Ovarian cancer remains one of the most lethal diseases for the female reproductive system with 22,530 new cases and more than 13,980 deaths predicted for 2019 in the United States alone, according to the American Cancer Society. Currently, there is no effective therapy for ovarian cancer patients, in particular for those who become resistant to chemotherapy (cisplatin). We need to identify novel targets for ovarian cancer therapy. We performed RNA deep-sequencing studies in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Several RNA (messengers and long noncoding) were differentially abundant in cisplatin-resistant versus cisplatin-sensitive cells. Many of these RNAs have not been previously studied in ovarian cancer. Therefore, we performed rigorous bioinformatic studies that included data filtering and survival rates (using Kaplan-Meier plot analysis) and IPA (Ingenuity Pathway Analysis) to select key candidate genes that can be used as potential targets for ovarian cancer therapy. Additional data filtering was used to select a list of candidate genes whose expression correlates with the overall survival and progression-free survival of ovarian cancer patients. Future experiments will investigate the biologic consequence of targeting each of these candidate genes in ovarian cancer cells and ovarian cancer mouse models. Citation Format: Ricardo Noriega, Jeyshka Reyes, Blanca Quiñones, Joseline Serrano, Pablo Vivas, Josué Pérez. Identification of novel targets for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A57.
Cytoreductive surgery in combination with platinum-based chemotherapy has been used for more than four decades for treat ovarian cancer. Although initially most ovarian tumors respond well to cisplatin treatment, many of those tumors become resistant to chemotherapy. Although many mechanisms of cisplatin resistance have been proposed, the molecular mechanism leading to the cisplatin resistance in ovarian cancer tumors has not been fully understood. In this study, we sought to identify novel proteins associated with the cisplatin resistance of ovarian cancer cells. A proteomic analysis showed 48 proteins differentially abundant in cisplatin-resistant (A2780CP20) compared to their counterpart cisplatin-sensitive (A2780) ovarian cancer cells. The quantitative analysis revealed low protein levels of Enolase-1 (ENO1) in A2780CP20 cells. Small-interference RNA (siRNA)-targeted ENO1 showed a reduction in the sensitivity of ovarian cancer cells to cisplatin treatment. In contrast, ectopic expression of ENO1 in cisplatin-resistant ovarian cancer cells reduced the sensitivity of these cells to cisplatin treatment. Since ENO1 is an enzyme involved in glucose metabolism, we evaluated ovarian cancer cells’ metabolic state by measuring their glucose consumption. Intracellular glucose uptake was measured in pairs of cisplatin-sensitive and cisplatin-resistant cells. The glucose content levels were higher in all cisplatin-resistant cells compared with their -sensitive counterparts. Overall, these results suggest that low levels of ENO1 are associated with the cisplatin resistance of ovarian cancer cells. Therefore, targeting the glycolytic pathways could be a strategy to overcome the cisplatin resistance of women with advanced and drug-resistant ovarian cancer. Citation Format: Robert J. Rabelo-Fernandez, Yasmarie Santana, Nilmary Grafals, Blanca Quiñones, Ginette Santiago, Eunice Lozada, Jeyshka Reyes, Pablo E. Vivas-Mejía. Increasing intracellular glucose levels decreased expression of Enolase-I promoting cisplatin resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A68.
Glioblastoma Multiforme (GBM) is the deadliest type of primary brain tumor being responsible for more than 14,000 deaths annually. The survival rate of GBM patients from time of diagnosis is 5 months if left untreated and 15 months with standard care of treatment. Despite great research efforts in the last 30 years, GBM survival rate has only increased by 2%. This is mostly due to high recurrence, treatment resistance, and the existence of the blood brain barrier (BBB) which restricts drug delivery to the tumor tissue. Therefore, the development of novel therapeutic modalities able to cross the BBB is urgently needed. MicroRNAs (miRNAs) are small (18-22 nt.) non-coding RNAs that regulate gene expression at the post-transcriptional level by binding to the 3’UTR of target mRNAs. Several dysregulated miRNAs have been reported in all tumor types, including GBM. Targeting oncogenic miRNAs with oligonucleotide miRNA inhibitors (OMIs) in vitro has shown therapeutic potential. However, in vivo administration requires the development of nanocariers capable of increasing the stability of OMIs in circulation and improving their delivery to target tissues. In addition, nanocarriers that can overcome the BBB are needed. The most studied and promising nanocarriers are gold nanoparticles (AuNP) and liposomes. While AuNPs have bioimaging and microscopy advantages, liposomes are clinically preferred. Therefore, we propose encapsulating OMIs-AuNPs to BBB targeted liposomes. In this study we present the characterization of miRNA inhibitors conjugated to AuNP. Briefly, 15 nm AuNP were functionalized to OMIs by two different techniques: Salt aging functionalization method and PEG and surfactant assisted conjugation method. Afterwards, both nanoconjugates were analyzed for particle size, zeta potential and loading capacity. The PEG and surfactant assisted functionalization proved to be superior in all of the analysis, resulting in 30 nm OMIs-AuNPs with a zeta potential of -8 mV and a loading capacity ratio of 64 oligonucleotides per AuNP. Further characterization studies such as cell internalization and cytotoxicity are under evaluation. Citation Format: Nilmary Grafals, Blanca I. Quiñones, Pablo E. Vivas, Gabriel Barletta. Targeting microRNAs in brain tumors with oligonucleotide nanoparticle conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3105. doi:10.1158/1538-7445.AM2017-3105
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