School Of Health Sciences
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Item Studies on Genomic Alterations in HER2-Positive Breast Cancer–Focus on Design, Synthesis & Evaluation of Anilinoquinazoline Analogues as Potential HER2 inhibitors(Central University of Punjab, 2019) Singla, Heena; Munshi, Anjana; Kumar, VinodHuman epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is an aggressive breast cancer subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. The current study was carried out to identify genomic alterations associated with HER2-positive breast cancer and evaluate their association with clinical outcome in response to trastuzumab therapy given to HER2- positive breast cancer patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes implicated in the disease. In addition, 20 formalin fixed paraffin-embedded (FFPE) tissue samples were also evaluated by GSA for identifying significant variations associated with the disease as well as response to trastuzumab therapy. A germline variant in HER2 gene (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2-positive breast cancer tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2-positive breast cancer. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA. Development of resistance and disease-relapse are the major problems associated with trastuzumab. Tyrosine-kinase inhibitors (TKIs) present better option to address the issues associated with trastuzumab. However, problems of resistance and ineffectiveness as monotherapy; persist with the currently available TKIs as well. We synthesized anilinoquinazoline-based compounds and evaluated them for anti-proliferative activity against HER2-positive breast cancer. Of the synthesized compounds (HS-2, HS-3, HS-5, HS-8 and HS-9), three (HS-3, HS-5 and HS-8) were evaluated for biological activity. HS-8 proved to be most-effective against SKBR3 (HER2-positive breast cancer cells) (IC50=2.8µM) iv with a lesser cytotoxicity towards the MDA-MB-231 (Triple-negative breast cancer cells) (IC50=3.2µM) and no toxicity towards FR-2 (normal breast epithelial cells).Item Analysis of pro‐ and anti‐inflammatory cytokine gene variants and serum cytokine levels as prognostic markers in breast cancer(Wiley, 2018) Kaur, Raman Preet; Vasudeva, Kanika; Singla, Heena; Benipal, Raja Paramjeet Singh; Khetarpal, Preeti; Munshi, AnjanaThe aim of current study was to evaluate the genetic variation in all the genes encoding pro‐ and anti‐inflammatory cytokines in association with breast cancer development in patients from Malwa region of Punjab. The importance of the levels of interleukin (IL)‐17, tumor necrosis factor, interferon γ, IL‐10, IL‐6, IL‐4, and IL‐2 with respect to clinicopathological data, prognosis, and disease‐free survival was also determined in these patients. Two hundred and fifty female breast cancer patients and 250 age‐matched controls were screened for variations in cytokine‐encoding genes using global screening array microchip and PCR‐RFLP. The level of cytokines was estimated in 150 patients and 60 age‐matched controls using BD™ Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit by BD Accuri flow cytometer. The difference in cytokine levels was evaluated by Mann–Whitney test. No significant variation in the genes encoding various cytokines was found between patients and controls. Out of the seven cytokines evaluated, the levels of IL‐6 and IL‐17a were found to be significantly high in patients in comparison with controls ( p = 0.001 and 0.02, respectively). The elevated levels of these cytokines are also associated significantly with poor outcome. We did not find any specific variation in the genes encoding various cytokines between patients and controls. However, there was a significant difference in the serum levels of IL‐6 and IL‐17a between patients and controls, and the elevated levels of these two cytokines associated significantly with poor outcome in breast cancer patients and, therefore, can be used as prognostic markers.Item Recent updates on the therapeutic potential of HER2 tyrosine kinase inhibitors for the treatment of breast cancer(Bentham Science Publishers B.V., 2018) Singla, Heena; Munshi, Anjana; Banipal, Raja Paramjit Singh; Kumar, VinodHER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer. ? 2018 Bentham Science Publishers.Item Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies(Elsevier Masson SAS, 2017) Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, AnjanaHER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. ? 2017 Elsevier Masson SAS