Abstract 1688: Autophagy inhibition enhances the antitumor effects of combretastatin A4 phosphate (CA4P).
Bibliographic record
Abstract
Abstract Vascular disruptive agents such as CA4P cause an acute shutdown of the tumor vasculature resulting in metabolic stress and central tumor necrosis. However, tumor recurrence may ensue from peripheral tissue that survives the vascular insult because of less severe metabolic conditions (i.e, viable rim). Autophagy is an evolutionarily conserved cellular response to stress that is either enabling cell survival or mediating cell death, depending on the circumstances. During cancer therapy, autophagy is usually thought to contribute to cell survival and thus to therapeutic resistance. Hence, we hypothesized that autophagy inhibition would amplify the antitumor effects of CA4P by lowering the threshold of peripheral tumor cells to withstand the metabolic stress due to CA4P administration. Since available pharmacological autophagy inhibitors lack specificity, we established pairs of isogenic autophagy-defective (ATG4BC74A) and autophagy-competent (vector control, i.e., mstr) prostate cancer cells by means of retrovirally transducing PC-3 and C4-2 human prostate cancer cells with ATG4BC74A (an inactive and dominant-negative mutant of the autophagy related gene atg4B). These paired cell lines were characterized in vitro (autophagy and proliferation assays in cells exposed to CA4P), and PC-3 xenograft tumors were grown subcutaneously in mice subjected to CA4P (100 mg/kg ip). We collected tumors after 24 hours and 1 week for cryosectioning and preparation of protein lysates. To document the autophagy status in tumors, lysates were analysed by LC-3 Western blotting. The degree of necrosis and senescence in tissue sections was measured by H&E and senescence-associated β-galactosidase histochemistry, respectively. Microvessel density was assessed by CD31 immunofluorescence. CA4P associated inhibition of proliferation was not influenced by the autophagy status of PC-3 and C4-2 (CA4 IC50 ∼7 nmol/L for both PC-3 and C4-2). We also observed similar growth kinetics of PC-3 ATG4BC74A and mstr tumors in control and CA4P treated mice. Furthermore, we documented a comparable decrease in CD31 microvessel density 24 hours after C4AP administration in PC-3 ATG4BC74A and mstr xenografts, a change that was reversed 1 week following C4AP treatment. However, CA4P caused more extensive central tumor necrosis as well as a larger number of senescent cells in autophagy-deficient PC-3 tumors both 24 hours and 1 week following CA4P therapy. In summary, autophagy inhibition amplifies the necrosis- and senescence-inducing properties of CA4P. Further investigations are aiming at assessing the impact of the autophagy status of PC-3 tumors on CA4-mediated apoptosis and hypoxia. We also plan to expand our analyses to the C4-2 model. Finally, we are currently studying if combined CA4P therapy and autophagy inhibition results in improved long-term tumor control. Such combination therapy could be rapidly translated into the clinic. Citation Format: Van C. Hoang, Annabelle Chow, Urban Emmenegger. Autophagy inhibition enhances the antitumor effects of combretastatin A4 phosphate (CA4P). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1688. doi:10.1158/1538-7445.AM2013-1688
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".