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1.
Sci Rep ; 8(1): 15545, 2018 10 19.
Article in English | MEDLINE | ID: mdl-30341378

ABSTRACT

Oral Squamous Cell Carcinoma (OSCC) patients respond poorly to chemotherapy. We analyzed the expression of 11 drug response-related genes in 31 OSCC biopsies, collected prior to any treatment, using custom-designed PCR array. Further, we investigated the drug response pattern of selected anticancer drugs by BH3 (Bcl2 Homology-3) profiling in the primary cells isolated from OSCC tissues. Then, we correlated the results of drug-response gene expression pattern with apoptotic priming to predict tumor response to chemotherapy. The best performing drug (BPD) and response differences (RD) between the drugs were identified using statistical methods to select the best choice of drug in a personalized manner. Based on the correlation, we classified OSCC tumors as sensitive (13 tumors), moderately responsive (16 tumors) or resistant (2 tumors) to chemotherapy. We found that up-regulation of genes linked with drug resistance facilitates survival of tumor samples, which was revealed by the percentage of apoptotic priming. Moreover, we found that paclitaxel-induced 40-45% apoptotic priming compared to other drugs. Average response difference (RD) analysis showed that 80% of tumors responded well to paclitaxel as compared to other drugs studied. Therefore, gene expression analysis with BH3 profiling reveals drug sensitivity that could be translated for drug selection before treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Squamous Cell/drug therapy , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor/methods , Epithelial Cells/drug effects , Gene Expression Profiling/methods , Mouth Neoplasms/drug therapy , Biopsy , Humans
2.
J Mol Biomark Diagn ; 8(5)2017 Sep.
Article in English | MEDLINE | ID: mdl-29285415

ABSTRACT

BACKGROUND AND PURPOSE: Predicting the efficacy of anticancer therapy is the holy grail of drug development and treatment selection in the clinic. To achieve this goal, scientists require pre-clinical models that can reliably screen anticancer agents with robust clinical correlation. However, there is increasing challenge to develop models that can accurately capture the diversity of the tumor ecosystem, and therefore reliably predict how tumors respond or resistant to treatment. Indeed, tumors are made up of a heterogeneous landscape comprising malignant cells, normal and abnormal stroma, immune cells, and dynamic microenvironment containing chemokines, cytokines and growth factors. In this mini-review we present a focused, brief perspective on emerging preclinical models for anticancer therapy that attempt to address the challenge posed by tumor heterogeneity, highlighting biomarkers of response and resistance. RECENT FINDINGS: Starting from 2-dimensional and 3-dimensional in-vitro models, we discuss how organoid co-cultures have led to accelerated efforts in anti-cancer drug screening, and advanced our fundamental understanding for mechanisms of action using high-throughput platforms that interrogate various biomarkers of 'clinical' efficacy. Then, mentioning the limitations that exist, we focus on in-vivo and human explant technologies and models, which build-in intrinsic tumor heterogeneity using the native microenvironment as a scaffold. Importantly, we will address how these models can be harnessed to understand cancer immunotherapy, an emerging therapeutic strategy that seeks to recalibrate the body's own immune system to fight cancer. CONCLUSION: Over the past several decades, numerous model systems have emerged to address the exploding market of drug development for cancer. While all of the present models have contributed critical information about tumor biology, each one carries limitations. Harnessing pre-clinical models that incorporate cell heterogeneity is beginning to address some of the underlying challenges associated with predicting clinical efficacy of novel anticancer agents.

3.
Sci Rep ; 7(1): 1502, 2017 05 04.
Article in English | MEDLINE | ID: mdl-28473715

ABSTRACT

KRAS mutation status can distinguish between metastatic colorectal carcinoma (mCRC) patients who may benefit from therapies that target the epidermal growth factor receptor (EGFR), such as cetuximab. However, patients whose tumors harbor mutant KRAS (codons 12/13, 61 and 146) are often excluded from EGFR-targeted regimens, while other patients with wild type KRAS will sometimes respond favorably to these same drugs. These conflicting observations suggest that a more robust approach to individualize therapy may enable greater frequency of positive clinical outcome for mCRC patients. Here, we utilized alive tumor tissues in ex-vivo platform termed CANscript, which preserves the native tumor heterogeneity, in order to interrogate the antitumor effects of EGFR-targeted drugs in mCRC (n = 40). We demonstrated that, irrespective of KRAS status, cetuximab did not induce an antitumor response in a majority of patient tumors. In the subset of non-responsive tumors, data showed that expression levels of EGFR ligands contributed to a mechanism of resistance. Transcriptomic and phosphoproteomic profiling revealed deregulation of multiple pathways, significantly the Notch and Erbb2. Targeting these nodes concurrently resulted in antitumor efficacy in a majority of cetuximab-resistant tumors. These findings highlight the importance of integrating molecular profile and functional testing tools for optimization of alternate strategies in resistant population.


Subject(s)
Colorectal Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Receptor, ErbB-2/metabolism , Receptors, Notch/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Base Sequence , Cetuximab/pharmacology , Cetuximab/therapeutic use , Codon/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/genetics , Gene Expression Profiling , Humans , Mutation/genetics , Neoplasm Metastasis , Proteomics , Reproducibility of Results
4.
Nat Commun ; 6: 6169, 2015 Feb 27.
Article in English | MEDLINE | ID: mdl-25721094

ABSTRACT

Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.


Subject(s)
Algorithms , Antineoplastic Agents/pharmacology , Extracellular Matrix Proteins/metabolism , Precision Medicine/methods , Tissue Engineering/methods , Tumor Microenvironment/drug effects , Analysis of Variance , Chromatography, Liquid , DNA Mutational Analysis , Gene Expression Profiling , Humans , Machine Learning , Microscopy, Electron, Scanning , Predictive Value of Tests , Tandem Mass Spectrometry
5.
Cancer Res ; 73(3): 1118-27, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23361299

ABSTRACT

The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1, and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from patients with head and neck cancer. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting that other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR are active in these tumors. Using an ex vivo platform, we identified putative responders to rapamycin, an mTOR inhibitor in these tumors. However, rapamycin did not induce antitumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition-induced AKT activation in all tumors but failed to induce antitumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our results suggest that, in addition to biomarker-based segregation, functional assessment of a patient's tumor before treatment with mTOR/AKT inhibitors may be useful for patient stratification.


Subject(s)
Head and Neck Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Apoptosis/drug effects , Cell Proliferation/drug effects , Female , Glucose Transporter Type 1/analysis , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/physiology
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