TNBC cells characterized by high levels of Pgp and resistance to doxorubicin, had low induction of the ER-dependent pro-apoptotic factor C/EBP-β LIP upon doxorubicin treatment and high activities of lysosome and proteasome that constitutively destroyed LIP. The combination of chloroquine and bortezomib restored doxorubicin sensitivity by activating multiple and interconnected mechanisms. First, chloroquine and bortezomib prevented C/EBP-β LIP degradation and activated LIP-dependent CHOP/TRB3/caspase 3 axis in response to doxorubicin. Second, C/EBP-β LIP down-regulated Pgp and up-regulated calreticulin that triggered the dendritic cell (DC)-mediated phagocytosis of tumor cell, followed by the activation of anti-tumor CD8+T-lymphocytes upon doxorubicin treatment. Third, chloroquine and bortezomib increased the endogenous production of nitric oxide that further induced C/EBP-β LIP and inhibited Pgp activity, enhancing doxorubicin’s cytotoxicity. In orthotopic models of resistant TNBC, intratumor C/EBP-β LIP induction - achieved by a specific expression vector or by chloroquine and bortezomib - effectively reduced tumor growth and Pgp expression, increased intra-tumor apoptosis and anti-tumor immune-infiltrate, rescuing the efficacy of doxorubicin.ConclusionsWe suggest that preventing C/EBP-β LIP degradation by lysosome and proteasome inhibitors triggers multiple virtuous circuitries that restore ER-dependent apoptosis, down-regulate Pgp and re-activate the DC/CD8+T-lymphocytes response against TNBC. Lysosome and proteasome inhibitors associated with doxorubicin may overcome the resistance to the drug in TNBC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0967-0) contains supplementary material, which is available to authorized users.

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“…Patient-derived xenografts (PDX) are currently considered the ''gold standard'' in modeling tumors and their microenvironment, in part because they can reflect the heterogeneity of tumor populations, and capture various host cell types (such as endothelial cells and fibroblasts) that compose the tumor microenvironment (122)(123)(124). These have become the preferred model to study drug sensitivity in tumors as well as chemotherapy and radiation resistance (125)(126)(127). PDX models are generally implanted in immunodeficient animals to prevent their rejection.…”

Section: Are Patient-derived Tumor Xenografts An Appropriate Model Fomentioning

confidence: 99%

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation

Patel¹,

Sohal

Manjili³

et al. 2020

Radiation Research

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Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer

Cited by 30 publications

References 61 publications

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation

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