Abstract A159: Dianhydrogalactitol (VAL-083) enhances activity of platinum drugs in non-small cell lung cancer
Bibliographic record
Abstract
Abstract Non-small cell lung cancer (NSCLC) is treated with surgery followed by chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but long term prognosis is poor. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with proven activity against NSCLC in preclinical and clinical studies. VAL-083 is approved for the treatment of lung cancer in the Peoples Republic of China (PRC, Approval No. Guayo Zhunzi H45021133); however, clinical use has been limited by lack of mechanistic data. Here we aimed to investigate in vitro i) the role of p53 status in VAL-083 activity, ii) VAL-083 cytotoxicity in a panel of NSCLC cell lines, iii) the combination of VAL-083 with cisplatin or oxaliplatin in NSCLC cells. We further studied the combination of VAL-083 with cisplatin in NSCLC in vivo. Dependence on p53 status was investigated in isogenic HCT-116p53-/- and HCT-116p53+/+ models. VAL-083, cisplatin and oxaliplatin cytotoxicity was tested in a panel of 9 human NSCLC cell lines: 4 wt, 4 mutant and 1 null for p53. The combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in 3 human NSCLC cell lines; H460 (p53wt), A549 (p53wt) and H1975 (p53mut) by determining superadditivity and synergy using the criteria of combination index (CI)<1. Cytotoxicity was monitored on day 5 with the MTT assay. The in vivo activity of VAL-083 (2, 2.5, or 3 mg/kg i.p.) in combination with cisplatin (2 mg/kg i.v.) was tested in Rag2 mice bearing A549 xenograft tumors. Studies in HCT-116 models showed that loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, while resistance to VAL-083 was <2-fold, suggesting a more p53-independent mechanism for VAL-083. As single agents, VAL-083, cisplatin and oxaliplatin showed good cytotoxicity in all NSCLC cell lines, with TKI-resistant cell line H460 as the most sensitive (IC50 < 0.5 uM). The combination of VAL-083 with cisplatin or oxaliplatin in H460, A549 and H1975 cells demonstrated significant super-additivity (p<0.05) and synergism (CI < 1) for both combinations in all 3 cell lines. This strongly favors non-overlapping mode of action between the platinum drugs and VAL-083 and demonstrates synergism in TKI-resistant cell lines. In the in vivo model, tumor growth delays of 11, 18 and 25 days were observed for cisplatin combined with 2, 2.5 or 3 mg/kg VAL-083, respectively, while no tumour growth delay was seen between untreated and cisplatin. The median survival time was increased by 2 days for cisplatin alone, while VAL-083 (2, 2.5 and 3 mg/kg) combined with cisplatin increased survival by 17, 17, and 14 days, respectively. In conclusion, when combined with cisplatin or oxaliplatin, VAL-083 demonstrates superadditivity/synergy against NSCLC cells, independent of their p53 status. Further, VAL-083 in combination with cisplatin significantly increased median survival in vivo. These results strongly suggest a potential for VAL-083 as part of combination treatment with platinum drugs for NSCLC, including drug-resistant phenotypes. A clinical trial is planned under the context of the existing PRC approval to investigate these observations in a clinical setting. Results, if favorable, will support expanded clinical use of VAL-083 in PRC and will serve as the basis for global development of VAL-083 as a potentially important chemotherapeutic agent in the treatment of NSCLC. Citation Format: Anne Steino, Jeffrey A. Bacha, Guanghan He, Sarath Kanekal, Nancy Dos Santos, Shun Lu, Dennis M. Brown, Zahid H. Siddik. Dianhydrogalactitol (VAL-083) enhances activity of platinum drugs in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A159.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".