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NQ01 as a Therapeutic Target for Canine Osteosarcoma

NQ01 as a Therapeutic Target for Canine Osteosarcoma

NQ01 as a Therapeutic Target for Canine Osteosarcoma

Veterinary Cancer Society
Veterinary Cancer Society
on behalf of Missouri Veterinary Medical Association

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Launch date: 15 Apr 2015

Expiry Date:

Last updated: 20 Apr 2016

Reference: 150688

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$ 12.50 $ 12.50 $ 12.50
NQ01 as a Therapeutic Target for Canine Osteosarcoma
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This course is only available to trainees days after purchase. It would need to be repurchased by the trainee if not completed in the allotted time period. This course is no longer available. You will need to repurchase if you wish to take the course again.

Description

Appendicular osteosarcoma (OS) is the most common tumor associated with malignant skeletal pain in dogs, and it is estimated that over 10,000 new cases per year will be diagnosed in the United States. For dogs perceived as poor surgical candidates, sufficient control of osteolytic pain and prevention of pathologic fracture is essential for maintaining quality-of-life scores. Although palliative strategies that incorporate conventional ionizing radiation are initially effective for alleviating bone pain, the durability for pain relief is disappointingly short, usually less than 3 months. Alternatively, stereotactic radiosurgery offers excellent pain control as a result of near complete field sterilization (> 90% percent necrosis), but consequently results in a high incidence of pathologic fracture due to longstanding avascular bone necrosis and sequestrum development. Upon localized failure, treatment options are extremely limited for dogs considered poor candidates for amputation; and euthanasia due to local tumor progression or treatment-associated complications (uncontrolled pain or pathologic fracture) rather than distant metastases is a disheartening, yet expected outcome. Treatment strategies that focus on selectively reducing localized OS tumor burden, and at the same time maintain or promote reparative osteoblastogenesis and angiogenesis, should theoretically provide non-surgical options that maximize the likelihood for achieving acceptable bone pain control and limb preservation.

Nicotinamide adenine dinucleotide phosphate quinone oxidoreductase (NQO1) is a flavoprotein found in most eukaryotic cells at very low levels. The normal function of NQO1 is to detoxify quinones by a two-electron reduction, forming a stable hydroquinone that is conjugated with glutathione by glutathione-S-transferase (GST) and secreted from the cell. Importantly, NQO1 is overexpressed in a number of human cancer cell lines, including osteosarcoma (OS). Significantly, with certain select quinones, such as β-lapachone and deoxynyboquinone (DNQ), NQO1 reduction produces a highly unstable hydroquinone, leading to rapid re-oxidation and robust generation of toxic ROS selectively in cells that express NQO1. Additionally, the expression of NQO1 in cells has the potential to be tunable, as exposure to ionizing radiation robustly upregulates NQO1 gene transcription.

The current investigation proposes to characterize the basal expression of NQO1 in canine OS cell lines and spontaneous tumor samples through western blot, immunohistochemistry, and enzyme activity assays. Furthermore, the druggability of NQO1 with the quinione DNQ is studied in canine OS cell lines alone and in combination with radiation therapy through the use of conventional apoptosis assays. The results derived from this preliminary study which characterizes the expression and tunability of NQO1 in canine OS has potential to justify future studies in which combining the targeted delivery of DNQ via isolated-limb perfusion with 2-staged ionizing radiation therapy might provide an exceptionally effective and durable non-surgical limb preserving treatment option in dogs with OS.

Objectives

Objectives
The results derived from this preliminary study which characterizes the expression and tunability of NQO1 in canine OS has potential to justify future studies in which combining the targeted delivery of DNQ via isolated-limb perfusion with 2-staged ionizing radiation therapy might provide an exceptionally effective and durable non-surgical limb preserving treatment option in dogs with OS.
Veterinary Cancer Society

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Veterinary Cancer Society
on behalf of Missouri Veterinary Medical Association

Dr. Timothy Fan received his Doctor of Veterinary Medicine Degree at Virginia-Maryland Regional College of Veterinary Medicine in 1995. He completed a Small Animal Rotating Internship at the University of Illinois from 1995 to 1996. Following the completion of his internship, Dr. Fan fulfilled a Small Animal Internal Medicine Residency at Cornell University in 1998. Following his stay at Cornell, Dr. Fan returned to the University of Illinois to receive advanced clinical training in the subspecialty of Medical Oncology. Dr. Fan completed his Board Certification in Internal Medicine in 2000 and in Medical Oncology in 2001. Following the completion of Dr. Fan’s clinical training, he pursued and completed a PhD in Tumor Immunology, whereby he investigated the anticancer effects of cytokine manipulation strategies for the treatment of locally-invasive and metastatic tumors in mouse models of disease. Upon completion of his PhD in 2007, Dr. Fan now serves as the principal investigator of the Comparative Oncology Research Laboratory housed in the Small Animal Clinic, Department of Veterinary Clinical Medicine. Dr. Fan’s laboratory works closely with other basic scientists for evaluating novel drugs or drug delivery strategies for the treatment of cancer. Uniquely, Dr. Fan’s training as a scientist and veterinarian, has allowed him the opportunity to rapidly investigate and translate novel treatment strategies in dogs with spontaneously-arising cancers, and conduct meaningful comparative oncology research which is hoped to eventually aid in treating cancer in not only companion animals, but also human beings.

Current Accreditations

This course has been certified by or provided by the following Certified Organization/s:

  • Missouri Veterinary Medical Association
  • 0.50 Hours -
    Exam Attempts: 3
    -
    Exam Pass Rate: 50

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