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Foroni C.,U.O. Multidisciplinare di Patologia Mammaria | Milan M.,U.O. Multidisciplinare di Patologia Mammaria | Strina C.,U.O. Multidisciplinare di Patologia Mammaria | Cappelletti M.,U.O. Multidisciplinare di Patologia Mammaria | And 15 more authors.
Breast Cancer Research and Treatment | Year: 2014

The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naïve bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA. © 2014 Springer Science+Business Media New York.


Parissenti A.M.,Laurentian University | Parissenti A.M.,RNA Diagnostics Inc. | Guo B.,Laurentian University | Guo B.,RNA Diagnostics Inc. | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2015

In a prior substudy of the CAN-NCIC-MA.22 clinical trial (ClinicalTrials.gov identifier NCT00066443), we observed that neoadjuvant chemotherapy reduced tumor RNA integrity in breast cancer patients, a phenomenon we term “RNA disruption.” The purpose of the current study was to assess in the full patient cohort the relationship between mid-treatment tumor RNA disruption and both pCR post-treatment and, subsequently, disease-free survival (DFS) up to 108 months post-treatment. To meet these objectives, we developed the RNA disruption assay (RDA) to quantify RNA disruption and stratify it into 3 response zones of clinical importance. Zone 1 is a level of RNA disruption inadequate for pathologic complete response (pCR); Zone 2 is an intermediate level, while Zone 3 has high RNA disruption. The same RNA disruption cut points developed for pCR response were then utilized for DFS. Tumor RDA identified >fourfold more chemotherapy non-responders than did clinical response by calipers. pCR responders were clustered in RDA Zone 3, irrespective of tumor subtype. DFS was about 2-fold greater for patients with tumors in Zone 3 compared to Zone 1 patients. Kaplan–Meier survival curves corroborated these findings that high tumor RNA disruption was associated with increased DFS. DFS values for patients in zone 3 that did not achieve a pCR were similar to that of pCR recipients across tumor subtypes, including patients with hormone receptor positive tumors that seldom achieve a pCR. RDA appears superior to pCR as a chemotherapy response biomarker, supporting the prospect of its use in response-guided chemotherapy. © 2015, Springer Science+Business Media New York.


Neschadim A.,View Inc | Pritzker L.B.,Rna Diagnostics Inc. | Pritzker K.P.H.,Rna Diagnostics Inc. | Pritzker K.P.H.,University of Toronto | And 8 more authors.
Endocrine-Related Cancer | Year: 2014

Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimedat theARpathway resultinginandrogen- independentorhormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for themanagement of prostate cancer.We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of humanH2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgenindependent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98%in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia-induced response. Our data support developing AT-001 for clinical use as an anti-relaxin hormonal therapy for advanced prostate cancer. © 2014 Society for Endocrinology.


Pritzker K.P.H.,University of Toronto | Pritzker L.B.,Rna Diagnostics Inc.
Expert Opinion on Medical Diagnostics | Year: 2012

Bioinformatics tools, techniques and resources are critical to biomarker discovery, assessment, validation, qualification, standardization and market acceptance into clinical practice. Huge scientific effort and economic investment over the past 20 years have resulted in thousands of new candidate biomarkers for diseases, yet relatively few biomarkers have entered clinical practice. Bioinformatics is central to all stages of biomarker development and implementation. Areas covered: This review examines bioinformatics advances that bear on each stage of biomarker development and suggests bioinformatics strategies to assist biomarkers towards clinical practice. This paper focuses on the steps of clinical biomarker development with an emphasis on the review literature from 2000 to June 2011. The intent of this paper is to describe the present role of bioinformatics in biomarker development including the controversies associated with various developmental stages. Expert opinion: The key message is that more effective biomarker development requires database input of higher quality, improved bioinformatics tools to identify more clearly the acceptable criteria for each development step, as well as more and better database linkages. © 2012 Informa UK, Ltd.


Edwardson D.W.,Laurentian University | Narendrula R.,RNA Diagnostics Inc. | Chewchuk S.,Laurentian University | Mispel-Beyer K.,Laurentian University | And 4 more authors.
Current Drug Metabolism | Year: 2015

Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use. © 2015 Bentham Science Publishers.


