Sook-Ja Kim

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene. Treatment of NB4 cells with 1 μM of ATRA, 0.5 μM of ATO, or 10 μM of PP2 for 72 h induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significantly higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed with NBT staining. These effects were not related to apoptosis. Annexin-V-fluorescein staining revealed that a combination of ATRA and ATO and combination of the three agents did not induce apoptosis in NB4 cells. The expression of ICAM-1 markedly increased in cells treated with the combination of the three agents. These findings suggest that the SFK inhibitor can enhance differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL with a combination of ATRA and ATO.

Src Family Kinase Inhibitor PP2 Has Different Effects on All-Trans-Retinoic Acid or Arsenic Trioxide-Induced Differentiation of an Acute Promyelocytic Leukemia Cell Line

Purpose Leukemic promyelocytes have the unique ability to undergo differentiation after exposure to retinoic acid and both differentiation and apoptosis after exposure to arsenic trioxide (ATO). Recent studies have shown that inhibition of Src family kinases (SFKs) resulted in enhancement of retinoic acid-induced myeloid differentiation. Materials and Methods In this study, we investigated the question of whether the SFK inhibitor PP2 enhanced the differentiation of NB4 cells when combined with ATO as well as when combined with all-trans-retinoic acid (ATRA). In addition, we attempted to determine the difference in retinoic acid-induced gene expression between cells treated with PP2 in combination with ATRA and in combination with ATO. Results SFK inhibitor PP2 induced significant enhancement of ATRA- or ATO-induced differentiation of NB4 cells. A significantly stronger synergistic effect was observed when PP2 was combined with ATRA than when combined with ATO. Flow cytometric analysis demonstrated a significant increase in CD11b-positive granulocytes up to 60.73% and 31.58%, respectively. These results were confirmed by nitroblue tetrazolium staining. These effects were not related to apoptosis. Results of Annexin-V-fluorescein staining revealed that PP2 combined with ATRA or PP2 combined with ATO did not induce apoptosis in NB4 cells. Retinoic acid-induced gene expression was different in both groups. Intercellular adhesion molecule-1 expression showed a significant increase in cells treated with PP2 in combination with ATRA, whereas cathepsin D expression showed a significant increase in cells treated with PP2 in combination with ATO. Conclusion Our data showed that SFK inhibitor PP2 enhanced acute promyelocytic leukemia cell differentiation when combined with either ATRA or ATO with difference in activation of retinoic acid-induced genes.

Abstract 3844: Venous thromboembolism in patients with pancreatic cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Venous thromboembolism (VTE) is a critical complication of malignant disease. Pancreatic cancer is one of the cancers most commonly associated VTE. In general, the VTE incidence rate of Asians is lower than that of Caucasians. In 2007, a Korean study reported that only four cases of VTE (5.3%) occurred in Seventy five patients with advanced pancreatic adenocarcinoma. We evaluated VTE incidence in pancreatic cancer and characteristics of pancreatic cancer patients with VTE. Method: We retrospectively reviewed the medical records of patients with histopathologically proven pancreatic cancer from January 2006 to December 2012 at Soonchunhyang university hospital. We detected VTE through CT (chest CT, pulmonary embolism CT) and low extremity ultrasoundgraphy. Results Five hundred and fourteen patients with pancreatic adenocarcinoma were enrolled. (M: F, 300:214, localized: locally advanced: metastatic=31:230:253, mean age: 66.7 years). Ninety six of 514 patients (18.6%, symptomatic: aymptomatic=38:58, PE: DVT: PE+DVT: visceral thrombosis=20:19:19:38) were diagnosed as VTE. At the time of DVT diagnosis, cancer status of 50 patients cancer was progression, and that of 15 was stable. Thirty one patients were diagnosed with the pancreatic cancer and VTE, at the same time. They all had metastatic lesions. Fifty VTE patients were treated with antithrombotic therapy. Ninety three of 96 patients died, and three of them have probability that cause of death was VTE. The others died of pancreatic cancer progression. From pancreatic cancer diagnosis to VTE diagnosis, the period is 1.7month. (95%CI 1.1-2.3 month). Median overall survival (OS) was not significantly different between pancreatic cancer with VTE or without VTE. OS was significantly longer VTE patients after pancreatic cancer diagnosis than VTE patients with pancreatic cancer at the same time (10.73m vs. 1.7, p=0.00). Conclusion The incidence of VTE (18.6%) in Soonchunhyang university hospital with pancreatic cancer was not lower than that in western groups. Citation Format: Seug Yun Yoon, Namsu Lee, Sook-Ja Kim, Hee-Jeong Cheong, Kyoung Ha Kim, Jong-Ho Won, Hee Sook Park. Venous thromboembolism in patients with pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3844. doi:10.1158/1538-7445.AM2014-3844

Abstract 3843: Pulmonary toxicities of molecular targeted antineoplastic agents

Background A better understanding of cancer cell biology has suggested many new targets for cancer drug discovery and development. And these drugs are widely used in treating cancer and usually have good toxicity profiles. But some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities. Among the toxicities, pulmonary toxicities are infrequent with most commonly used targeted therapies. The aim of this study was to review the pulmonary toxicities caused by molecular targeted agents and analyze the various radiologic findings and clinical outcomes in these patients group. Methods We retrospectively reviewed the medical records and chest image findings of 549 patients who were treated by molecular targeted anti-neoplastic agents at Soonchunhyang University Hospital between May 2003 and September 2012. Patients who had chest image findings that suspected infection, pulmonary hemorrhage caused by other cause and primary disease progression were excluded. Results Of these 549 patients, 364 patients performed chest CT or HRCT during targeted agent therapy. Thirty-four patients (6.2%) with drug induced pulmonary toxicities confirmed by radiologist and oncologist were identified. The most common targeted agent that induced pulmonary toxicities was gefitinib (9/34 patients), followed by rituximab, imatinib, erlotinib, cetuximab, trastuzumab, bevacizumab, bortezomib, and dasatinib. Pneumonitis (44.1%) and pleural effusion (32.4%) were common radiological findings. Dyspnea was the main presenting initial symptom and proportion in symptomatic patients (18/34 patients, 52.9%) was mostly 83.3% (15/18 patients). Sixteen patients stopped being treated with targeted agents, 11 patients were simultaneously treated with glucocorticoids. Sixteen patients did not receive any other treatment and were observed with regular follow ups. Of 34 patients, 20 patients (58.8%) resolved pulmonary toxicity from chest CT imaging. There were four patients (11.7%) who died from drug related pulmonary toxicity. Conclusion Pulmonary toxicities caused by targeted agents are rare but important to recognize. Dyspnea appears to be the main presenting symptom. In conclusion, we should be aware of pulmonary toxicities and symptoms presenting dyspnea during targeted agent therapy. If we suspect drug induced pulmonary toxicities, we should perform immediate imaging studies and keep a possibility of variable radiological patterns in mind. The cessation of the implicated causative targeted agents and treatment with systemic glucocorticoids resulted in an improvement both in symptoms and image findings, but fatal pulmonary toxicities occurred in some patients. Citation Format: Seug Yun Yoon, Namsu Lee, Sook-Ja Kim, Hee-Jeong Cheong, Kyoung Ha Kim, Jong-Ho Won. Pulmonary toxicities of molecular targeted antineoplastic agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3843. doi:10.1158/1538-7445.AM2014-3843