Search

Introduction & background: Ten to 20 % of patients of Chronic Myeloid Leukemia in chronic phase (CML CP) have suboptimal molecular response (MR) to first line Imatinib maleate (IM). Treatment options include IM dose increase or switch to a 2nd generation tyrosine kinase inhibitor (TKI), Nilotinib or Dasatinib. Recently, synergy has been demonstrated when PPAR γ agonists are added to TKIs. We describe our initial results on 15 patients of CML CP treated with the combination of IM and pioglitazone, a PPAR γ agonist. Patients and methods: Fifteen patients of CML CP with suboptimal MR (bcr/abl:abl RQ-PCR between 1 to 10) after more than two years of IM were recruited in this pilot study. Because of economic considerations, these patients were not candidates for 2nd gen. TKIs. Patients given IM 600 mg/day and pioglitazone 30 mg/day. Blood counts and biochemistry monitored monthly, bcr/abl tested every 3 months using a cartridge based IS assay using the Cepheid GenXpert. Results & conclusions: Twelve of the 15 patients achieved significant MR, with 6/16 achieving a major MR at 9 months. Only 3/15 did not show a response (Table). Treatment with pioglitazone was well tolerated. One patient was not analysed due to intolerance to pioglitazone are first dose. Two patients had grade 1 elevation of hepatic enzymes which returned to normal after one week treatment cessation. We conclude that the combination of imatinib with pioglitazone is effective and well tolerated in patients with a sub-optimal MR to TKI in patients with CML-CP. The combination could be a cost-effective strategy in treating imatinib non/sub-optimal responders in the developing world. The combination needs further and larger studies for confirmation and evaluation of the mechanisms of the synergy. S. No.Patient ID/SexDiagnosis dateBCR-ABL (Before Pio)BCR-ABL (After Pio)At 3 monthAt 6 monthAt 9 month1SCM/MOct 20125.352.741.830.0052MD/FAug 20061.130.880.480.13GPJ/MJan 20142.860.43ND0.54RRC/MOct 20082.861.070.25ND5RK/MMar20081.390.770.350.416RDS/FOct 200010.15.994.870.677RDR/FApril 20039.045.780.360.058MM/MMay 20114.48NDND0.149RD/FJuly 20108.331.290.440.7310RB/FJuly 20153.253.022.891.3911BRR/MJan 20107.135.613.821.7712BK/FNov 20042.060.040.030.0713DPS/MJan 20116.155.471.020.8414JKM/MApril 20074.2215.49.117.6215CS/MOct 20121.721.170.840.08 Citation Format: Hemant Malhotra, Ajay Yadav, Ashwin Mathur, Debashish Biswas, Bharti Malhotra. PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1835.

The Bmi-1 oncogene is overexpressed in a number of malignancies including breast cancer. In addition to Bmi-1, mammalian cells also express four other polycomb group (PcG) proteins that are closely related to Bmi-1. Virtually nothing is known about the role of these PcG proteins in oncogenesis. We have recently reported that Mel-18, a Bmi-1–related PcG protein, negatively regulates Bmi-1 expression, and that its expression negatively correlates with Bmi-1 in proliferating and senescing human fibroblasts. Here, we report that the expression of Bmi-1 and Mel-18 inversely correlates in a number of breast cancer cell lines and in a significant number of breast tumor samples. Overexpression of Mel-18 results in repression of Bmi-1 and reduction of the transformed phenotype in malignant breast cancer cells. Furthermore, the repression of Bmi-1 by Mel-18 is accompanied by the reduction of Akt/protein kinase B (PKB) activity in breast cancer cells. Similarly, Bmi-1 knockdown using RNA interference approach results in down-regulation of Akt/PKB activity and reduction in transformed phenotype of MCF7 cells. Importantly, we show that overexpression of constitutively active Akt overrides tumor-suppressive effect of Mel-18 overexpression and the knockdown of Bmi-1 expression. Thus, our studies suggest that Mel-18 and Bmi-1 may regulate the Akt pathway in breast cancer cells, and that Mel-18 functions as a tumor suppressor by repressing the expression of Bmi-1 and consequently down-regulating Akt activity. [Cancer Res 2007;67(11):5083–9]

