Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.

https://www.mdpi.com/2072-6694/13/16/4069/pdf

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications.

While the modern therapeutic armamentarium to treat multiple myeloma (MM) patients allows a longer control of the disease, this second-most-frequent hematologic cancer is still uncurable in the vast majority of cases. Since MM plasma cells are subjected to various types of chronic cellular stress and the integrity of specific stress-coping pathways is essential to ensure MM cell survival, not surprisingly the most efficacious anti-MM therapy are those that make use of proteasome inhibitors and/or immunomodulatory drugs, which target the biochemical mechanisms of stress management. Based on this notion, the recently realized discoveries on MM pathobiology through high-throughput techniques (genomic, transcriptomic, and other "omics"), in order for them to be clinically useful, should be elaborated to identify novel vulnerabilities in this disease. This groundwork of information will likely allow the design of novel therapies against targetable molecules/pathways, in an unprecedented opportunity to change the management of MM according to the principle of "precision medicine." In this review, we will discuss some examples of therapeutically actionable molecules and pathways related to the regulation of cellular fitness and stress resistance in MM.

/pdf/actionable-strategies-to-target-multiple-myeloma-plasma-cell-8wc2v3hib9.pdf

Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From "Omics" Research.

In this work, miRNA-10b in the glioblastoma (GBM) tumor tissues has been detected by a novel electrochemiluminescence (ECL) biosensor. Firstly, a new kind of bright luminescent Zn2GeO4:Mn NPs were prepared as ECL nanoprobe, which possessed high fluorescence quantum yield and ECL quantum efficiency. Secondly, Ti3C2 MXene hydrogel (MXG) have been developed as the sensing interface. The MXG retained the inherent biocompatibility and mechanical features of hydrogel. Furthermore, the uniform distribution of metallic Ti3C2 MXene in the hydrogel microstructure provided the good conductivity and multiple binding sites for biomolecules. MXene also can promote the separation of the electrons and holes to accelerate the electron-transfer rate and improve ECL efficiency. Due to these synergistic effects, the screen printed electrode was successfully modified with MXG as sensing platform to enhance the ECL intensity of Zn2GeO4:Mn NP, which greatly improved the detection efficiency and facilitated the high-throughput analysis. Finally, the toehold mediated strand displacement (TMSD) strategy was employed with then biosensor to detect miRNA-10b with the range of 10 fM to 1 nM. The limit of detection was 5 fM. This ECL biosensor has been used to analyze miRNA-10b expression in GBM tumor tissues, which possessed the great potential value for clinical diagnosis. 

Bright luminescent Zn2GeO4:Mn NP/MXene hydrogel-based ECL biosensor for glioblastoma diagnosis.

Introduction: The repurposing of drugs for their anticancer potential is gaining a lot of importance in drug discovery. Aims: The present study aims to explore the potential of Simvastatin (SIM), a drug used in the treatment of high cholesterol, and thymoquinone (Nigella Sativa) (THY) for its anti-cancer activity on breast cancer cell lines. Thymoquinone is reported to have many potential medicinal properties exhibiting antioxidant, antiinflammatory, anti-cancer, and activities like tissue growth and division, hormone regulation, immune response and development, and cell signaling. Methods: In this analysis, we explored the inhibitory effects of the combination of simvastatin ad thymoquinone on two breast cancer cell lines viz MCF-7 and MDA-MB-231 cells. The combined effect of simvastatin ad thymoquinone on cell viability, colony formation, cell migration, and orientation of more programmed cell death in vitro was studied. Cell cycle arrest in the G2/M phase was concomitant with the combined effect of SIM and THY persuading apoptosis and generating reactive oxygen species (ROS). Results: The cell cycle arrest in combined treatment was 8.1% on MCF-7 cells and 3.8 % for MDA-MB-231 cells an increased apoptosis was observed when cells were treated in combination which was about 76.20% and 58.15 % respectively for MCF-7 and MDA-MB-231 cells. Conclusion: It was concluded that the combined effect of simvastatin and thymoquinone stimulates apoptosis in breast cancer cells. 

Evaluation of Enhanced Cytotoxicity Effect of Repurposed Drug Simvastatin/ Thymoquinone Combination against Breast Cancer Cell Line

Glioblastoma (GBM) is the most common type of malignant brain tumor.The discovery of microRNAs and their unique properties have made them suitable tools as biomarkers for cancer diagnosis, prognosis, and evaluation of therapeutic response using different types of nanomaterials as sensitive and specific biosensors. In this review, we discuss microRNA-based electrochemical biosensing systems and the use of nanoparticles in the evolving development of microRNA-based biosensors in glioblastoma. 

MicroRNA biosensors for detection of glioblastoma.

HOXA9 Is a Novel Therapeutic Target in Multiple Myeloma.


