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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
OA19.05 - High Oncofetal Chondroitin Sulfate Expression is an Independent Prognostic Factor of Poor Survival in Early-Stage NSCLC (ID 5601)
11:00 - 12:30 | Author(s): M. Daugaard
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
P3.02c-007 - Assessment of Dianhydrogalactitol in the Treatment of Relapsed or Refractory Non-Small Cell Lung Cancer (ID 4639)
14:30 - 15:45 | Author(s): M. Daugaard
Non-small cell lung cancer (NSCLC) is treated with surgery and chemotherapy with either tyrosine kinase inhibitors (TKIs) or platinum-based regimens, but drug-resistance is frequent and long-term prognosis poor. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent with proven activity against NSCLC in clinical studies. VAL-083 has demonstrated superior activity to cisplatin in both in vitro and in vivo NSCLC models, including TKI-resistant NSCLC, and circumvents cisplatin-resistance in ovarian cancer cells. VAL-083 is approved for the treatment of lung cancer in China; however, clinical adoption is limited by lack of modern data related to mechanism-of-action and utility in the context of standard-of-care platinum-based chemotherapy. Here we aimed to investigate in vitro i) the distinct mechanism-of-action of VAL-083, ii) VAL-083 cytotoxicity in a panel of NSCLC cell-lines with varying p53 status, and iii) the combination of VAL-083 with cisplatin or oxaliplatin.
VAL-083 cytotoxicity was investigated in a panel of 11 human NSCLC cell-lines: 3 wild-type (H460, A549, H226), 6 mutant (H1975, SkLU1, H2122, H157, H1792, H23) and 2 null (H838, H1299) for p53. Cell-cycle and DNA damage was investigated by propidium iodide and immunofluorescent staining in synchronized cultures of H2122, H1792, A549. Cytotoxicity was determined by MTT assay. Combination potential for VAL-083 with cisplatin or oxaliplatin was investigated in H460, A549, H1975 (TKI-resistant) by determining superadditivity and synergy using the combination index (CI)<1 criteria.
VAL-083 treatment caused persistent S/G2 cell-cycle arrest and cell-death. Furthermore, one-hour pulse treatment led to phosphorylation of DNA double-strand break sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting activation of the homologous repair pathway. S/G2 phase cell-cycle arrest and increased γH2A.X in cancer cells persisted >72 hours after treatment, indicating irreversible DNA lesions. Importantly, VAL-083 was active against all cell-lines tested, irrespective of their p53 status, suggesting a mechanism-of-action that differs from other alkylating agents, including cisplatin. When combined with either cisplatin or oxaliplatin in vitro, VAL-083 demonstrated significant superadditivity (p<0.05) and synergism (CI<1) for both combinations in all NSCLC cell-lines. This strongly suggests non-overlapping modes-of-action between the platinum drugs and VAL-083 and demonstrates synergism in TKI-resistant cell-lines.
This preclinical data strongly suggests VAL-083 as a potential treatment for platinum and TKI-resistant NSCLC. An open-label post-market clinical trial in China will investigate the activity of VAL-083 in relapsed/refractory NSCLC. Results will provide guidance to physicians under the context of VAL-083’s current approval in China, as well as serve as proof-of-concept for expanded development worldwide.