High-throughput combination drug screening to nominate potent drug combinations. High-throughput combination drug screening to nominate potent drug combinations.

Slides:

Advertisements

Similar presentations

Kui Wang May 6th, 2017.

Advertisements

Integrated genomic and proteomic analysis identifies PTEN loss and AKT/MTOR as drivers of resistance to MEK inhibitors in NSCLC cells Dianren Xia1, Lauren.

Antitumor effect of the combination of IL-2 IC and anti–CTLA-4.

Dose-escalation patient response.

PARP and Other DNA Damage Repair Inhibitors in Solid Tumors: An Update

Figure 1: Assessment of eribulin activity in twenty-five cell lines

Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS. A, schematic for altering.

Carlos L. Arteaga, Jeffrey A. Engelman Cancer Cell

A B C Supplementary Figure S1. Trabectedin decreases viability of primary MPM cell cultures. A and B, dose-dependent impact of trabectedin on epithelioid.

A High Content Clonogenic Survival Drug Screen Identifies MEK Inhibitors as Potent Radiation Sensitizers for KRAS Mutant Non–Small-Cell Lung Cancer Steven.

High-throughput drug screen and validation to nominate patient-specific therapeutic options. High-throughput drug screen and validation to nominate patient-specific.

18F-FDG uptake is a noninvasive biomarker of combined MEK–mTORC1 inhibition. 18F-FDG uptake is a noninvasive biomarker of combined MEK–mTORC1 inhibition.

Figure 2 The association between CD8+ T‑cell density of the tumour

NF1 silencing confers resistance of PC9 lung adenocarcinoma cells to erlotinib (erl). NF1 silencing confers resistance of PC9 lung adenocarcinoma cells.

WES detects a limited number of clinically targetable alterations in patients with advanced cancer. WES detects a limited number of clinically targetable.

A B MCF7-ERaWT MCF7-ERaY537S MCF7-ERaY537N MCF7-ERaY537C MCF7-ERaD538G

Identification of a MEK2 mutation in a melanoma sample resistant to dabrafenib/trametinib. Identification of a MEK2 mutation in a melanoma sample resistant.

AKT dependence of ovarian cancer cell lines.

Michael S. Glickman, Charles L. Sawyers Cell

ASSIGNMENT 10 Use the UP and DOWN tags as provided and query the LINCS. These are the KRAS-DEP (UP) and KRAS-IND (DOWN) gene signatures from Singh et al.

Drug network derived from the core EGFR interactome and combination strategy to overcome the resistant cells. Drug network derived from the core EGFR interactome.

Fig. 1. Drug combination screen identifies BETi as acting synergistically with PARPi. Drug combination screen identifies BETi as acting synergistically.

Patient organoids respond more diverse to drugs and with lower therapeutic potential than 2D cultured patient cells Patient organoids respond more diverse.

The therapeutic effects of HDAC and mTOR inhibitors are mediated by the suppression of class I HDACs and require oxidative stress. The therapeutic effects.

A genome-wide RNAi pooled screen identifies NF1 as a key determinant of RAF inhibitor sensitivity in melanoma cells. A genome-wide RNAi pooled screen identifies.

An siRNA screen identifies BER pathway members as sensitizers to temozolomide (TMZ) in pediatric GBM. A and B, SJG2 and KNS42 cells were transfected with.

Culture type determines effectivity of targeted drugs like SRC inhibitor dasatinib and mTOR inhibitors AZD2014 and temsirolimus Culture type determines.

Pharmacologic inhibitors of PI3Kγ suppress PDAC growth and metastasis.

Pharmacologic inhibition of eIF5A hypusination sensitizes KRas-driven tumor cells to MEK and KRas inhibition. Pharmacologic inhibition of eIF5A hypusination.

Combined HDAC and mTOR inhibitors kill NF1-mutant malignancies in vitro and in vivo. Combined HDAC and mTOR inhibitors kill NF1-mutant malignancies in.

A B Supplementary Figure 1

Antitumor efficacy of PI3K inhibitor NVP-BKM120 alone and in combination with olaparib. Antitumor efficacy of PI3K inhibitor NVP-BKM120 alone and in combination.

CPI-444 efficacy requires CD8+ T cells and is associated with increased CD73 expression. CPI-444 efficacy requires CD8+ T cells and is associated with.

The contributions of anti-Ad antibody and T-cell responses to viral clearance in tumor and antitumor efficacy of Ad5 therapy. The contributions of anti-Ad.

GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality. GR cells are dependent.

Sensitivity analysis of cellular responses to perturbation of the DNA damage response signaling in the presence of chemotherapies. Sensitivity analysis.

Percentage of peripheral blood samples that demonstrated >5-fold in vitro expansion. Percentage of peripheral blood samples that demonstrated >5-fold in.

EHop-016 and INK128 treatment of myxofibrosarcoma xenografts in NSG mice. EHop-016 and INK128 treatment of myxofibrosarcoma xenografts in NSG mice. A,

Time to onset of hypothyroidism after first treatment with immune checkpoint inhibitors in the combination therapy and monotherapy groups. Time to onset.

Transcriptional and genomic targets of EN1 in TNBC cells.

High-throughput siRNA screening results and corresponding patient gene expression data for PP2A subunits. High-throughput siRNA screening results and corresponding.

Location of common clinically relevant mutations in EGFR

FcRγ signaling regulates BTK activation and mediates PDAC growth.

High-throughput drug screen (HTDS) reveals ARS1620 and PI3K pathway inhibitors synergies and a heterogeneous pattern of RTK synergies. High-throughput.

