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Rida P.C.G.,Georgia State University | Rida P.C.G.,Novazoi Theranostics Inc. | Cantuaria G.,Northside Hospital Cancer Institute | Reid M.D.,Emory University | And 2 more authors.
Cancer and Metastasis Reviews | Year: 2015

Cancer is truly an iconic disease—a tour de force whose multiple formidable strengths can be attributed to the bewildering heterogeneity that a tumor can manifest both spatially and temporally. A Darwinian evolutionary process is believed to undergird, at least in part, the generation of this heterogeneity that contributes to poor clinical outcomes. Risk assessment in clinical oncology is currently based on a small number of clinicopathologic factors (like stage, histological grade, receptor status, and serum tumor markers) and offers limited accuracy in predicting disease course as evidenced by the prognostic heterogeneity that persists in risk segments produced by present-day models. We posit that this insufficiency stems from the exclusion of key risk contributors from such models, especially the omission of certain factors implicated in generating intratumoral heterogeneity. The extent of centrosome amplification and the mitotic propensity inherent in a tumor are two such vital factors whose contributions to poor prognosis are presently overlooked in risk prognostication. Supernumerary centrosomes occur widely in tumors and are potent drivers of chromosomal instability that fosters intratumoral heterogeneity. The mitotic propensity of a proliferating population of tumor cells reflects the cell cycling kinetics of that population. Since frequent passage through improperly regulated mitotic divisions accelerates production of diverse genotypes, the mitotic propensity inherent in a tumor serves as a powerful beacon of risk. In this review, we highlight how centrosome amplification and error-prone mitoses contribute to poor clinical outcomes and urge the need to develop these cancer-specific traits as much-needed clinically-facile prognostic biomarkers with immense potential value for individualized cancer treatment in the clinic. © 2015, Springer Science+Business Media New York.


Mittal K.,Georgia State University | Ogden A.,Georgia State University | Reid M.D.,Emory University | Rida P.C.G.,Novazoi Theranostics Inc. | And 2 more authors.
Cell Cycle | Year: 2015

Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients. © 2015 Taylor & Francis Group, LLC.


Rida P.C.G.,Novazoi Theranostics Inc | Rida P.C.G.,Georgia State University | Livecche D.,Georgia State University | Ogden A.,Georgia State University | And 2 more authors.
Medicinal Research Reviews | Year: 2015

Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino-noscapine, 9-nitronoscapine, 9-bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds. © 2015 Wiley Periodicals, Inc.


McBride M.,Georgia State University | Rida P.C.G.,Georgia State University | Rida P.C.G.,Novazoi Theranostics Inc. | Aneja R.,Georgia State University
Molecular Aspects of Medicine | Year: 2015

Although the existence of intratumoral heterogeneity (ITH) in the expression of common biomarkers has been described by pathologists since the late 1890s, we have only recently begun to fathom the staggering extent and near ubiquity of this phenomenon. From the tumor's perspective, ITH provides a stabilizing diversity that allows for the evolution of aggressive cancer phenotypes. As the weight of the evidence correlating ITH to poor prognosis burgeons, it has become increasingly important to determine the mechanisms by which a tumor acquires ITH, find clinically-adaptable means to quantify ITH and design strategies to deal with the numerous profound clinical ramifications that ITH forces upon us. Elucidation of the drivers of ITH could enable development of novel biomarkers whose interrogation might permit quantitative evaluation of the ITH inherent in a tumor in order to predict the poor prognosis risk associated with that tumor. This review proposes centrosome amplification (CA), aided and abetted by centrosome clustering mechanisms, as a critical driver of chromosomal instability (CIN) that makes a key contribution to ITH generation. Herein we also evaluate how a tumor's inherent mitotic propensity, which reflects the cell cycling kinetics within the tumor's proliferative cells, functions as the indispensable engine underpinning CIN, and determines the rate of CIN. We thus expound how the forces of centrosome amplification and mitotic propensity collaborate to sculpt the genetic landscape of a tumor and spawn extensive subclonal diversity. As such, centrosome amplification and mitotic propensity profiles could serve as clinically facile and powerful prognostic biomarkers that would enable more accurate risk segmentation of patients and design of individualized therapies. © 2015 Elsevier Ltd. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 207.54K | Year: 2015

