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PubMed | University of Western Ontario, Cancer Research Laboratory Program, Trillium Therapeutics, London Health Sciences Center and Lorus Therapeutics Inc.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do-not-eat) signal by binding signal-regulatory protein (SIRP) on macrophages. CD47 is over-expressed in cancer cells and its expression is associated with poor clinical outcomes. TTI 621 (SIRPFc) is a fully human recombinant fusion protein that blocks the CD47:SIRP-axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPFc constructs with different Fc tails.TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its anti-tumor activity, presumably by engaging activating Fc receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.


Al-Qawasmeh R.A.,University of Jordan | Huesca M.,Lorus Therapeutics Inc. | Nedunuri V.,Lorus Therapeutics Inc. | Peralta R.,Lorus Therapeutics Inc. | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A new series of antimicrobial derivatives [3-(4,5-diaryl-1H-imidazol-2-yl)- 1H-indole)] have been synthesized with potent activity against strains of Staphylococcus aureus, including methicillin-resistant strains (MRSA). Compound 17 [3-(4,5-bis(4-fluorophenyl)-1H-imidazol-2-yl)-5-bromo-1H-indole], the most active derivative was shown to inhibit the growth of all Gram-positive strains tested, including vancomycin resistant Enterococcus faecalis and Enterococcus faecium with no activity against Gram-negative bacteria. © 2010 Elsevier Ltd.


Patent
Lorus Therapeutics Inc. | Date: 2010-12-22

The present invention provides therapeutically effective 2,4,5-trisubstituted imidazole compounds, methods of preparing the same, and compositions comprising the compounds alone or in combination with other agents. The present invention further provides for the use of the compounds as anti-microbial agents. The anti-microbial properties of the compounds include anti-bacterial and/or anti-fungal activity.


PubMed | Lorus Therapeutics Inc.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

4116 Background: Virulizin (V) is a novel antitumor immune modulator that improves survival in pancreatic cancer patients (pts) as monotherapy. A double-blind, multicenter, randomized, phase III study was conducted to evaluate the survival benefits and safety of V in combination with gemcitabine (G) in pts with advanced pancreatic cancer.Chemo-naive pts with locally advanced or metastatic pancreatic cancer with ECOG Performance Status (PS) of 0, 1 or 2 were enrolled. Pts were randomized to receive intramuscular injections of either V or placebo (P) 3 times weekly + G (1,000 mg/mThe intent to treat (ITT) population comprised 434 pts, of which 377 were efficacy evaluable (EE). Median overall survival for V + G was 6.3 months for the ITT population (6.8 months for EE pts) and 6 months for P + G for both ITT and EE pts. While differences in survival times were not statistically significant, exploratory analysis showed encouraging results in specific subgroups treated with V + G ( table ). Importantly, a significant difference was found in stage 3 pts who received V in a salvage setting compared to pts who received P.Pancreatic cancer pts with either low ECOG PS or metastatic cancer showed a survival benefit when treated with V + G, which was significant in pts who continued to receive V as a salvage therapy. Further studies in these targeted patient populations are being considered. [Table: see text] No significant financial relationships to disclose.


PubMed | Lorus Therapeutics Inc.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

2078 Background: GTI-2501 (GTI) is a 20-mer oligonucleotide that is complementary to the R1 subunit of the RNR mRNA. The R1 protein is overexpressed in multiple tumour cell lines. GTI displays anti-tumour activity against prostate cancer xenografts in mice as a single agent and in combination with mitoxantrone. GTI also adds to the anti-tumour efficacy of taxanes in breast cancer xenografts in mice. A Phase 1 study of a 14 day continuous infusion of GTI in patients with solid tumours showed no dose limiting toxicities at doses up to 210.9 mg/mMen with metastatic HRPC were enrolled at 3 centres in Canada. GTI was given as a 14d continuous IV infusion every 21d with D IV infusion started 2 hrs prior to the end of the GTI infusion. Planned dose escalation cohorts are summarized in table .13 men were enrolled to the 3 cohorts. All patients are evaluable for toxicity. There was one possible DLT - an episode of grade 4 neutropenia reported at cycle 2 day 1 in the highest dose cohort - but the duration of neutropenia could not be confirmed. 3 additional patients were accrued to that cohort with no DLTs. The most common gr 3/4 toxicity was attributable to D (10 pts with Gr 3/4 neutropenia). The observed incidence of Gr 3/4 neutropenia was expected since patients had weekly CBCs. Only 1 patient had febrile neutropenia. 11 pts had fatigue (4 Gr 3) related to D and /or GTI. Other GTI attributable adverse events were Gr 1/2 including transient rises in transaminases and PTT. The pharmacokinetic data which is summarized in the table will be presented in full at the meeting.GTI can be given safely at its highest planned dose with standard doses of D. A Phase II evaluation of the GTI + D combination is planned for men with HRPC. [Table: see text] [Table: see text].


PubMed | Lorus Therapeutics Inc.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

2537 Background: Virulizin (V), has demonstrated strong antitumor activity in a variety of human tumor xenograft models including skin, pancreatic, breast, ovarian and prostate cancer. V is currently undergoing a pivotal Phase III clinical trial for the treatment of advanced pancreatic cancer in combination with Gemcitabine. A significant role of macrophages and NK cells was implicated in the antitumor mechanism of V where expansion as well as increased activity of macrophages and NK cells were observed in mice treated with V. The aim of this study is to evaluate the role of the inflammatory cytokine IL-17E (IL-25) in the antitumor mechanism of V. IL-17E is a proinflammatory cytokine, which can induce a TAntitumor activity of V was assessed on human melanoma C8161 xenograft in CD-1 nude mice. Alteration of IL-17E production in sera from V-treated mice was identified by 2-D gel electrophoresis and MALDI-TOF. The level of IL-17E in the sera was also determined by ELISA. IL-17E mRNA expression was determined by quantitative real-time RT-PCR. Intracellular expression of IL-17E was examined by flow cytometric analysis. The cell surface marker CCR3 on eosinophils was analyzed by flow cytometry.Cytokine IL-17E was increased in sera of V-treated mice bearing human melanoma xenograft, as shown by 2-D gel electrophoresis and ELISA. Treatment of splenocytes in vitro with V resulted in increased IL-17E mRNA expression, which peaked between 24 and 32 hours post-stimulation. Both in vitro and in vivo experiments demonstrated that B lymphocytes produce IL-17E upon V treatment. Furthermore, V treatment in vivo resulted in increased blood eosinophilia.In addition to activating innate immune system, V may manifest its antitumor activity through induction of IL-17E in B cells. This may lead to the recruitment of the proinflammatory cell type, eosinophils, which may function in parallel with macrophages and NK cells in mediating tumor destruction. No significant financial relationships to disclose.


Small interfering RNA (siRNA) molecules that target a mammalian ribonucleotide reductase gene, and which are capable of inhibiting the expression of their target gene are provided. The siRNA molecules of the invention are capable of attenuating neoplastic cell growth and/or proliferation in vitro and in vivo and, therefore, can be used to attenuate the growth and/or metastasis of various types of mammalian cancers.


The present invention provides antisense oligonucleotides directed to a mammalian ribonucleotide reductase R2 gene and combinations of the antisense oligonucleotides with one or more chemotherapeutic agents for use in the treatment of cancer.


Trademark
Lorus Therapeutics Inc. | Date: 2014-10-22

pharmaceuticals. scientific and medical research services; patient information services.


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