Immunotherapy: An Emerging Modality to Checkmate Brain Metastasis

The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche and metabolic reprogramming via regulation of their target genes. However, the role of miRNA in breast cancer brain metastasis (BCBM) is poorly explored. Thus, identification and understanding of miRNAs in the pathobiology of BCBM may identify a novel candidate miRNA for the early diagnosis and prevention of this devastating process. In this review, we focus on understanding the role of candidate miRNAs in the regulation of BC brain metastatic processes as well as designing novel miRNA-based therapeutic strategies for BCBM

Evaluation of FOXM1 inhibitor (FDI-6) as a potential therapeutic molecule for small cell lung cancer

Lung cancer is the leading cause of cancer deaths accounting for about 22% of all cancer related cases in both males and females. Lung cancers are broadly grouped into two types mainly small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with SCLC accounting for about 15% of all lung cancer cases. SCLC is different from NSCLC because in most cases it originates centrally in the bronchi and is frequently seen in smokers. SCLC is aggressive and one of the most malignant forms of tumor characterized by uncontrolled rapid growth of certain cells in the lungs. SCLC displays poor prognosis because of early-stage metastasis, acquisition of chemoresistance, and has a high rate of recurrence. One of major drivers of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that is responsible for modulating cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In order to explore properties of SCLC cancer cell lines, human non-bone metastatic SBC3, bone metastatic SBC5, H1688, and murine (RPM) cells were treated with a FOXM1 inhibitor known as FDI-6. As a transcription factor FOXMI binds sequence-specific motifs on DNA through its DNA-binding domain activating proliferation and differentiation-associated genes. Anomalous overexpression of FOXMI is a crucial characteristic in oncogenesis and the development of SCLC. FDI-6 is a novel small molecule inhibitor of FOXM1, and it works by binding directly to FOXM1 protein, to displace FOXM1 from genomic targets in SCLC cells prompting concomitant translational downregulation. Functional assays performed confirm that FDI-6 is a viable FOXMI inhibitor showing therapeutic efficacies in SCLC.https://digitalcommons.unmc.edu/surp2021/1044/thumbnail.jp

RNA-Based Therapies: A Cog in the Wheel of Lung Cancer Defense

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clinical trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies

MiR-1253 Potentiates Cisplatin Response in Pediatric Medulloblastoma by Regulating Ferroptosis

Introduction Among CNS tumors, medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four subgroups, group 3 (G3MB) tumors fare the worst. Haploinsufficiency of 17p13.3 is a hallmark of these high-risk tumors; included within this locus is miR-1253, which has tumor suppressive properties in medulloblastoma. Therapeutic strategies capitalizing on the anti-neoplastic properties of miRNAs can provide promising adjuncts that can improve efficacy while mitigating toxicity of current chemotherapeutic drugs. Objective In this study, we explored the potentiation of miR-1253 on cisplatin cytotoxicity in group 3 MB. Methods We used RNA Sequencing to isolate a putative target for miR-1253 that is upregulated in G3MB, has a poor prognostic profile, and is involved in iron balance/ferroptosis. Calein AM quenching, COX IV staining and multiple stains for iron were used to study mitochondrial vs. free cytosolic iron generation. Confocal microscopy and FACs analyses were used to examine ROS generation and lipid peroxidation. Using 2 classical group 3 MB cell lines, possessing c-Myc amplification and i17q, we determined the IC50 of cisplatin in the presence of miR-1253 expression using MTT assay. We also studied colony formation, apoptosis and oxidative stress, as cisplatin is an inducer of both. Finally, ROS and ferroptosis inhibitors were used to study effects on tumor cell rescue from miR-1253 and cisplatin therapy. Results In silico and in vitro analyses revealed upregulation of ABCB7 in G3MB cancer cells and tumors. Overexpressing miR-1253, in turn, suppressed ABCB7, revealing it as a putative target with poor survival in high-expressing MB tumors. Overexpression also led to a suppression of GPX4, a ferroptosis regulator, consequently increasing labile iron pool within the mitochondria and resulting in mtROS induction. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. In miR-1253-overexpressing cancer cells, we observed a cumulative effect on cell death and colony formation with cisplatin; treatment with ROS and ferroptosis inhibitors abrogated these effects. Conclusions We conclude that miR-1253 potentiates the ferroptotic effects of cisplatin via targeting miR-1253/ABCB7/GPX4 axis.https://digitalcommons.unmc.edu/chri_forum/1010/thumbnail.jp

Liquid Biopsies to Occult Brain Metastasis

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM

GDF15 Promotes Prostate Cancer Bone Metastasis and Colonization Through Osteoblastic CCL2 and RANKL Activation

Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis

MiR-212-3p Functions as a Tumor Suppressor Gene in Group 3 Medulloblastoma via Targeting Nuclear Factor I/B (NFIB)

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence