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Deregulated signal transduction is a cancer hallmark, and its complexity and interconnectivity imply that combination therapy should be considered, but large data volumes that cover the complexity are required in user-friendly ways. Here, we present a searchable database resource of synthetic lethality with a PI3 kinase signal transduction inhibitor by performing a saturation screen with an ultra-complex shRNA library containing 30 independent shRNAs per gene target. We focus on Ras-PI3 kinase signaling with T cell leukemia as a screening platform for multiple clinical and experimental reasons. Our resource predicts multiple combination-based therapies with high fidelity, ten of which we confirmed with small molecule inhibitors. Included are biochemical assays, as well as the IPI145 (duvelisib) inhibitor. We uncover the mechanism of synergy between the PI3 kinase inhibitor GDC0941 (pictilisib) and the tubulin inhibitor vincristine and demonstrate broad synergy in 28 cell lines of 5 cancer types and efficacy in preclinical leukemia mouse trials.
This article was published in the following journal.
Name: Cell reports
Short hairpin RNAs (shRNAs) expressed from vectors have been used as an effective means of exploiting the RNA interference (RNAi) pathway in mammalian cells. Genome-scale screening with shRNA librarie...
Adenosine to inosine editing is common in the human transcriptome and changes of this essential activity is associated with disease. Children with ADAR1 mutations develop fatal Aicardi-Goutières synd...
Dysregulation of the alternative NF-κB signaling has severe developmental consequences that can ultimately lead to oncogenesis. Pivotal for the activation of the alternative NF-κB pathway is the sta...
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, and up to 30% DLBCL patients eventually died by using first-line chemotherapy regimens. Currently, Bruton tyrosine kinase (BT...
The anti-cancer effect of high doses of intravenous vitamin C (high-dose vitamin C) remains controversial despite growing evidence that high-dose vitamin C exerts anti-tumorigenic activity by increasi...
The purpose of the study is to evaluate the efficacy and safety of autologous CD34+ cells that stably express multiplexed shRNA to treat HIV infection.
This is a pilot study designed to evaluate the cutaneous effect of systemic inhibition of the tyrosine kinase pathway in the presence or absence of solar simulated light exposure. A maxim...
Autologous FANG vaccine expresses rhGMCSF and bi-shRNAfurin from the FANG plasmid. The GMCSF protein is a potent stimulator of the immune system, recruiting immune effectors to the site o...
This phase I trial studies the side effects and best dose of multitargeted tyrosine kinase inhibitor PLX3397 (PLX3397) when given together with radiation therapy and antihormone therapy in...
The purpose of this study is to learn if kinase, a protein found in the heart, contributes to thickening of the heart muscle in people with high blood pressure. A protein called myosin ca...
A raf kinase subclass found at high levels in neuronal tissue. The B-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.
Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.
A tumor of both low- and high-grade malignancy. The low-grade grow slowly, appear in any age group, and are readily cured by excision. The high-grade behave aggressively, widely infiltrate the salivary gland and produce lymph node and distant metastases. Mucoepidermoid carcinomas account for about 21% of the malignant tumors of the parotid gland and 10% of the sublingual gland. They are the most common malignant tumor of the parotid. (From DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p575; Holland et al., Cancer Medicine, 3d ed, p1240)
Ventilatory support system using frequencies from 60-900 cycles/min or more. Three types of systems have been distinguished on the basis of rates, volumes, and the system used. They are high frequency positive-pressure ventilation (HFPPV); HIGH-FREQUENCY JET VENTILATION; (HFJV); and high-frequency oscillation (HFO).
A hereditary disease characterized by multiple ectodermal, mesodermal, and endodermal nevoid and neoplastic anomalies. Facial trichilemmomas and papillomatous papules of the oral mucosa are the most characteristic lesions. Individuals with this syndrome have a high risk of BREAST CANCER; THYROID CANCER; and ENDOMETRIAL CANCER. This syndrome is associated with mutations in the gene for PTEN PHOSPHATASE.
Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...