Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.

Background: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models.

Methods: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action.

From primary myelofibrosis to chronic myeloid leukemia, + B-Lymphoblastic leukemia, and back to primary myelofibrosis: An illustration of dynamic clonal evolution.

The simultaneous detection of :: and V617F was rarely reported and their clonal relationship and dynamic clonal shift were not characterized. Here, we described a unique case with the initial presentation as V617F+ primary myelofibrosis, followed by the emergence of + chronic myeloid leukemia. The patient then developed B-lymphoblastic leukemia.

Targetable vulnerability of deregulated FOXM1/PLK1 signaling axis in diffuse large B cell lymphoma.

FOXM1 is a transcription factor that controls cell cycle regulation, cell proliferation, and differentiation. Overexpression of FOXM1 has been implicated in various cancer types. However, the activation status and functional significance of FOXM1 in diffuse large B cell lymphoma (DLBCL) have not been well investigated.

Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer.

Prevention of estrogen receptor-negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer. PI3K pathway activation has been detected in tamoxifen-resistant ER- breast lesions of patients. Here, we further ratified that the PI3K pathway is significantly activated in premalignant ER- breast lesions compared with paired normal tissues of patients, which prompted our assessment of targeting PI3K on inhibition of ER- mammary tumor initiation and progression.

DeepVISP: Deep Learning for Virus Site Integration Prediction and Motif Discovery.

Approximately 15% of human cancers are estimated to be attributed to viruses. Virus sequences can be integrated into the host genome, leading to genomic instability and carcinogenesis. Here, a new deep convolutional neural network (CNN) model is developed with attention architecture, namely DeepVISP, for accurately predicting oncogenic virus integration sites (VISs) in the human genome.

Loss of ARID1A Promotes Epithelial-Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress.

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice.

Blocking c-Met and EGFR reverses acquired resistance of PARP inhibitors in triple-negative breast cancer.

The limited treatment options and therapeutic failure due to acquired resistance for patients with triple-negative breast cancer (TNBC) represent a significant challenge. Inhibitors against poly (ADP-ribose) polymerase (PARP), olaparib and talazoparib, were recently approved for the treatment of metastatic breast cancer (including TNBC) in patients with germline mutations. Despite impressive response rates of ~60%, the prolongation in median progression-free survival with a PARPi is modest, suggesting the emergence of resistance.

Inhibition of c-MET upregulates PD-L1 expression in lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in multiple clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies.

USP37 is a SNAI1 deubiquitinase.

SNAI1, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, promotes tumor metastasis and resistance to apoptosis and chemotherapy. SNAI1 protein levels are tightly regulated by proteolytic ubiquitination. Here, we identified USP37 as a SNAI1 deubiquitinase that removes the polyubiquitination chain from SNAI1 and prevents its proteasomal degradation.

Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling.

The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown.

Pooled library screening with multiplexed Cpf1 library.

Capitalizing on the inherent multiplexing capability of AsCpf1, we developed a multiplexed, high-throughput screening strategy that minimizes library size without sacrificing gene targeting efficiency. We demonstrated that AsCpf1 can be used for functional genomics screenings and that an AsCpf1-based multiplexed library performs similarly as compared to currently available monocistronic CRISPR/Cas9 libraries, with only one vector required for each gene. We construct the smallest whole-genome CRISPR knock-out library, Mini-human, for the human genome (n = 17,032 constructs targeting 16,977 protein-coding genes), which performs favorably compared to conventional Cas9 libraries.

Irradiation-induced dynamic changes of gene signatures reveal gain of metastatic ability in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC), arising from the nasopharynx epithelium, is prevalent among South and East Asia. The radiotherapy is the primary treatment for NPC patients. However, the acquired radioresistance dramatically diminishes the therapeutic effect of radiotherapy.

Ubiquitin-specific peptidase 2a (USP2a) deubiquitinates and stabilizes β-catenin.

β-catenin is not only a key component of adherens junctions but also a transcriptional co-activator downstream of canonical Wnt signaling. The Wnt/β-catenin pathway plays critical roles in animal development and tissue homeostasis, while mutation or overexpression of β-catenin often leads to tumorigenesis and metastasis. Ubiquitination-mediated proteasomal degradation of β-catenin is a key molecular event in the Wnt/β-catenin pathway.

Cancer in a dish: progress using stem cells as a platform for cancer research.

Cancer models derived from patient specimens poorly reflect early-stage cancer development because cancer cells acquire numerous additional molecular alterations before the disease is clinically detectable. Earlier studies have used differentiated cells derived from induced pluripotent cancer cells (iPCCs) to partially mirror cancer disease phenotype, but the highly heterogeneous nature of cancer cells as well as difficulties with reprogramming cancer cells has limited the application of this technique. An alternative approach to modeling cancer in a dish entails reprogramming adult differentiated cells from patients with cancer syndromes to pluripotent stem cells (PSCs), followed by directed differentiation of those PSCs.

Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention.

The prevention of estrogen receptor-negative (ER-) breast cancer remains a major challenge in the cancer prevention field, although antiestrogen and aromatase inhibitors have shown adequate efficacy in preventing estrogen receptor-positive (ER) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early-stage lesions of patients.

Stat3 Signaling Promotes Survival And Maintenance Of Medullary Thymic Epithelial Cells.

Medullary thymic epithelial cells (mTECs) are essential for establishing central tolerance by expressing a diverse array of self-peptides that delete autoreactive thymocytes and/or divert thymocytes into the regulatory T cell lineage. Activation of the NFκB signaling pathway in mTEC precursors is indispensable for mTEC maturation and proliferation resulting in proper medullary region formation. Here we show that the Stat3-mediated signaling pathway also plays a key role in mTEC development and homeostasis.

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors.

Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model.

14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation.

14-3-3ζ is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors, whereas control mice did not.

SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.

Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model.

ADVANTAGES OF MCNPX-BASED LATTICE TALLY OVER MESH TALLY IN HIGH-SPEED MONTE CARLO DOSE RECONSTRUCTION FOR PROTON RADIOTHERAPY.

Monte Carlo simulations are increasingly used to reconstruct dose distributions in radiotherapy research studies. Many studies have used the MCNPX Monte Carlo code with a mesh tally for dose reconstructions. However, when the number of voxels in the simulated patient anatomy is large, the computation time for a mesh tally can become prohibitively long.