Laboratory activities and projects carried out by the COP laboratory have the specific goal of improving the understanding of the impact of anti-cancer agents on comparative aspects of metastasis biology by virtue of parallel study of murine, canine and human cell lines in a variety of in vitro, ex vivo/in vivo (Pulmonary Metastasis Assay or PuMA) model systems. Data generated in this manner improves understanding of naturally-occurring canine osteosarcoma (OS) models and could be employed to answer unique in vivo questions regarding the anti-metastatic potential of agents, via the COTC clinical trial mechanism. A major focus of the COP laboratory is defining the impact of PDGFRa-targeted therapy for osteosarcoma. PDGF signaling, as manifested via overexpression and/or dysregulation of PDGF ligands and their receptors, is known to play a role in the pathogenesis, invasion and metastasis of several human pediatric cancers, including osteosarcoma and rhabdomyosarcoma. New understanding of signaling pathways involving PDGFR and related tyrosine kinases is needed for ongoing development and validation of targeted therapeutic strategies. To provide rationale and support of a comparative oncology approach, recent investigations demonstrate a potential role for PDGF/PDGFR signaling in canine OS via an autocrine and/or paracrine loop. These investigations could be supported through additional study of treatment-naive canine OS patient samples via the CCOGC biospecimen repository. Indeed, this adds further value to the inclusion of canine OS in the development and optimization of PDGFR-targeted therapies. Olaratumab (IMC-3G3) is a fully humanized IgG1 monoclonal antibody that selectively binds human PDGFRa with high affinity, blocking ligand binding and thus, downstream signaling. Published Phase I data in human patients with advanced solid tumors demonstrate tolerability of weekly or biweekly dosing of Olaratumab, and the potential for significant survival benefit in these patients. Phase Ib/II clinical trials (NCT02451943; NCT01185964) are also in progress in patients with advanced soft tissue sarcoma (STS). The COP, in collaboration with Eli Lilly Research Laboratories, is investigating the impact of Olaratumab on human OS using the spontaneous metastasis animal model described in Section II/Program Activities. We are also characterizing the impact of a canine chimera of Olaratumab designed expressly for this project by Eli Lilly with the same binding affinity and blocking activity for canine PDGFRa as exists for Olaratumab. The innovative aspects of this approach lie in the use of both human and canine-specific reagents and OS cell lines that are unique to our lab, wherein we employ a novel approach to study a common companion animal spontaneous cancer to advance our knowledge of a rare human pediatric cancer. This specific project, and the study of PDGFRa-directed therapies within the context of metastasis modeling in general, represents a novel and relevant line of investigation that exemplifies our mission to translate data generated in the lab into potential clinical applications for dogs and humans. Application of the data generated within this collaboration will directly support a clinical trial of a canine-specific version of Olaratumab as first-line adjuvant therapy in treatment-naive pet dogs with OS via the COTC mechanism, which will in turn uniquely and directly inform the use of Olaratumab as a therapeutic strategy for pediatric OS. Future directions for the COP laboratory. We continue to work with a variety of pharmaceutical and biotechnology companies regarding the opportunities that can be realized by collaborating with the COP and evaluating novel agents within our existing assays to determine their anti-metastatic potential. One area of future growth will be to delve more deeply into OS metabolomics and metabolic imaging via collaboration with Dr. Peter Choyke/MIP, see letter of collaboration. We possesspreliminary data to suggest that cellular energetics are deranged between our clonally-related pair of low and high metastasizing OS cell lines and plan to interrogate these differences more quantitatively using a variety of techniques such as Seahors extracellular flux analysis and 13C-pyruvate hyperpolarized MRI, for in vitro and in vivo investigations, respectively.
| Ren, Ling; Hong, Ellen S; Mendoza, Arnulfo et al. (2017) Metabolomics uncovers a link between inositol metabolism and osteosarcoma metastasis. Oncotarget 8:38541-38553 |
