Thyroid cancer is one of the most common endocrine cancers, with an increasing trend in the last few decades. Although papillary thyroid cancer is the most frequent subtype compared with follicular or anaplastic thyroid cancer, it can dedifferentiate to a more aggressive phenotype, and the recurrence rate is high. The cells of follicular adenomas and follicular carcinomas appear identical in cytology, making the preoperative diagnosis difficult. On the other hand, anaplastic thyroid cancer poses a significant clinical challenge due to its aggressive nature with no effective therapeutic options. In the past several years, the roles of genetic alterations of thyroid tumors have been documented, with a remarkable correlation between genotype and phenotype, indicating that distinct molecular changes are associated with a multistep tumorigenic process. Besides mRNA expression profiles, small noncoding microRNA (miRNA) expression also showed critical functions for cell differentiation, proliferation, angiogenesis, and resistance to apoptosis and finally activating invasion and metastasis in cancer. Several high-throughput sequencing studies demonstrate that miRNA expression signatures contribute clinically relevant information including types of thyroid cancer, tumor grade, and prognosis. This review summarizes recent findings on miRNA signatures in thyroid cancer subtypes.

Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED. Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1754.

Prostate cancer (PCa) is the second most common cancer in American men, with men of African ancestry (AA) having twice the mortality of men of European ancestry (AA). Although taxane-based chemotherapy is the last line of defense in men with advanced PCa, it ultimately fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of advanced PCa. Specifically, PSMA radioligand therapy (PSMA-RLT) is a theranostics (therapy + diagnostics) option for men with advanced PCa. However, about 30% of men with advanced PCa have limited response to PSMA-RLT due to the presence of neuroendocrine-like PCa (NEPC), which lacks PSMA expression. A promising alternative to PSMA targeting is the glycolytic enzyme enolase (ENO), which localizes to the cell surface in advanced tumors. There are three enolases with similar functions, with ENO-1 and ENO-2 implicated in PCa. Previously, we showed that AA and EA men with PCa show differential serum antibody reactivity to ENO. While circulating serum antibodies from EA-PCa patients recognized ENO in both docetaxel (DTX)-sensitive and -resistant PCa cell lines, sera from AA-PCa men only recognized ENO in DTX-sensitive cells, with loss of immunoreactivity in the resistant cells. Here, we demonstrate, using immunoblotting and specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, DTX-resistant cells only express ENO-1 with a clear loss of ENO-2. This pattern is identical to that produced by the AA-PCa serum antibodies, suggesting the possibility that AA-PCa patients may generate a preferential antibody response to ENO-2, with EA-PCa patients preferentially targeting ENO-1. This differential immunoreactivity may reflect differences between AA and EA PCa patients in tumor immunobiology, consistent with emerging literature. The loss of ENO-2 in chemoresistant PCa cells also generates a metabolic vulnerability due to the loss of ENO redundancy. We hypothesize that ENO-1 is expressed on the surface of NEPC cell lines and can be targeted with small molecule inhibitors (SMIs) that could be used as potential theranostics agents. Current studies are identifying ENO-1 surface expression on NEPC cell lines using monoclonal antibodies as well as AA and EA patient antibodies, via immunofluorescence microscopy, membrane fractionation analysis, and flow cytometry. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant NEPC cells. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel theranostics target. This could benefit AA-PCa patients, which may not mount a strong antitumor ENO-1 immune response. Citation Format: Krystal R. Santiago, Alfonso M. Duran, Carlos A. Casiano, Frankis G. Almaguel, Bhaskar Das. Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C063.

Filipino Americans (FA) are known to have a higher incidence, recurrence, and mortality of thyroid cancer (TC) than other Asians Americans or European Americans (EA). Understanding the molecular mechanisms that underpin the genetic defect in metabolism and their impact on thyroid cancer oncogenesis in FA are critical for addressing the health disparity. Mechanisms that link genetic defects and lifestyle factors to thyroid cancer progression have not been defined. Lifestyle and genetic variations among FA lead them to a higher risk of metabolic diseases but no study showed to elucidate the mechanism of thyroid health disparities cancer so far. Recent studies clearly demonstrate that miRNA plays an important role in carcinogenesis via targeting both oncogene and tumor suppressor gene and lifestyle changes may potentially alter miRNA signatures. Therefore, we hypothesize that miRNA expression contributes to tumor grade, prognosis, and thyroid cancer health disparities. We examined miRNA expression profiles in FA vs. EA. We analyzed miRNA-sequence (miRNA-seq) by next-generation sequencing (NGS). The pathways linked to miRNAs were analyzed by ingenuity pathway analysis (IPA) software. Correlations between disease staging to miRNA upregulation and downregulation were elucidated. Both upregulated and downregulated miRNAs were validated by quantitative real-time PCR (qPCR) using miRNA extracted from paraffin-embedded thyroid tissues. We found hundreds of upregulated and downregulated miRNA and piRNA from this study. We chose 10 miRNA down-regulated, and 10 up-regulated miRNA FA compared to EA TC patients (p<0.05). Quantitative PCR (qPCR) was done to confirm our NGS data. Differential miRNA expressions between FA vs. EA patient tumor tissues were observed with advanced staging. Evolutionarily conserved miRNA clusters, which are known to initiate malignancy, were shown to be upregulated in FATC vs. EATC. While those miRNAs are known to regulate pathways involved in cancer invasion and metastasis, they were shown to be down-regulated in FATC patients vs. EATC. The significantly top ten down-regulated/upregulated miRNA-signature suggests that it can be a diagnostic, prognostic, and predictive biomarker in TC health disparities. Citation Format: Ryan Davis, Yan C Wongworawat, Mia C Perez, Krystal Santiago, Saurav Roy, Charles Wang, Alfred A Simental, Salma Khan. Upregulated and downregulated microRNA-signatures in thyroid cancer health disparities [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B093.