Background: There are very few options for the treatment of patients of SCCHN who relapse after surgery and/or radiotherapy and/or chemotherapy other than best supportive care (BSC). Over expression of the EGFR has been demonstrated in more than 80% of patients with SCCHN. In the present study, we compared the response rates, overall survival, toxicity profile and quality of life in patients of recurrent SCCHN receiving oral methotrexate versus a combination of EGFR inhibitor (Gefitinib) + COX II inhibitor (Etoricoxib). Patients and Methods: Twenty five patients of Advanced and Recurrent HNSCC were included in each group. Patients were randomly assigned to receive Gefitinib (250 mg twice a day before meals) plus Etoricoxib (120 mg/day) [Group A] or Oral Methotrexate (15 mg/week) [Group B]. All patients received BSC. Patients were follow-up 4 weekly with routine blood investigations and quality of life questionnaires - QLQ C-30 and QLQ H & N-35. CT scan of Head and Neck was done every 8 weeks. EGFR mutation studies were not performed. Results : Partial Response (PR) was seen in 6.25% of patients in group-A; and 0% from group-B. Stable Disease (SD) observed in 25% of patients from group-A and 10% patients from group-B. At the end of study, mean overall survival (OS) in group-A was 107.15 days; whereas mean overall survival in group-B was 73.95 days. The difference in survival was statistically significant (P Conclusions: In this small pilot study, in patients with advanced and recurrent SCCHN, dual targeted treatment (EGFR and COX II) with combination of Gefitinib plus Etoricoxib improved response rates, quality of life and overall survival as compared to oral methotrexate. The combination was well tolerated with minor side-effects and should be considered in this poor prognostic subset of patients. Larger, multi-centric studies are needed to confirm these results. Citation Format: Hemant Malhotra, Archit Joshi, Sandeep Jasuja, Ajay Yadav. Gefitinib [epidermal growth factor receptor (EGFR) inhibitor] plus etoricoxib (COX-2 inhibitor) versus oral methotrexate in advanced, recurrent head and neck squamous cell carcinoma (HNSCC): results of a randomized pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2582. doi:10.1158/1538-7445.AM2015-2582

Introduction: Aberrant activation of the Epidermal Growth Factor Receptor (EGFR) oncoprotein is a molecular hallmark of glioblastomas. Two-thirds of tumors with excessive EGFR activation show alteration of the EGFR gene. The mechanism of deregulation of EGFR in the other third remains poorly understood. Nuclear factor of κB inhibitor alpha (NFKBIA) is a potential tumor suppressor. Methods: Multidimensional molecular profiles for NFKBIA and EGFR and clinical profiles of 732 malignant glioma patients from multiple academic institutions, The Cancer Genome Atlas Pilot Project, the Repository of Molecular Brain Neoplasia Data, and a randomized phase III trial of temozolomide. NFKBIA mutational and functional analyses in a glioblastoma cell model. Results: We found that about 25% of glioblastomas harbor heterozygous NFKBIA gene deletions at chromosome 14q13. NFKBIA functions as a haploinsufficient tumor suppressor in glioblastomas by terminating EGFR signaling. Tumors with NFKBIA deletion lacked EGFR amplifications, indicating functional redundancy of both genetic events in glioblastoma pathogenesis. Loss of NFKBIA gene dosage was significantly associated with briefer patient survival. Patients with low NFKBIA expression had a significantly worse outcome than patients with intact NFKBIA expression. NFKBIA expression was also significantly associated with patient survival in subsets of tumors with unmethylated promoter of the O6-methylguanine DNA methyltransferase (MGMT) gene. A combined outcome predictor model of NFKBIA and MGMT proved highly predictive of duration of survival. Conclusion: Deletion of NFKBIA is an alternative mechanism for tumorigenic increase in EGFR signaling in glioblastomas. NFKBIA inactivation is associated with shorter survival of patients with malignant gliomas. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1789.