Publications by authors named "E Dadachova"

161 Publications

Novel Human Antibodies to Insulin Growth Factor 2 Receptor (IGF2R) for Radioimmunoimaging and Therapy of Canine and Human Osteosarcoma.

Cancers (Basel) 2021 May 4;13(9). Epub 2021 May 4.

Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.

Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS. This approach known as radioimmunotherapy (RIT) can therefore be developed as a novel treatment for OS. In addition, OS is one of the common cancers in companion dogs and very closely resembles human OS in clinical presentation and molecular aberrations. In this study, we have developed human antibodies that cross-react with similar affinities to IGF2R proteins of human, canine and murine origin. We used naïve and synthetic antibody Fab-format phage display libraries to develop antibodies to a conserved region on IGF2R. The generated antibodies were radiolabeled and characterized in vitro and in vivo using human and canine OS patient-derived tumors in SCID mouse models. We demonstrate specific binding to IGF2R and tumor uptake in these models, as well as binding to tumor tissue of canine OS patients, making these antibodies suitable for further development of RIT for OS.
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http://dx.doi.org/10.3390/cancers13092208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124616PMC
May 2021

LETTER TO THE EDITOR: ON POTENTIAL USE OF RADIOLABELED ANTIBODIES FOR IMAGING AND TREATMENT OF COVID-19.

J Nucl Med 2021 Jan 28. Epub 2021 Jan 28.

University of Saskatchewan, Canada.

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http://dx.doi.org/10.2967/jnumed.120.261874DOI Listing
January 2021

Transcriptomic and genomic changes associated with radioadaptation in .

Comput Struct Biotechnol J 2021 19;19:196-205. Epub 2020 Dec 19.

University of Saskatchewan, College of Pharmacy and Nutrition, Saskatoon, Canada.

Melanized fungi have been isolated from some of the harshest radioactive environments, and their ability to thrive in these locations is in part due to the pigment melanin. Melanin imparts a selective advantage to fungi by providing a physical shield, a chemical shield, and possibly a signaling mechanism. In previous work we demonstrated that protracted exposure of the melanized yeast to mixed alpha-, beta-, and gamma-emitting radiation resulted in an adapted strain able to mount a unique response to ionizing radiation in the environment in a melanin-dependent fashion. By exploring the genome and transcriptome of this adapted melanized strain relative to a non-irradiated control we determined the altered response was transcriptomic in nature, as whole genome sequencing revealed limited variation. Transcriptomic analysis indicated that of the adapted isolates analyzed, two lineages existed: one like the naïve, non-adapted strain, and one with a unique transcriptomic signature that exhibited downregulation of metabolic processes, and upregulation of translation-associated genes. Analysis of differential gene expression in the adapted strain showed an overlap in response between the control conditions and reactive oxygen species conditions, whereas exposure to an alpha particle source resulted in a robust downregulation of metabolic processes and upregulation of DNA replication and repair genes, and RNA metabolic processes. This suggest previous exposure to radiation primes the fungus to respond to subsequent exposures in a unique way. By exploring this unique response, we have expanded our knowledge of how melanized fungi interact with and respond to ionizing radiation in their environment.
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http://dx.doi.org/10.1016/j.csbj.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772362PMC
December 2020

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models.

Cancer Med 2021 02 21;10(3):1128-1140. Epub 2020 Dec 21.

University of Saskatchewan, Saskatoon, Canada.

Purpose: Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. Actinium-lintuzumab ( Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.

Experimental Design: Here we investigated the potential for Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML.

Results: We demonstrated that Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models.

Conclusions: There results suggest that the combination of Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.
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http://dx.doi.org/10.1002/cam4.3665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897952PMC
February 2021