Cancer
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30804
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Browsing Cancer by Author "Basha, Riyaz"
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Item Association of Specificity Proteins with Hepatocellular Carcinoma Patients Survival(2022) Iloani, Nwamaka Amy; Dulemba, Victoria; Hafeez, Areeba; Bao, Serena; Basha, RiyazPresenter: Nwamaka Amy C. Iloani Authors: Nwamaka Iloani, Victoria Dulemba, Areeba Hafeez, Serena Bao and Riyaz Basha Title: Association of Specificity Proteins with Hepatocellular Carcinoma Patients Survival Background: Liver cancer is one of the most diagnosed cancers worldwide and ranks third in cancer mortality, leading to over 700,000 deaths per year. Of these liver cancers, the most common is hepatocellular carcinoma (HCC), accounting for nearly 80% of all liver cancer diagnoses. Since the current treatment options have limited improvement in prognosis over the years, identifying novel targets to induce therapeutic efficacy and reduce resistance to current therapeutic option is urgently needed. Specificity protein (Sp) transcription factors Sp1 and Sp3 are associated with incidences and poor prognosis of several cancers. Sp1 is implicated in the development and metastasis of HCC by binding to GC-rich sequences of the promoter region. Sp1 influences genetic transcription of the oncogenes encoding for the HCC by binding to gene regions such as RING1 and YY1 Binding Protein (RYBP), Ras guanine nucleotide-releasing protein 1 (RasGRP1) and many others to regulate their genetic expression. Sp3 works in a similar fashion and binds to GC and GT rich sequences in regulatory genes to affect HCC cell expression. The objective of this study is to ascertain the association of Sp1 and Sp3 expression with the survival of HCC patients using publicly available data bases. Method: Information regarding the expression levels of Sp1, Sp3, RYBP, RasGRP1 and Kaplain-Meier curves were obtained from accessing the data in the public data basses, R2 genomics visualization platform and The Cancer Genome Atlas (TCG). These data used to assess the probabilities of HCC patients with high vs low expression of Sp1 or Sp3. Results: The analysis of these data indicated significant findings. When comparing normal liver cell lines and HCC cell lines, HCC cell lines showed increased expression of both Sp1 and Sp3. The high expression of Sp1 or Sp3 is associated with decreased probability and chance of survival in comparison to individuals with decreased expression (Sp1: p< 0.027; Sp3: p< 0.0087). The survival curves of RYBP and RasGRP1 also following similar patten, however the relevance to Sp1 and Sp3 has higher impact and poor prognosis. Conclusion: Higher expressions of Sp1 and Sp3 are typically associated with poorer patient survival rates. These results suggest that the therapeutic interventions that focus on targeting Sp1, Sp3 and their downstream mechanisms have the chance for impeding HCC tumorigenesis. We are investigating the association of Sp1 and Sp3 regulated oncogenes with HCC. Investigational agents with inhibitory effect against Sp1 and Sp3 are also currently being tested against HCC proliferation. Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number (R25HL125447). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Item Investigational Agents to Target Specificity Protein1 Transcription Factor and Survivin for Inhibiting Medulloblastoma Cells Growth(2022) Bao, Serena; Kishinchandani, Sachi; Lambring, Christoffer B.; Basha, Riyaz; Sankpal, Umesh; Nwamaka, IloaniAbstract Presenter: Serena Bao Authors: Serena Bao, Sachi Kishinchandani, Briggs Lambring, Umesh Sankpal, Iloani Nwamaka, Riyaz Basha Title: Investigational Agents to Target Specificity Protein1 Transcription Factor and Survivin for Inhibiting Medulloblastoma Cells Growth Background: Medulloblastoma (MB) is a brain cancer predominantly arising in children. It accounts for 20% of all childhood brain tumors. The treatment for MB includes a combination of surgery and radiation therapy. Although around 70% of the patients have shown remission with treatment today, these therapies are associated with significant morbidity, especially in the youngest patients. Therefore, widespread interest is shown to develop more successful treatments. One potential target of cancer treatment is a protein known as survivin. Survivin inhibits cell death and is upregulated in most cancers, including MB. A transcription factor known as Sp1 upregulates survivin by binding to its promoter region. Therefore, suppressing Sp1 activities indirectly down-regulates survivin and can serve as a target for MB therapy. Our aim is to find and test appropriate investigational agents that inhibit Sp1, thereby inhibit survivin and cancer cell growth. In addition, we want to use an in silico analysis to determine the expression of Specificity protein1 (Sp1) and survivin in MB patients, and see how it correlates with the survival of these patients. It has been previously determined that the investigational agents Tolfenamic acid (TA) and its derivative copper-tolfenamic acid (CuTA) are effective at inhibiting Sp1 in some cancer cells. In this project, we investigated the growth inhibitory effect of TA and CuTA using DAOY cell line. Method: DAOY cell lines (purchased from a commercial source, American Type Culture Collection, Manassas, Virginia; IBC-2016-0038) were cultured and seeded (2,000 cells per well) in a 96 well plate. Cells were treated using increasing concentrations (0, 10, 20, 40, 80 µM) of TA or Cu-TA. After a 48-hour incubation, the viability of the sample was measured via a luminance assay using the CellTiterGlo. Dose curves were generated, and the dose required to inhibit 50% of the viability (IC50 value) was determined using Graphpad Prism Software. Data from the R2 genomics visualization platform was used to generate Kaplain-Meier curves. The presented curves compare survival probabilities in Medulloblastoma patients