In Vitro Activity and Target Modulation of PV-10 Against Relapsed and Refractory Pediatric Leukemia
Bibliographic record
Abstract
Abstract Introduction: Leukemias are the most common childhood cancers, accounting for 30% of all pediatric cancer diagnoses. Although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Approximately 15-20% of pediatric acute lymphoblastic leukemia (ALL) patients and 30-40% of acute myeloid leukemia (AML) patients relapse, with relapsed ALL identified as the fourth most common malignancy in children. Treatment of relapsed pediatric leukemia includes intensification of chemotherapeutic regimens and use of bone marrow transplantation (BMT). However, increasing the intensity of combination chemotherapies and introduction of second-line drugs is often accompanied by cumulative toxicity with marginal incremental benefits. Therefore, research to identify and develop novel tolerable and effective agents is urgently needed. PV-10 (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a novel therapeutic that induces direct cytotoxicity in adult and pediatric solid tumors and stimulates tumor specific immune activation through immunogenic cell death. Our studies aim to identify the potential of PV-10 in future clinical trials for relapsed and refractory pediatric leukemias. Methods: A panel of eleven cell lines derived from patients with either primary or relapsed pediatric leukemia (CEM-C1, CCRF-SB, Kasumi-1, KOPN8, Molm-13, Molt-3, Molt-4, MV4-11, SEM, SUP-B15 and TIB-202) and cells from three primary leukemia patient specimens (T-ALL, AML, Infant AML) were treated with increasing concentrations of PV-10 and cell viability was measured by alamar blue assay, 96 h post-treatment. Target modulation and induction of cell death pathways were investigated by western blot, phase-contrast microscopy and time-lapse video microscopy. Analysis of cell cycle alterations and induction of apoptosis were measured by flow cytometry. Combination studies will be performed to identify anti-cancer agents that are synergistic with PV-10 and animal models of pediatric leukemia used to identify the activity of PV-10 against pediatric leukemia in vivo. Results: PV-10 decreased cell viability in a concentration and time dependent manner in the eleven pediatric leukemia cell lines (mean IC50 93 µM), and three primary leukemia samples (mean IC50 122 µM) tested. Observation of four different leukemia cell lines (Molm-13, MV4-11, SEM, TIB-202) by phase-contrast and time-lapse video microscopy indicated that PV-10 was cytotoxic and not cytostatic to cells. Quantification of dead cells from time-lapse video microscopy experiments showed that PV-10 was cytotoxic in a cell line and concentration dependent manner. At 24 h post-treatment with 100 µM PV-10, 88% of MV4-11 cells, 69% of Molm-13 cells, 27% of TIB-202 cells and 25% of SEM cells had undergone cell death. When the concentration of PV-10 was increased to 200 µM, 100% of MV4-11 and Molm13 cells, 94% of SEM cells and 60% of TIB-202 cells had undergone cell death, 24 h after treatment. Additionally, observation by time-lapse video microscopy suggested that cells were dying by apoptosis, as treatment with PV-10 led to cell shrinkage. Induction of apoptosis by PV-10 was confirmed by dose and time dependent PARP cleavage, detected by western blot. Conclusions: Our studies provide first proof-of-concept pre-clinical data for the activity and mechanisms of action of PV-10 in pediatric leukemia. These data provide the rationale for additional studies and the formulation of an early-phase clinical trial for patients with relapsed and refractory pediatric leukemia. Disclosures No relevant conflicts of interest to declare.
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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".