Indiana Breast Cancer Research Center

poster abstractIUPUI is now positioned to take advantage of the breast cancer research related infrastructure that has been built on this campus over the last 9 years by establishing the Indiana Center for Breast Cancer Research. It is our intention to build on our unique research and clinical translational strengths to create a center of excellence dedicated to the prevention, early detection, and treatment of breast cancer. 16 basic and clinical investigators at IUPUI form the faculty of the Center. The charge of this Center is the rapid movement of laboratory discoveries into the clinic. To do this the Indiana Center for Breast Cancer Research seeks to understand the biology underlying breast cancer, to apply this understanding of breast cancer biology to improve prevention, diagnosis, and treatment, and to foster research that is interdisciplinary and translational in nature. To identify the molecular, biochemical and physical events that underlay the development and maintenance of breast cancer and to apply these findings to enhance the prevention, diagnosis and treatment of the disease requires a multidisciplinary approach encompassing basic and clinical science expertise. To facilitate this, the Director of this Center identified a very strong team of dedicated breast cancer investigators that span the clinical translation arena, and include: structural biology, gene expression, pathology, animal models, proteomics, genomics, biostatistics and bioinformatics. The research to be pursued by the Center faculty is conceptually linked in that each investigator is engaged in the study and discovery of breast cancer molecular phenotypes. The unique feature of this Center in the National breast cancer research field will be the novel molecular and therapeutic pathways and approaches pursued by the Center investigators. The breast cancer work to be carried out by the investigators will be exclusive to the Center and the first of its kind in the Nation. The spectrum of studies performed includes the development of novel agents, technologies, and markers for the better diagnosis, prognosis, screening, prevention, and treatment of breast cancer. Another overarching goal of the Center is that it serves as the starting and focal point for a planned application to the National Cancer Institute (NCI) to establish a Breast Cancer Specialized Program of Research Excellence (SPORE) here on the IUPUI campus. (There has never been a SPORE for any type of cancer at any of the IU campuses or within the State of Indiana). The Indiana Center for Breast Cancer Research will permit the growth of a sharply focused multidisciplinary program that will form the basis of the research and infrastructure required to successfully compete in the highly competitive process of securing a NCI SPORE for breast cancer. We estimate that establishment of the Indiana Center for Breast Cancer Research will permit us to submit a NCI SPORE application in the next 2 – 3 years

Clinical Significance of Serum Biomarkers in Pediatric Solid Mediastinal and Abdominal Tumors

Childhood cancer is the leading cause of death by disease among U.S. children between infancy and age 15. Despite successes in treating solid tumors such as Wilms tumor, disappointments in the outcomes of high-risk solid tumors like neuroblastoma have precipitated efforts towards the early and accurate detection of these malignancies. This review summarizes available solid tumor serum biomarkers with a special focus on mediastinal and abdominal cancers in children

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Error-promoting DNA synthesis in ovarian cancer cells

AbstractObjectiveThe objective of this study is to determine whether an altered DNA replication process is responsible for some of genetic damage observed in ovarian cancer.MethodsThe replication fidelity of the DNA synthetic process was evaluated in both malignant and non-malignant human ovarian cells. The types of replication errors produced were identified. In addition, kinetic analyses of the efficiency of ovarian cancer DNA polymerases for misincorporating nucleotides were performed.ResultsWe report for the first time that ovarian cancer cells harbor an error promoting DNA replication apparatus which contributes to the decrease in DNA synthetic fidelity exhibited by these cells. Our study also shows that the decrease in DNA replication fidelity was not a result of an increased DNA replication activity. In addition, it was observed that the higher rate of DNA replication errors does not result in significant differences in the type of DNA replication-errors made during the DNA replication process; just the relative abundance. A detailed kinetic analysis of the efficiency of misincorporating nucleotides demonstrated that the DNA polymerases within the ovarian cancer cells exhibited a significant propensity for creating purine–pyrimidine nucleotide mismatches relative to non-malignant ovarian cells, while being only slightly more efficient at incorrectly pairing a purine nucleotide with a purine nucleotide.ConclusionsAll together, these data suggest that the systematic analysis of the DNA replication process in ovarian cancer could uncover information on some of the molecular mechanisms that drive the accumulation of genetic damage, and probably contribute to the pathogenesis of the disease

Dissecting the PI3K Signaling Axis in Pediatric Solid Tumors: Novel Targets for Clinical Integration

Children with solid tumors represent a unique population. Recent improvements in pediatric solid tumor survival rates have been confined to low- and moderate-risk cancers, whereas minimal to no notable improvement in survival have been observed in high-risk and advanced-stage childhood tumors. The development of novel therapeutic agents likely holds the key for patients with advanced disease that are frequently plagued with treatment failure and relapse. In the last years, biological advances have allowed for improved molecular characterization of signaling molecules and pathways contributing to tumor formation and growth. Exploiting these oncogenic cascades holds the promise for development of therapies that target alterations unique to an individual child’s tumor. An emerging target includes the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which is activated in many adult solid cancers. Antagonists targeting this pathway have the potential to inhibit multiple key nodes and the use of selected rational combinations of these PI3K/Akt/mTOR inhibitors may be required to achieve the maximal cytotoxic response. Here, we examine the role of the PI3K/AKT/mTOR axis in selected pediatric solid tumors, review the pathway specific agents currently in clinical trials, and explore the ongoing challenges of the inhibition of this pathway in the clinical development of these agents in children

Partial Purification of a Megadalton DNA Replication Complex by Free Flow Electrophoresis

<div><p>We describe a gentle and rapid method to purify the intact multiprotein DNA replication complex using free flow electrophoresis (FFE). In particular, we applied FFE to purify the human cell DNA synthesome, which is a multiprotein complex that is fully competent to carry-out all phases of the DNA replication process in vitro using a plasmid containing the simian virus 40 (SV40) origin of DNA replication and the viral large tumor antigen (T-antigen) protein. The isolated native DNA synthesome can be of use in studying the mechanism by which mammalian DNA replication is carried-out and how anti-cancer drugs disrupt the DNA replication or repair process. Partially purified extracts from HeLa cells were fractionated in a native, liquid based separation by FFE. Dot blot analysis showed co-elution of many proteins identified as part of the DNA synthesome, including proliferating cell nuclear antigen (PCNA), DNA topoisomerase I (topo I), DNA polymerase δ (Pol δ), DNA polymerase ɛ (Pol ɛ), replication protein A (RPA) and replication factor C (RFC). Previously identified DNA synthesome proteins co-eluted with T-antigen dependent and SV40 origin-specific DNA polymerase activity at the same FFE fractions. Native gels show a multiprotein PCNA containing complex migrating with an apparent relative mobility in the megadalton range. When PCNA containing bands were excised from the native gel, mass spectrometric sequencing analysis identified 23 known DNA synthesome associated proteins or protein subunits.</p></div