Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs

Abstract

The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.Patients and Methods: A total of 324 pet dogs diagnosed with treatment-na€ ve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy AE oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1-and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.Results: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC þ sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.Conclusions: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Proteomic Assessment of Extracellular Vesicles from Canine Tissue Explants as a Pipeline to Identify Molecular Targets in Osteosarcoma: PSMD14/Rpn11 as a Proof of Principle

“…Several studies have demonstrated that cancer cells have a particularly heightened dependence on proteasomes, given their increased expression of mutated proteins and excessive protein synthesis due to aneuploidy [ 54 ]. This suggests that cancer cells are particularly sensitive to proteasome inhibition which can lead to fatal consequences [ 55 ].…”

There and back again: Translating adoptive cell therapy to canine cancer and improving human treatment

“…To augment the rigour and reproducibility of these translational clinical trials, the COP has established the Comparative Oncology Trials Consortium, a network of academic veterinary oncology centers working together to garner information on the efficacy of novel therapeutics 54 . In conjunction with the Morris Animal Foundation (https://www.morrisanimalfoundation.org/), this program has facilitated immuno‐oncology trials including the evaluation of a recombinant, attenuated Listeria monocytogenes expressing a chimeric human HER2/neu protein as an adjuvant therapy in dogs with osteosarcoma (COTC026), the results of which will be compared against a prospective cohort of dogs treated with standard of care carboplatin chemotherapy (COTC022) 55 . Additional philanthropic and governmental efforts to provide immunotherapy for dogs include the V foundation (https://http://www.v.org), the American Kennel Club Canine Health Foundation (https://www.akc.org), and the Pre‐medical Cancer Immunotherapy Network Canine Trials (PRECINCT, https://www.precinctnetwork.org).…”

Spontaneously occurring canine cancer as a relevant animal model for developing novel treatments for human cancers

“…Recently, this project reported a multicenter, randomized, prospective clinical trial focused on the use of a mammalian target of rapamycin (mTOR) inhibitor, sirolimus in 324 dogs with osteosarcoma treated with amputation and chemotherapy. However, the results showed no advantage with the use of sirolimus, but this is a good example of a preclinical clinical trial for drugs aimed to treat osteosarcoma [38].…”