Abstract A74: The HIV protease inhibitor nelfinavir, alone or in combination with the proteasome inhibitor bortezomib, is cytotoxic to high-grade serous ovarian cancer cells regardless of platinum sensitivity
Bibliographic record
Abstract
Abstract High-grade serous ovarian cancer (HGSOC) is a deadly disease, affecting women worldwide. Major challenges in treating HGSOC patients involve overcoming resistance to platinum (Pt)-based therapy by developing novel treatment approaches. Nelfinavir (NFV), an anti-HIV drug, has shown to be effective against cancers of high secretory capacity—e.g., multiple myeloma—by aggravating the stress of the endoplasmic reticulum (ER). Its potential therapeutic role against HGSOC, however, remains unclear. We hypothesized that simultaneous ER stress aggravation by NFV and blockage of the proteolytic capacity of the proteasome with a proteasome inhibitor should cause sufficient ER stress to tilt cells to a death fate. In this study, we investigated the cytotoxicity of the ER aggravator NFV as monotherapy and in combination with the proteasome inhibitor bortezomib (BZ) against HGSOC cells having differential sensitivities to cisplatin (CDDP). NFV caused cell cycle arrest associated with increased expression of cyclin-dependent kinase inhibitor p27kip1, while triggering the unfolded protein response (UPR) in a dose-dependent manner and assessed by increased subrogate ER stress biomarkers GRP78 and CHOP. We also discovered that blocking the ubiquitin proteasome system (UPS) using cytostatic concentrations of BZ causes accumulation of poly-ubiquitinated proteins and further activation of the UPR. More importantly, when we combined BZ with NFV, we observed a potentiation of the action of BZ leading to HGSOC lethality regardless of Pt sensitivity. These results suggest that NFV could potentially be used following standard Pt-based treatment, either as monotherapy or in conjunction with proteasome inhibitors, to kill the remaining HGSOC cells that otherwise recur and recreate the disease. In addition, the data provide the rationale for rapid repurposing to treat HGSOC of two drugs clinically approved for other uses, as their systemic toxicities have already been assessed. Citation Format: Mahbuba R. Subeha, Alicia A. Goyeneche, Michael A. Lisio, Carlos M. Telleria. The HIV protease inhibitor nelfinavir, alone or in combination with the proteasome inhibitor bortezomib, is cytotoxic to high-grade serous ovarian cancer cells regardless of platinum sensitivity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A74.
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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) | 0.003 | 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".