Targeting EVI1-Overexpressing AML with Darinaparsin
Notice bibliographique
Résumé
Abstract Abstract 4269 Ecotropic viral integration site 1 (EVI1) is a critical oncogene driving a subset of myeloid malignancies and overexpression of EVI1 predicts an extremely poor prognosis in both adult and pediatric AML patient populations. 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 arsenical, darinaparsin (an organic form of arsenic), to treat a patient with EVI1-overexpressing AML, as a 10th line of chemotherapy. 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 complete remission lasting 5 years after which time her AML relapsed. Three high dose regimens, including VP16 (4g) and cyclophosphamide (2.7g), failed to induce another remission (>80% blasts in the bone marrow). She was offered an investigational combination therapy of ribavirin and low dose cytarabine but after one month, her peripheral blast count rose to >60 and was not responding to hydrea (8g) or mitoxantrone (20mg). At this time, we compared the anti-tumor activity of arsenic trioxide and darinaparsin on the patient’s peripheral blasts in vitro 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. She regained her energy and appetite and 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, 36 days after receiving the first dose 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 cells undergoing apoptosis. Although EVI1 protein levels were difficult to measure consistently, we analyzed the transcriptional repression activity of EVI1 by measuring PTEN mRNA expression. Intriguingly, we found a significant increase in PTEN mRNA in leukemic blasts following each course of darinaparsin, supporting the hypothesis that darinaparsin may target EVI1 or its activity. We utilized cDNA microarray expression profiling and found that gene expression of her tumor changed dramatically 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 these data, we conclude that darinaparsin should be further explored as a treatment for EVI1-overexpressing myeloid malignancies using the transcriptional repression activity of EVI1 by measuring PTEN mRNA expression as a biomarker for identification of patients likely to respond to therapy. Disclosures: Mann: ZIOPHARM Oncology Inc: Research Funding. Morgan:ZIOPHARM Oncology Inc: Employment. Miller:ZIOPHARM Oncology Inc: Research Funding.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».