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Marta Roman Moreno
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-039 - Preventive and Therapeutic Action of Id1 Inhibition in KRAS-Mutant (KM) Lung Adenocarcinoma (LAC) Tumors in a Xenograft Murine Model (ID 9574)
09:30 - 09:30 | Presenting Author(s): Marta Roman Moreno
- Abstract
Background:
Id1 has been shown to be involved in cell viability and migration of lung cancer cell lines and confer poor prognosis in LAC-patients. The most frequently mutation in LAC is KRAS, but no targeted therapy has been successfully developed. Here we study the role of Id1 in a KM-LAC murine model.
Method:
The expression of Id1 was analyzed in a panel of human LAC cell lines by qPCR and Western-Blot. Several human cell lines with known mutations (H1792-604, H2009, H358, H1568, H1437, H1703, H2126) were selected to deplete Id1 expression by inducible short hairpin RNA (shRNA) regulated by doxycycline. Proliferation, cell cycle and apoptosis assays were performed to study the cellular mechanism underlying the effect of Id1 deficiency. Mouse xenograft models were generated by subcutaneous injection of KM-LAC cells (H1792-604 and H2009), both shId1 and shGFP cells, in flanks of immunodeficient mice treated with doxycycline (drinking water) from the time of inoculation or once the tumors were established.
Result:
Id1 overexpression was observed in 11 out of 12 cell lines as occurs in previously reported clinical data. Id1 inhibition was achieved in all cell lines compared to controls. In absence of Id1, proliferation assays showed a significant impairment of cell growth in KM-LAC cell lines [H1792-604 31.61% ± 3.96 (P < 0.001); H2009 52.73% ±4.74 (P < 0.001); H358 70.85% ± 8.01 (P < 0.001)]. In KM cells, a significant arrest in G2/M phase of cell cycle was observed when Id1 was inhibited whereas no significant changes were observed in wild type(WT) KRAS cells [KM 1.86 ± 0.28;WT 1.02 ± 0.05 (P < 0.001)]. KM-cells showed a significant apoptosis increase compared to WT-cells [KM-cells 1.66 ± 0.41;WT-cells 0.99 ± 0.13 (P = 0.001)]. In vivo, we observed a significant decrease in tumor volume in mice injected with H1792-604-shId1 cells (60% ± 32.39) compared to shGFP group (356.29% ± 115.32)(P < 0.001). Moreover, mice injected with H2009-shId1 cells did not develop tumors compared to control mice (168.35 ± 68.71)(P < 0.001). Activation of shId1 in established tumors induced a significant reduction of tumor volume in both xenograft models. The inhibition led to regression of 4 out of 10 tumors H1792-604 and all tumors in H2009 inoculated mice.
Conclusion:
These findings support a crucial role of Id1 in tumor development in KRAS-driven adenocarcinoma of the lung. Id1 targeting was proven effective in both, tumor prevention and treatment in our humanized murine model of KM LAC.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-035 - Lymphocytes and Neutrophils Count After Two Cycles and TTF1 Expression as Early Outcome Predictors During Immunotherapy (ID 10308)
09:30 - 09:30 | Author(s): Marta Roman Moreno
- Abstract
Background:
Non-small cell lung cancer (NSCLC) therapeutic paradigm has dramatically changed with immune checkpoint blockers. The unconventional response patterns seen in patients treated with immunotherapy (IT) make it difficult to differentiate patients who respond from non-responders early on in treatment; and biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT.
Method:
We enrolled 32 consecutive patients with advanced NSCLC treated with IT at Clínica Universidad de Navarra (Spain) since 2015. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC (<1,000 vs >1,000) and ANC (<4,000 vs >4,000) after 2 cycles and response to IT. TTF1 expression was correlated with IT response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC.
Result:
TTF1 tumor expression in adenocarcinoma histology (n= 18) was significantly associated with response to IT (88% vs 45%, p= 0.03). Patients with ANC <4,000 after two cycles showed a longer median OS (NR vs 4.9 months; p=0.02). An ALC increase after 2 cycles was associated with DCR compared to progression (147 vs -155; p=0.05). ALC >1,000 after 2 cycles seemed to be more frequent among patients with TTF1+ tumors (82% vs 45%; p= 0.05) and among those experiencing DCR compared to progression (73% vs 58%; p=0.30).
Conclusion:
Our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger series.
