Research Article: The Comparative Oncology Trials Consortium: Using Spontaneously Occurring Cancers in Dogs to Inform the Cancer Drug Development Pathway

Date Published: October 13, 2009

Publisher: Public Library of Science

Author(s): Ira Gordon, Melissa Paoloni, Christina Mazcko, Chand Khanna

Abstract: Chand Khanna and colleagues describe the work of the Comparative Oncology Trials Consortium (COTC), which provides infrastructure and resources to integrate naturally occurring dog cancer models into the development of new human cancer drugs, devices, and imaging techniques.

Partial Text: Despite evidence of drug efficacy in mouse models of cancer, many novel anti-cancer agents fail in human cancer patients because of unacceptable toxicity or poor efficacy [1]. Naturally occurring tumors in dogs and other animals have clinical and biological similarities to human cancers that are difficult to replicate in other model systems. A recently launched cooperative effort, the National Cancer Institute’s (NCI’s) Comparative Oncology Trials Consortium (COTC; http://ccr.cancer.gov/resources/cop/COTC.asp), now provides infrastructure and resources needed to integrate these naturally occurring cancer models into the development of new human cancer drugs, devices, and imaging techniques.

Murine cancer models have been extremely useful for analyzing the biology of pathways involved in cancer initiation, promotion, and progression. However, they frequently do not adequately represent many of the features that define cancer in humans, including long periods of latency, genomic instability, and the heterogeneity of both tumor cells and their surrounding microenvironment. Most importantly, the complex biology of cancer recurrence and metastasis, integral to outcomes in human patients, are not appreciably reproduced in the conventional mouse models used in cancer drug development. Furthermore, in many cases, there has been inadequate consideration of relevant exposures for new drugs that are evaluated in mice. The development and approval of novel cancer drugs is lengthy and expensive [2]–[5]; therefore, additional models that better represent the human disease are needed.

The COTC was launched through the intramural NCI’s Center for Cancer Research–Comparative Oncology Program. The COTC operates as a collaborative effort between the NCI and extramural academic comparative oncology centers and functions to design and execute clinical trials in dogs with cancer in collaboration with the pharmaceutical industry and nongovernmental groups interested in cancer drug development. Support for the oversight and management of the COTC comes from the NCI. Trial sponsors, most often pharmaceutical companies, support the clinical costs of studies conducted by the COTC academic centers. The goal of this effort is to answer biological questions that can inform the development path of novel agents for future use in human cancer patients in a timely and integrated manner. Trials conducted by the COTC are designed to include clinical and biological endpoints, i.e., pharmacokinetics and pharmacodynamics, so as to optimally inform the design of early phase human trials. Trials are carried out at COTC member institutions, which currently include 18 veterinary academic centers, currently in the United States.

Dogs have historically been useful, informative models in the development and discovery of many novel cancer therapeutic strategies. The efficacy of liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in dogs with osteosarcoma served as part of the rationale for its evaluation in Phase III studies in children. Indeed, similar results with L-MTP-PE have been observed in both dogs and children [24],[25]. Dogs have been used to develop and evaluate surgical limb sparing techniques [26] and were valuable models in the investigation of the combination of hyperthermia with radiation [27],[28]. Dogs have also been included in the development of novel targeted anticancer agents [20],[29].

As with all novel approaches and perspectives, integrating studies with pet dogs with cancer into the development pathway is associated with some hesitation and perception of risk. One of the goals of the COTC is to define and address perceived risks and actual challenges and to mitigate them when possible.

The increasing availability of banked canine tumors and associated “omic” annotations for these cancers will allow for rapid identification of valid tumor targets in canine cancers. To this end, a second community initiative, the Canine Comparative Oncology and Genomics Consortium (CCOGC; http://www.ccogc.net/) was recently developed to facilitate strategic partnerships and collaborations across a diversity of these disciplines and to develop a tissue biospecimen repository. This repository has initiated sample collections and expects to provide tissues to the community in late 2009.

Source:

http://doi.org/10.1371/journal.pmed.1000161

 

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