Abstract 1696: Targeting EVI1-overexpressing AML with darinaparsin
Bibliographic record
Abstract
Abstract Activation of EVI1, due to chromosomal translocation, inversion or transcriptional upregulation, occurs in 8-10% of AML and results in both activation and repression of specific gene sets. Importantly, the tumor suppressor PTEN is repressed by EVI1. Arsenic trioxide targets EVI1 for degradation, suggesting that arsenicals may be effective in treating EVI1-positive malignancies. Indeed, MDS patients with EVI1 deregulation had greater benefit from the combination of arsenic trioxide (inorganic arsenic) and thalidomide than patients without EVI1 deregulation. Here, we describe the use of a novel organic arsenical, darinaparsin, to treat a patient with EVI1-overexpressing AML. A 36 year old woman was diagnosed with AML inv(3)(q21q26.2) where two copies of inv(3) were detected. Her initial treatment included two induction regimens followed by an allogeneic stem cell transplant. She had a complete remission lasting 5 years after which time her AML relapsed. After three high dose regimens and another investigational combination therapy failed to induce remission (>80% blasts in the bone marrow), we treated the patient's peripheral blasts ex vivo and found that darinaparsin induced significantly more cell death than arsenic trioxide. Thus, the patient started darinaparsin (300 mg/m2 IV over 60 minutes for 5 days every 21 days). Within 10 hours of receiving her first dose, her fever and night sweats had resolved. Her performance status and appetite improved, and she was discharged home 2 days after her last dose. Unlike previous drug regimens, darinaparsin allowed the patient to enjoy a good quality of life for more than 30 days with an ECOG performance status of 1. Unfortunately, while darinaparsin stabilized her peripheral white blood cell counts, the patient died of extramedullary manifestations and complications of her AML, 12 days after receiving a second cycle of darinaparsin. Darinaparsin decreased her peripheral white blood cell counts during the five days of treatment, which was followed by an additional decrease in the white blood cell count when serum arsenic levels were low to undetectable. We observed visible nuclear and cytoplasmic blebbing consistent with apoptosis. Despite the anti-tumor activity, neither EVI1 protein levels nor the transcriptional repression activity as measured by PTEN mRNA expression were altered within the first 72 hours of darinaparsin treatment. cDNA microarray expression profiling showed a dramatic change in gene expression of her tumor between the first and second cycle, including a significant increase in the pro-survival NF-κB pathway. NF-κB family member (i.e. NFKB1, 2, IA, IB, IE, RELA, TANK, TRAF1 and TRAF2) mRNA expression increased 2-8 fold following the first cycle of darinaparsin. Based on our clinical observations and correlative studies, future studies will investigate a link between EVI1 overexpression, NF-κB signaling and darinaparsin sensitivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1696. doi:1538-7445.AM2012-1696
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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) | 0.001 | 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".