Identification of compounds that enhance TMZ cytotoxicity in melanoma cells by screening the Spectrum Collection library. Identification of compounds that.

Quantitative PTEN protein expression is associated with pertuzumab sensitivity in vitro and trastuzumab resistance in vivo. Quantitative PTEN protein expression.

Combined inhibition of coamplified RTKs is required for response.

Identification of general and tissue-specific essential genes.

Targeted compounds exhibit cancer-selective ex vivo drug responses in AML. A, waterfall plot that highlights the most potent cancer-selective drugs for.

The effects of AZD1775 and olaparib on DNA damage response signaling.

siRNA screen validation.

Validation of MYC-driven drug responses.

Heterogeneous resistance mechanisms develop in response to W+T combination treatment in the EGFRL858R/T790M genetically engineered mice. Heterogeneous.

CREBBP regulates antigen processing and presentation gene enhancers.

NEDD9 binding to AURKA decreases the efficacy of AURKA inhibitors in vitro. NEDD9 binding to AURKA decreases the efficacy of AURKA inhibitors in vitro.

High nuclear β-catenin levels confer resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastasis in colon cancer.

Global analysis of the chemical–genetic interaction map.

An isogenic cell line screen reveals genomic drivers of drug response.

THZ1 in combination with targeted therapy enhances cell death and hinders the establishment of drug-resistant colonies in diverse oncogene-addicted cellular.

SCLC PDX models recapitulate patient responses to an experimental therapy. SCLC PDX models recapitulate patient responses to an experimental therapy. A,

IL2Cx alone or in combination with anti–CTLA-4 increases the CD8/Treg ratio in the tumor. IL2Cx alone or in combination with anti–CTLA-4 increases the.

The ovarian cancer cell lines modestly recapitulate the spectrum of mutations found in primary ovarian tumors. The ovarian cancer cell lines modestly recapitulate.

Coculture with U937 cells enhances DNMT1 expression in gastric cancer cells. Coculture with U937 cells enhances DNMT1 expression in gastric cancer cells.

Genomic and proteomic profiling of ovarian cancer cell lines.

BIM expression predicts the response of patients with EGFR-mutant lung cancers. BIM expression predicts the response of patients with EGFR-mutant lung.

Synthetic lethality of ROS1 inhibition in E-cadherin–deficient breast tumor cell lines. Synthetic lethality of ROS1 inhibition in E-cadherin–deficient.

Response and resistance to savolitinib and osimertinib in a patient with EGFR-mutant NSCLC harboring MET amplification. Response and resistance to savolitinib.

Combining IGF1R inhibitors with MEK or RAF inhibitors enhances the differential impact upon mutant KRAS cells. Combining IGF1R inhibitors with MEK or RAF.

Characteristic gene expression patterns distinguish LCH cells from other immune cells present in LCH lesions. Characteristic gene expression patterns distinguish.

AXL is not necessary for maintenance of intrinsic resistance.

Presentation transcript:

High-throughput combination drug screening to nominate potent drug combinations. High-throughput combination drug screening to nominate potent drug combinations. Using a combination of the genomics (EXaCT-1) and drug sensitivities from the primary drug screen, secondary drug screens were performed on the patient-derived tumor organoids from the same four cases. A, D, G, and J, Heat maps of the single therapy (left) and combination drug (right) screens depicting the relative sensitivity of the patients' tumor cells from most resistant (red) to most sensitive (blue). Black dots indicate agents that were selected for validation. B, E, H, and K, Graphs of the response of patient's tumor cells to each compound in the library as a Z-score in the presence of the combination treatments (y-axis) and the fold change of the IC50 identified with each compound in combination as compared with the agent as a monotherapy. C, F, I, and L, The in vitro validation of selected drugs in our 3-D Matrigel system. Patient A: A sensitizing drug screen using a PI3K inhibitor (buparlisib), as the investigational most advanced selective inhibitor of p110α/β/δ/γ did show an enhanced drug effect for HDAC inhibitors (vorinostat and belinostat; Supplementary Table S3). However, a high-throughput combination drug screen using vorinostat (at its IC30) showed that many of the investigational PI3K/AKT pathway drugs were enhanced compared with monotherapeutic use (Supplementary Table S4). A significant difference using vorinostat (IC30) with buparlisib in combination was seen compared with buparlisib alone (2-way ANOVA: ****, P < 0.0001). Vorinostat also enhanced the effects of EGFR inhibitors in this patient's tumor cells (Supplementary Table S2). Patient B: Sensitizing screen with buparlisib for patient B enhanced the drug effects of drugs such as HDAC inhibitors and olaparib (Supplementary Table S5). For the validation of the olaparib and buparlisib combination, we extended the drug assay up to 6 days and noticed a significant difference compared with olaparib as monotherapy (2-way ANOVA: ****, P < 0.0001). Patient C: The combination drug screen using trametinib has increased the efficacy of several compounds (Supplementary Table S6). As an example, celecoxib did not have an effect on cell survival as a single compound activity but showed a significant effect in combination (2-way ANOVA: ****, P < 0.0001). Patient D: Afatinib-sensitizing drug screen for patient D showed enhanced effects for HDAC and IGF1R inhibitors, which were confirmed in our 3-D Matrigel system (Supplementary Table S7). A significant difference using vorinostat with afatinib (IC30) in combination was seen compared with vorinostat alone (2-way ANOVA: ****, P < 0.0001). Chantal Pauli et al. Cancer Discov 2017;7:462-477 ©2017 by American Association for Cancer Research