with high vs. low expression of Sp1 and survivin. Results: The in silico analyses using R2 genomics visualization platform demonstrated MB patients who express higher levels of Sp1 is associated with low survival time(p = 0.033). Similarly, MB patients with higher levels of survivin expression show poor prognosis (p = 0.049) As per the IC50 values, Cu-TA is 3.6 times more effective against MB cells without affecting non-cancerous cells than TA Conclusion: Higher expression of Sp1 or survivin is associated with low survival time in medulloblastoma patients. Both TA and Cu-TA are inhibiting DAOY cell growth, however, Cu-Ta is more effective than TA against MB cell line. With increased resistance to standard therapies, TA and Cu-TA potentially enhance the therapeutic efficacy of chemotherapy and radiation.Item Racial disparities in the effectiveness of treatment of Her2 positive breast cancer as measured by pathological complete response(2022) Angell, Callie; Bullock, Jolonda; Diaz, Anna; Basha, Riyaz; Narra, KalyaniPurpose: Pathologic complete response (pCR) is a surrogate marker for long term survival that can be used to evaluate neoadjuvant chemotherapy. It has been shown in a previous study that black breast cancer patients have lower pCR rates than non-Hispanic white (NHW) patients, particularly in the hormone receptor (HR) negative Human epidermal growth factor receptor 2 (Her2) positive subtype. Because John Peter Smith Hospital (JPS) has a high proportion of black patients, making up about 30% of their breast cancer patients in particular, further research on racial disparities in the treatment of Her2 positive breast cancers is needed. Methods: This retrospective study was conducted to investigate the pCR rates of Her2+ breast cancer patients treated with neoadjuvant trastuzumab based regimens. Data was obtained from the institutional registry of the JPS Oncology and Infusion Center in Fort Worth, TX. Eligible patients were diagnosed with Her2 positive breast cancer between 1/1/2016 and 12/31/2019 and underwent neoadjuvant trastuzumab based chemotherapy. Information on treatment regimen, diagnostic stage, and ER and PR status were collected as well as demographic information. pCR was collected from pathology reports from the JPS Department of Pathology and was defined as ypT0/isypN0. Results: JPS had 45 eligible patients for this study: 12 NHW, 15 black, and 11 Hispanic. 40 of the 45 patients were treated with docetaxel, carboplatin, trastuzumab, and pertuzumab, of which 21 achieved pCR. 4 of the other 5 patients who received different combinations including trastuzumab achieved pCR. Of all 45 patients, 25 achieved pCR; 8 NHW, 7 Black, and 6 Hispanic. For HR negative patients, 3 of 4 NHW, 1 of 5 black, and 3 of 5 Hispanic patients achieved pCR, for a total of 9 out of 17 patients. Conclusion: This study was limited by the number of eligible patients and should not be extrapolated to larger populations, but it shows how disparity is present in this urban safety net hospital. At JPS, only 47% of black patients and 55% of Hispanic patients achieved pCR compared to 67% of NHW patients. For HR negative cases, black patients were even less likely to achieve pCR. More research on the treatment of breast cancer for different races is necessary because they are not experiencing the same results. Studies in this area are limited and earlier trials (NEOSPHERE and TRYPHAENA) had very low numbers of black patients and did not recruit Hispanic patients. Further investigations are warranted to understand the differences between ethnicities in treating Her2 positive breast cancer. The research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number ( R25HL125447).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Item Targeting Sp1 in Ewing Sarcoma: A multi-approach method for the utilization of Mithramycin(2022) Lambring, Christoffer B.; Sankpal, Umesh; Basha, RiyazPurpose: Ewing Sarcoma (ES) is a bone and soft tissue cancer affecting young adults and children. ES mostly occurs in the bones or soft tissue of the arms, legs, and pelvis. Localized ES presents with 5-year survival rate of 70%, but metastatic 5-year survival rate is between 15% and 30%. Our laboratory is interested in combination treatments using less toxic agents to induce sensitization to chemotherapy in ES. The anti-cancer activity of an antineoplastic antibiotic, Mithramycin, against ES cells has been shown. Mithramycin inhibits Specificity protein 1 (Sp1) a marker associated with aggressive cancer cell growth and resistance to chemo/radiation therapies. However, its mechanistic effects on survivin, an anti-apoptotic protein associated with poor prognoses in multiple cancers, are continuing to be elucidated in ES. This studies purpose is to evaluate the effectiveness of Mithramycin and various combinations with other chemotherapeutics, Etoposide and Vincristine, to inhibit ES cell growth and effect various cancer related proteins. Methods: Anti-proliferative activity of Mithramycin and/or Vincristine and Etoposide against ES cell lines, TC205 and CHLA10, was evaluated using CellTiterGlo kit. Dose curves were plotted and IC50 values were determined by Sigma-Plot software. The expression of Sp1 and survivin was determined by Western blot analysis. Cell lines were obtained from Children's Oncology Group (COG). Results: Mithramycin significantly decreased ES cell line viability and showed the ability to reduce the expression of Sp1 and offer differing effects on survivin expression, indicative of anti-apoptotic mechanisms being implemented in the ES cell lines. IC50 values of both chemotherapeutics and Mithramycin were decreased by nearly 50% when used in combination and this effect was mirrored in Sp1 expression. Conclusions: Mithramycin may effectively sensitize certain ES cells and improve the response of chemotherapy while lowering necessary effective dosages. Studies to understand the mechanisms of action of Mithramycin on Sp1 and survivin are underway.