Abstract A106: BRCA mutation sensitizes pancreatic tumors to treatment with cisplatin
Bibliographic record
Abstract
Abstract Rationale: Recent clinical observations in pancreatic cancer suggest that cancers arising in germline BRCA1/2 mutation carriers are highly sensitive to Cisplatin chemotherapy. Both BRCA1 and BRCA2 are required for DNA double-strand break repair by homologous recombination (HR). Platinum chemotherapy generates interstrand cross-links that can only be adequately repaired by HR-based DNA repair, and consequently BRCA1/2-deficient cells are highly sensitive to platinum chemotherapy both in vitro and in vivo. With a strong biological rationale and favourable clinical observations, we aim to investigate whether BRCA mutation indeed sensitize to Cisplatin treatment and if the addition of the PARP inhibitor ABT-888 further reduces tumor growth in patient-derived pancreatic xenografts Methods: Primary xenografts were derived from three patients with known BRCA2 germline mutations (2 from surgical resections, 1 from ascites fluid). All 3 patients experienced a major response when treated with cisplatin. These models were used to assess the in vivo sensitivity to the drugs Cisplatin, Gemcitabine and the PARP inhibitor ABT-888, all of which are being used in the clinic. Treatment sensitivities were compared to 2 primary xenografts that were BRCA w/t. For single treatments, animals were treated with 4mg/kg Cisplatin weekly, 100mg/kg Gemcitabine biweekly or 12.5mg/kg ABT-888 daily for 30 days. For the combination treatment, animals were treated with a single dose of 4mg/kg Cisplatin followed by 30 days of 12.5mg/kg ABT-888 daily. Results: Preliminary results show no difference in tumor growth between BRCA2 wt and mt models was observed in response to treatment with ABT-888 alone. Treatment with cisplatin or gemcitabine on the other hand significantly reduced tumor growth and increased survival in all 3 BRCA2 mutated xenograft models, while being mostly ineffective in BRCA w/t tumors. The combination of Cisplatin and ABT-888 significantly reduced tumor growth when compared to ABT-888 alone. Conclusions: The results suggest that BRCA1/2 mt pancreatic xenograft models are highly sensitive to cisplatin. The availability of these models facilitates “near-clinical” testing of alternative strategies for optimizing the individualized treatment of patients carrying these rare mutations, and for the exploration of protocols incorporating novel agents. Citation Format: Ines Lohse, Pinjian Cao, Emin Ibrahimov, Ming-Sound Tsao, David W. Hedley. BRCA mutation sensitizes pancreatic tumors to treatment with cisplatin. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A106.
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) | 0.004 | 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".