DESCRIPTION provided by applicant Breast cancers in African American AA women are characterized by earlier onset higher aggressiveness more extensive metastases and increased mortality rates compared to those in European American EA women This breast cancer related health disparity is partly due to the fact that AA women are more likely than EA women to develop a particularly aggressive breast cancer subtype called Triple Negative Breast Cancer TNBC TNBC is characterized by fast progression to metastasis and high mortality rates Furthermore there are no targeted therapies for TNBC Critical barriers to progress in improving outcomes for AA TNBC patients are i a lack of reliable risk predictive biomarkers that can identify TNBCs at high risk of progressing rapidly to metastatic disease and ii targeted therapies for TNBCs Since tumor biology between AA and EA women with TNBC can vary greatly the optimal way to combat TNBC may differ between AA and EA patients Thus it is critical to identify key biomarkers that may have special therapeutic and prognostic value within certain ethnic subgroups We recently found that AA TNBC patients were times as likely as EA TNBC patients to have high nuclear levels of HSET a centrosome clustering kinesin We found that higher nuclear HSET levels were also associated with more aggressive tumor features and decreased metastasis free survival As a result nuclear HSET may be a racial disparity biomarker in TNBC Furthermore HSET may be a valuable target to suppress metastasis because we found that TNBC cell migration was inhibited by HSET knockdown Overexpression of Npap L a nucleoporin isoform is known to suppress nuclear import In a search of publically available gene expression databases we found that AA TNBCs have lower Npap L levels than EA TNBCs Therefore we hypothesize that low Npap L levels in AA TNBCs promotes nuclear accumulation of HSET Our novel paradigm that ethnic differences in nuclear transport pathways promote different subcellular localization of HSET a key mediator of metastasis is a groundbreaking conceptual advancement It holds translational promise not only in metastatic risk prediction but also in providing an anti metastatic therapeutic target for TNBC patients with high nuclear HSET AIM will establish nuclear HSET as a racial disparity biomarker by evaluating its nuclear expression as a predictor of a metastasis b poor progression free survival and c poor overall survival in AA TNBC patients AIM will test whether racial differences in the levels of a nucleoporin protein Npap L involved in nuclear import promotes nuclear retention of HSET in AA TNBCs The overall impact of this project will be to validate HSET as a racial disparity biomarker and mechanistically define the Npap L HSET axis as a new pathway that can be targeted to thwart metastatic onset in AA TNBC patients and alleviate ethnic breast cancer related health disparity PUBLIC HEALTH RELEVANCE Critical barriers to progress in treating triple negative breast cancer TNBC a particularly aggressive breast cancer subtype that is times more common in African American AA than European American women is a lack of reliable risk predictive biomarkers and targeted therapies for TNBC The goal of this project is i to validate nuclear HSET as a novel racial disparity biomarker that predicts poor clinical outcomes for TNBC and ii to understand why AA TNBC cells accumulate more HSET in their nuclei Successful outcomes of this STTR proposal may lead to the development of a clinically facile immunohistochemistry kit that would enable identification of TNBC patients with high risk of progressing rapidly to metastatic disease


Patent
Novazoi Theranostics Inc. | Date: 2015-05-29

A protocol for assessing the prognosis for a patient diagnosed with a neoplasm or suspected of having a neoplasm is provided herein. The protocol involves the steps of determining a mitotic cells to proliferating cells ratio (M:P ratio) in a neoplastic tissue sample obtained from the patient and producing a prognosis for the neoplasm based on the M:P ratio.


Patent
Novazoi Theranostics Inc. | Date: 2015-05-29

A protocol for assessing the prognosis for a patient diagnosed with a neoplasm or suspected of having a neoplasm is provided herein. The protocol involves the steps of determining a mitotic cells to proliferating cells ratio (M:P ratio) in a neoplastic tissue sample obtained from the patient and producing a prognosis for the neoplasm based on the M:P ratio.

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