 Despite many advances in cancer treatment, metastatic disease is estimated to be responsible for 90% of all cancer-related deaths. Current treatments for metastatic disease target various aspects of carcinogenesis but not specifically the metastatic process, representing a major unmet clinical need. MicroRNA-10b, a small non-coding RNA, offers tremendous potential as a treatment target for metastatic disease. It is implicated in invasion, migration, and viability of metastatic cells across a variety of cancer types, and it is upregulated in metastases compared to their matched primary tumor, establishing miR-10b as a potential treatment target unique to metastatic niche. We have previously developed a therapeutic targeting miR-10b in metastases and tested it in murine models of metastatic breast cancer. This therapeutic, consisting of an anti-miR-10b antisense oligonucleotide conjugated to iron oxide-based nanoparticles, prevents metastasis and eradicates pre-existing metastases in murine breast cancer models. With an outlook to clinical translation of our approach, we seek to test our therapeutic strategy in larger animal models. Feline mammary carcinomas are considered by most to be the best large animal model for human breast cancer due to similarities such as relative age of onset, histopathology, metastatic patterns, and treatment response. To support the use of this model with our therapeutic, we investigated the characteristics of miR-10b expression in spontaneous metastatic breast cancer in companion cats. Archival blocks of matched primary tumors and metastatic lymph nodes from companion cats diagnosed with mammary carcinoma (n=9, 44%TNBC, 56%HER2+) were obtained from the tissue bank of the Michigan State University (MSU) Veterinary Diagnostic Laboratory (VDL). Tissues were analyzed for miR-10b and its target HOXD10 expression using qRT-PCR and in situ hybridization. qRT-PCR revealed that miR-10b expression was significantly upregulated in 55.5% of lymph node metastases compared to their matched primary tumor, mirroring findings in human metastatic cancer. This was validated by qRT-PCR for HOXD10 gene expression (a direct target of miR-10b), which was significantly downregulated in these metastases compared to their matched primary tumor. In situ hybridization demonstrated that miR-10b expression was increased at the invasive edge of tumors and in actively invading cells, suggesting miR-10b plays a similar role in invasion in feline breast cancer as it does in human breast cancer. Altogether, these findings support the use of feline mammary carcinomas as a model of human breast cancer and as an excellent candidate for treatment with our therapeutic.
 Citation Format: Alan Halim, N. Anna Savan, Paulo Vilar Saavedra, Vilma Yuzbasiyan-Gurkan, Matti Kiupel, Lorenzo Sempere, Anna Moore. Prospective Use of Feline Mammary Carcinomas to Study MiR-10b and Metastasis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-02.

Abstract P3-08-02: Prospective Use of Feline Mammary Carcinomas to Study MiR-10b and Metastasis

Introduction: Recent studies have shown that miRNA-10b is highly expressed in high-grade glioblastoma multiforme (GBM), and its inhibition leads to deregulation of multiple pathways in tumorigenesis, resulting in repression of tumor growth and increased apoptosis. Thus, we hypothesized that suppressing miR-10b could enhance the cytotoxicity of conventional GBM chemotherapy with temozolomide (TMZ). Methods: Inhibition of miR-10b in glioblastoma cells was achieved using an experimental therapeutic consisting of anti-miR10b antagomirs conjugated to iron oxide nanoparticles (termed MN-anti-miR10b). The nanoparticles serve as delivery vehicles for the antagomirs as well as imaging reporters guiding the delivery in future animal studies. Results: Treatment of U251 and LN229 human glioblastoma cells with MN-anti-miR10b led to inhibition of miR-10b accompanied by repression of growth and increase in apoptosis. We next explored whether MN-anti-miR10b could enhance the cytotoxic effect of TMZ. During these studies, we unexpectedly found that TMZ monotherapy increased miR-10b expression and changed the expression of corresponding miR-10b targets. This discovery led to the design of a sequence-dependent combination treatment, in which miR-10b inhibition and induction of apoptosis by MN-anti-miR10b was followed by a sub-therapeutic dose of TMZ, which caused cell cycle arrest and ultimately cell death. This combination was highly successful in significant enhancement of apoptosis and decrease in cell migration and invasiveness. Discussion: Considering the unexpected effects of TMZ on miR-10b expression and possible implications on its clinical application, we reasoned that comprehensive in vitro studies were warranted before embarking on studies in animals. These intriguing findings serve as a solid foundation for future in vivo studies and offer promise for the successful treatment of GBM.

/pdf/co-administration-of-temozolomide-tmz-and-the-experimental-2i7zvkis.pdf

Co-administration of temozolomide (TMZ) and the experimental therapeutic targeting miR-10b, profoundly affects the tumorigenic phenotype of human glioblastoma cells

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HOXA9 Is a Novel Therapeutic Target in Multiple Myeloma.

Abstract P3-08-02: Prospective Use of Feline Mammary Carcinomas to Study MiR-10b and Metastasis

Co-administration of temozolomide (TMZ) and the experimental therapeutic targeting miR-10b, profoundly affects the tumorigenic phenotype of human glioblastoma cells