Patent
Rna Diagnostics Inc. and Laurentian University | Date: 2011-08-10

Provided are methods of determining a response to a chemotherapeutic agent in a subject with ovarian cancer, comprising: determining a RNA integrity value of a sample comprising ovarian cancer cell RNA from the subject after the subject has received one or more doses of the chemotherapeutic agent; wherein a low RNA integrity value and/or RNA degradation of the cancer cell RNA is indicative that the cancer is responding to the chemotherapeutic agent and/or a high RNA integrity value and/or stable RNA integrity of the ovarian cancer cell RNA is indicative that the cancer is resistant to the chemotherapeutic agent.


Patent
Rna Diagnostics Inc. | Date: 2014-10-06

A method for the prediction and/or prognosis of survival time of a patient suffering from cancer, comprising the steps of: a) measuring a RDA score in a tumor tissue sample comprising cellular RNA from said patient after said patient has received one or more doses of a cancer treatment; b) comparing said RDA score to one or more predetermined RNA disruption reference values; and c) providing a favorable prediction and/or prognosis of survival time for said patient when said RDA score is higher than said predetermined RNA disruption reference value; or providing an unfavorable prediction and/or prognosis of survival time for said patient when said RDA score is lower than said predetermined RNA disruption reference value, wherein the RDA score is proportional to the degree of RNA disruption.


Patent
Rna Diagnostics Inc. | Date: 2013-12-03

A method of evaluating a cancer cell sample, the method comprising: a. obtaining a cancer cell sample, optionally a breast cancer cell sample or an ovarian cancer cell sample, after the cancer cells have been exposed to a radiation dose; b. assaying the cancer cell sample to obtain a RNA integrity value and/or a RNA concentration of the cancer cell sample.


Patent
Rna Diagnostics Inc. | Date: 2013-04-24

Various embodiments are described herein related to an assay, method and apparatus for performing an RNA Disruption Assay (RDA) for cellular RNA optionally in response to a cytotoxic treatment such as chemotherapy and/or radiation treatment. The method comprises obtaining at least one electropherogram dataset corresponding to a unique biological sample comprising the cellular RNA at a time point, optionally during or after the treatment; determining values for features from at least two shifted regions of the at least one electropherogram dataset, the shifting being due to the treatment; and optionally determining an RDA score based on a combination of the values of the features.


PubMed | Advanced Medical Research Institute of Canada, Laurentian University and RNA Diagnostics Inc.
Type: | Journal: BMC cancer | Year: 2016

Cellular stressors and apoptosis-inducing agents have been shown to induce ribosomal RNA (rRNA) degradation in eukaryotic cells. Recently, RNA degradation in vivo was observed in patients with locally advanced breast cancer, where mid-treatment tumor RNA degradation was associated with complete tumor destruction and enhanced patient survival. However, it is not clear how widespread chemotherapy induced RNA disruption is, the extent to which it is associated with drug response or what the underlying mechanisms are.Ovarian (A2780, CaOV3) and breast (MDA-MB-231, MCF-7, BT474, SKBR3) cancer cell lines were treated with several cytotoxic chemotherapy drugs and total RNA was isolated. RNA was also prepared from docetaxel resistant A2780DXL and carboplatin resistant A2780CBN cells following drug exposure. Disruption of RNA was analyzed by capillary electrophoresis. Northern blotting was performed using probes complementary to the 28S and 18S rRNA to determine the origins of degradation bands. Apoptosis activation was assessed by flow cytometric monitoring of annexin-V and propidium iodide (PI) binding to cells and by measuring caspase-3 activation. The link between apoptosis and RNA degradation (disruption) was investigated using a caspase-3 inhibitor.All chemotherapy drugs tested were capable of inducing similar RNA disruption patterns. Docetaxel treatment of the resistant A2780DXL cells and carboplatin treatment of the A2780CBN cells did not result in RNA disruption. Northern blotting indicated that two RNA disruption bands were derived from the 3-end of the 28S rRNA. Annexin-V and PI staining of docetaxel treated cells, along with assessment of caspase-3 activation, showed concurrent initiation of apoptosis and RNA disruption, while inhibition of caspase-3 activity significantly reduced RNA disruption.Supporting the in vivo evidence, our results demonstrate that RNA disruption is induced by multiple chemotherapy agents in cell lines from different tissues and is associated with drug response. Although present, the link between apoptosis and RNA disruption is not completely understood. Evaluation of RNA disruption is thus proposed as a novel and effective biomarker to assess response to chemotherapy drugs in vitro and in vivo.

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