Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs
âResults of this study demonstrate that rapamycin can be administered to dogs at pharmacokinetic exposures that are safe and translationally relevant (i.e. achievable in human cancer). These exposures modulate the proximate targets of the mTOR pathway in canine tumors and PBMC without inducing AKT phosphorylation. Inhibition of S6RP phosphorylation was a highly sensitive marker of exposure to rapamycin, even in the lowest dose cohorts, such that its pharmacodynamic modulation was not dose dependent. The biological behavior and histological features of canine and human osteosarcoma are indistinguishable. Many questions remain regarding the optimal use of mTOR inhibitors in cancer and in pediatric osteosarcoma in particular. Responses in clinical trials using mTOR inhibitors have been sporadic and not necessarily predicted by cancer histology. Furthermore modulation of traditional PD biomarkers such as phospho-S6RP, as found in this study, is unlikely to define clinically relevant exposures of rapamycin or rapalogs. This finding was supported by recent PK-PD evaluations(1) in human
patients with solid tumors that found phosphorylation of S6RP in skin surrogates did not correlate with rapamycin dose or responseâ
(1) Sci-Hub | Pharmacodynamic-Guided Modified Continuous Reassessment MethodâBased, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors. Journal of Clinical Oncology, 26(25), 4172â4179 | 10.1200/JCO.2008.16.2347
"The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. No objective responses occurred, but five previously progressing patients received at least 12 cycles. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection
A pharmacodynamic study of rapamycin in men with intermediate to high risk localized prostate cancer:
ResultsâThirty-two subjects were accrued, 20 at 3 mg, 2 at 6 mg, 10 controls. No dose-limiting
toxicities (DLTs) were observed at 3 mg; however, 2/2 men enrolled at 6 mg experienced DLTs
including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg
included stomatitis, rash, ileus, and neutropenia. PD studies demonstrated tumor S6
phosphorylation inhibition in 50% of 10 evaluable rapamycin treated men with sufficient paired tissue (median 58% decline, p=0.049 vs. 2% decline in controls, p=0.75) with no significant effect on AKT activity. There was no change in Ki-67 or caspase-3 cleavage but we noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin. Prostate tissue rapamycin concentrations were 3â4 fold higher than blood. We found that rapamycin inhibited the activity of a downstream target of TORC1, S6 kinase, in over half of evaluable patients without dose limiting toxicity, thus demonstrating the intended target inhibition and meeting our primary endpoint. However, we found no physiologically relevant effects of rapamycin on tumor cellular proliferation, post-treatment tumor grade or stage, PSA, or apoptosis over a 2 week exposure period. We did not find a correlation between PTEN expression in biopsy and RP specimens, despite using a validated PTEN assay with genetic controls, indicating that different heterogeneous tumors were sampled and analyzed before and after rapamycin, that PTEN expression may have been altered by rapamycin, or a limited power to detect these changes. We additionally found that many of the PD biomarkers such as Akt, p27, caspase-3, Ki-67, and PTEN have wide variability in this setting during specimen collection and processing across multiple centers, highlighting the challenges inherent in these pharmacodynamic studies and the need for standardized collection, processing, and ascertainment of these markers, with consideration of final sample size based on evaluable tissue"
ConclusionsâAt 3 mg daily, rapamycin successfully and safely inhibited PC S6
phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT
phosphorylation or tumor proliferation or apoptosis was observed"
Yeah, better hope on other meds or higher level treatmentsâŠthe clinical history of rapamycin alone and metastatic cancer is not good. I think we need to think primary prevention with rapamycinâŠstopping cancer from starting.
