Abstract 5101: Defining exposure-PD and efficacy relationships with the novel liver-targeting nucleotide prodrug MIV-818 for the treatment of liver cancers
Bibliographic record
Abstract
Abstract Background: Many systemic chemotherapeutics have failed to show efficacy in hepatocellular carcinoma (HCC), often because systemic toxicity prevents efficacious liver levels of the drug from being reached. MIV-818, a nucleotide prodrug of troxacitabine-monophosphate (TRX-MP) has been designed as a novel approach to deliver high levels of the chain-terminating nucleotide troxacitabine-triphosphate (TRX-TP) to the liver after oral dosing while minimizing systemic exposure. We investigated MIV-818 and troxacitabine using in vivo models in order to identify therapeutic levels of TRX-TP required in the tumors. Methods: MIV-818 or troxacitabine were administered to nude mice with subcutaneous Hep3B or Huh7 xenografts. LC-MS/MS was used to assess MIV-818 and its metabolites. Effects on tumor growth, plasma AFP, inhibition of proliferation and induction of DNA damage were examined and correlated with exposures to TRX-TP in the tumor. Quantitative immuno-fluorescent histology was used to assess DNA damage (pH2AX) proliferation (BrdU), and hypoxia (pimonidazole). Results: Compared to the parent nucleoside troxacitabine, MIV-818 has increased potency of inhibition of HCC cell line growth, increased conversion to its active metabolite TRX-TP and in vitro properties optimized for oral bioavailability and liver targeting, including permeability and intestinal stability. MIV-818 also shows strong synergistic anti-proliferative activity with sorafenib in a number of HCC cell lines in vitro. Pronounced tumor growth inhibition of 70-100% and extensive tumor growth delays of up to 26 days were observed in the Hep3B xenograft model following a five day period of dosing. 12-32-fold induction of DNA damage was seen throughout the tumor sections, consistent with the expected mechanism of action, and with associated inhibition of proliferation. Clear PD responses were apparent even in hypoxic regions of the tumor, indicating effective distribution of TRX-TP even far from blood vessels. DNA damage persisted for up to 7 days after the final dose, demonstrating long-lasting effects and indicating that intermittent dosing is likely to be effective. Similar dosing regimens given to Huh7 xenograft models resulted in significant tumor growth inhibition and induction of DNA damage. Intratumoral TRX-TP exposures across both models were correlated with anti-tumor effects including DNA damage induction, proliferation inhibition and tumor growth inhibition. Conclusions: We have identified TRX-TP exposures required for pronounced anti-tumor effects to give a comprehensive understanding of PK-PD-efficacy relationships for the active metabolite of MIV-818. These data could be used to guide dosing and dose selection in clinical studies. MIV-818 is currently in preclinical development in preparation for the initiation of clinical trials in patients with advanced HCC and other liver cancers. Citation Format: Mark Albertella, Biljana Rizoska, Alastair Kyle, Andrew Minchinton, Annelie Linqvist, Sanja Juric, Susanne Sedig, Karin Tunblad, Fredrik Öberg, Björn Classon, Anders Eneroth, John Öhd, Richard Bethell. Defining exposure-PD and efficacy relationships with the novel liver-targeting nucleotide prodrug MIV-818 for the treatment of liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5101. doi:10.1158/1538-7445.AM2017-5101
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".