Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs

Hafner, Marc; Niepel, Mario; Chung, Mirra; Sorger, Peter K.

doi:10.1038/nmeth.3853

Cited by 542 publications

(813 citation statements)

References 40 publications

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“…Possible explanations include unfavorable pharmacokinetics (Undevia et al, 2005), the difficulty of scoring synergy in pre-clinical data (Hafner et al, 2016), and the sensitivity of synergy to genetic variation. Drug interactions are also known to vary with dose and our analysis is relevant only to clinical dosing, which frequently differs from pre-clinical dose.…”

Section: Discussionmentioning

confidence: 99%

Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy

Palmer

Sorger

2017

Cell

501

457

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SUMMARY Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient can benefit solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and design combination therapies.

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Section: Discussionmentioning

confidence: 99%

Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy

Palmer

Sorger

2017

Cell

501

457

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“…Metabolic activity for treated samples was normalized to the untreated control. Additionally, growth rate inhibition (GR), as described in Hafner et al [57], was measured in hydrogels at concentrations of 0, 25, 100, 250, and 500 µM TMZ after 7 days of culture. Relative cell count was assessed after 48 hours after treatment with the CellTiter-Glo Luminescent Cell Viability assay (Promega, Madison, WI) using a protocol derived from Lin et al [58].…”

Section: Analysis Of Gbm Response To Temozolomide (Tmz)mentioning

confidence: 99%

Section: Analysis Of Gbm Response To Temozolomide (Tmz)mentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine howthe presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair.Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBMmediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM.Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

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“…Drug response was expressed as IC 50 and GR 50 values. 3 Drug response metrics were associated with genomic alterations in the cell lines. These were retrieved from the Catalogue of Somatic Mutations in Cancer database and filtered for relevance in primary patient tumours.…”

Section: Cell Line Panel Profiling Of All Clinically Approved Kinasementioning

confidence: 99%

PO-455 Epigenetic insights: resminostat regulates targets associated with the pathogenesis of cutaneous T cell lymphoma (CTCL)

Bretz¹,

Wulff²,

Parnitzke³

et al. 2018

ESMO Open

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glucose has a greater stimulatory effect on insulin secretion than intravenous glucose. GLP-1 binds to a specific GLP-1 receptor (GLP-1R), which is expressed in many tissues including; pancreatic beta cells, gastric mucosa, kidney, lung, heart, skin, immune cells, and the hypothalamus. In addition, those receptors are expressed in some types of cancers; including medullary thyroid, ovarian and colorectal cancers. The aim of our study is to explore the effect of GLP-1R agonist (exendin-4) and GLP-1 antagonist (exendin 9-39) on human pheochromocytoma (hPheo1) and colorectal cancer (HT29) cell proliferation and migration. Material and methods GLP-1 receptor expression was detected by Western Blotting and real time PCR in 4 different cell lines; colorectal HT29, HCT116, [m1] pheochromocutoma (hPheo1) and neuroblastoma (SH-SY-5Y). Different concentrations (0.1-100 mM) of exendin-4 and exendin 9-39 (5 and 10 mM) were applied on hPheo1 and HT29 cell lines. The effect on proliferation was detected after 48 and 72 hours by cell viability assay (MTT). Cell migration assay was detected by wound healing experiment through measuring migration distance rate. Statistical significance was assessed using ANOVA, followed by post hoc Tukey Kramer test when groups were significantly different. Results and discussions The GLP1R gene is expressed in all 4 cell lines cell lines. Exendin-4 increased proliferation of hPheo and HT29 cell lines at 0.1mM and 1mM concentrations, as compared to control group (p<0.001). No proliferative effect was observed of exendin-4 at 10 mM, or exendin 9-39 in both hPheo1 and HT29 cell. Combination of exendin 4 and exendin 9-39 significantly decreased cell proliferation in both cell lines (p<0.001). There was no significant difference on cell migration distance rate after 24 hour-treatment of cells with either exendin-4 or exendin 9-39 or combination of both. Conclusion The GLP-1R agonists may increase the proliferation of cancer cells initially and at low doses, whereas higher doses decreases the proliferation rate. They are likely to have no effect, or potentially favourable suppressing effect on cancer cell proliferation and migration in pheochromocytoma and colorectal cancer. Introduction Brassinosteroids (BS) are plant steroid hormones playing an important roles in various physiological processes and being of particular interest because of their antiproliferative activities towards human cancer cells. The study was dedicated to the synthesis of novel BS analogues and to the analysis of their effects on breast cancer (BC) cells and normal epithelium. Material and methods We developed an approach for the synthesis of novel secasterol derivatives with variations in the B cycle and side chain. Six new compounds, BS2-BS7, were obtained. Biological experiments were performed on the MCF-7 BC and MCF-10A normal breast epithelium cell cultures. The cytotoxicity was assessed by MTT test. Dock6 and Autodock Vina were used for molecular docking. Binding energies were evalueted using MM_PBSA approach on the 15 n...

show abstract

Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs

Cited by 542 publications

References 40 publications

Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy

Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

PO-455 Epigenetic insights: resminostat regulates targets associated with the pathogenesis of cutaneous T cell lymphoma (CTCL)

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