Goodison, Steven

AbstractThe etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor–negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women.

Abstract Cancer treatment is complicated when patients develop resistance to standard therapies. Hence, developing strategies to address resistance to chemo therapy and improving therapeutic efficiency is of great importance in treating cancer successfully. Results from various preclinical studies showed that specificity protein (Sp) transcription factors regulate key genes associated with tumorigenesis, angiogenesis, and metastasis in several cancer models. Sp1 and Sp3 modulate the expression of survivin, an inhibitor of apoptosis protein (IAP) and we previously showed that targeting Sp transcription factors induced the response to radiation in pancreatic cancer cells and mice tumors. Research from our laboratory and others demonstrated the anti-cancer activity of a small molecule Tolfenamic Acid (TA) in some preclinical models of cancer including pancreatic cancer. It has been proposed that the anti-cancer activity of TA is associated with modulation of Sp proteins; however the precise underlying mechanisms are not extensively known. In this investigation, we have conducted a molecular profiling analysis in three pancreatic cancer cell lines, Panc1, L3.6 pl and MiaPaCa2 to elucidate the mechanisms involved in the anti-cancer activity of TA. We also evaluated the potential of TA for improving the therapeutic efficacy of chemotherapeutic agents in pancreatic cancer cell lines and mice xenografts using two standard chemotherapeutic agents, 5-Flurouracil (5FU) and gemcitabine (GEM). Human pancreatic cancer cells, Panc1, L3.6pl and MiaPaCa2 were treated with 5FU or GEM or TA for 24-72 h to establish the dose curves. After monitoring the time/dose-response curves, optimized doses were used for the combination treatment. Cells were treated 5FU or GEM or TA or combinations (5FU+TA or GEM+TA) and the cell viability was measured at 48 h post-treatment. The tumor growth inhibitory response of individual and combination treatment was determined in mice xenografts. Nude mice were treated with 5FU (40 mg/kg, 3 times/wk for 2 wk) or GEM (50 mg/kg, 2 times/wk for 2 wk) or TA (50 mg/kg, 3 times/wk for 4 wk) or TA+5FU or TA+GEM as per the established methods. After the termination of the experiment, animals were euthanized; tumors were harvested and measured to determine the changes in tumor weight and volume. Analysis of molecular profiling revealed that Sp1 and survivin are among the top candidates modulated by TA treatment; however TA modulates many genes associated with cancer and cell survival. The combination treatment experiments showed a significant increase in the anti-proliferative response of 5FU or GEM when used along with TA. Mice xenograft experiments also confirmed that TA enhanced the tumor growth inhibitory response of 5FU or GEM. Experiments using drug-resistant cell lines and functional studies to understand the underlying mechanisms of these combination therapies are ongoing. These preclinical studies support the potential of TA for chemo sensitization and induction of the therapeutic response of standard chemotherapeutic agents in pancreatic cancer. Since enhancing the responses of standard therapeutic options is highly beneficial in treating cancer, these findings may lead to advances in developing novel strategies for treating aggressive malignancies like pancreatic cancer. Financial Support: Shirley E. Noland Foundation; UFHCC, Orlando Health, Orlando, FL and Institute for Cancer Research, UNT Health Science Center, Fort Worth, TX. Citation Format: Umesh T. Sankpal, Steven Goodison, Omar Kayaleh, Riyaz Basha. Tolfenamic acid induces the response of chemotherapy in pancreatic cancer: Preclinical study. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A03.