Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.

MYC, a well-studied proto-oncogene that is overexpressed in >20% of tumors across all cancers, is classically known as “undruggable” due to its crucial roles in cell processes and its lack of a drug binding pocket. Four decades of research and creativity led to the discovery of a myriad of indirect (and now some direct!) therapeutic strategies targeting Myc. This review explores the various mechanisms in which Myc promotes cancer and highlights five key therapeutic approaches to disrupt Myc, including transcription, Myc-Max dimerization, protein stability, cell cycle regulation, and metabolism, in order to develop more specific Myc-directed therapies.

One approach to protect new-borns against respiratory syncytial virus (RSV) is to vaccinate pregnant women in the last trimester of pregnancy. The boosting of circulating antibodies which can be transferred to the foetus would offer immune protection against the virus and ultimately the disease. Since non-human primates (NHPs) have similar reproductive anatomy, physiology, and antibody architecture and kinetics to humans, we utilized this preclinical species to evaluate maternal immunization (MI) using an RSV F subunit vaccine. Three species of NHPs known for their ability to be infected with human RSV in experimental challenge studies were tested for RSV-specific antibodies. African green monkeys had the highest overall antibody levels of the old-world monkeys evaluated and they gave birth to offspring with anti-RSV titers that were proportional to their mother. These higher overall antibody levels are associated with greater durability found in their offspring. Immunization of RSV seropositive AGMs during late pregnancy boosts RSV titers, which consequentially results in significantly higher titers in the vaccinated new-borns compared to the new-borns of unvaccinated mothers. These findings, accomplished in small treatment group sizes, demonstrate a model that provides an efficient, resource sparing and translatable preclinical in vivo system for evaluating vaccine candidates for maternal immunization.

For decades, chemotherapy has remained the standard of care for ovarian cancer patients. Although 70% of patients initially respond to platinum-based therapy, >90% succumb to chemoresistance. There is a need to uncover targeted drugs for ovarian cancer. A quicker, more cost-effective, and lower-risk route to identify new treatments is through repurposing FDA approved drugs. Using a computational drug repositioning platform, DrugPredict, we previously uncovered that the antiarrhythmic drug amiodarone potently decreases cell viability and triggers apoptosis in numerous patient-derived ovarian cancer cell lines through the degradation of c-Myc. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship to identify DL78, which lacks hERG activity but retains the anti-cancer properties and ability to regulate Myc. DL78 is significantly more potent and tumor specific than amiodarone. It rapidly induces G2/M arrest which ultimately leads to loss of Myc, mitotic catastrophe, and apoptosis in several types of cancer cells. Furthermore, pharmacokinetics studies show that the compound is retained in the tumor upon intraperitoneal injection and has reasonable solubility and permeability, yielding good absorption, distinct from amiodarone. Given its structural and molecular differences, we expect that DL78 works through a different mechanism that amiodarone and could represent an effective treatment for ovarian cancer and other MYC-driven tumors. Additional studies will establish the foundation for further development of this novel compound, as well as reveal targeted ovarian cancer vulnerabilities. Citation Format: Jessica McAnulty, Michele Dziubinski, Agharnan Gandhi, Margaret Farah, Pil Lee, Andrew D. White, Analisa DiFeo. Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4003.

Rodents are macrosmatic; they depend heavily on the olfactory system, which includes the olfactory bulb and anterior piriform cortex, to navigate their environment. The olfactory system is key to the survival of neonatal pups in order to learn the scents of the dam, which aid in nipple attachment and overall attachment to the caregiver. This attachment‐based learning was mimicked in rodents using a laboratory‐based experimental design in which neonatal pups were classically conditioned to associate the novel scent of peppermint with stroking, an action that mimics sensory cues associated with caregiving. The effects of attachment‐based learning on mRNA levels of epigenetic regulators, as well as epigenetic modifications of Bdnf and Reln, genes involved in neuroplasticity, are unknown.We investigated changes in gene expression of Bdnf, Reln, and epigenetic regulators (DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC2, HDAC5, TET1, Gadd45B, and MeCP2) following infant olfactory learning. Using an odor‐stroke paradigm, Long‐Evans rat pups (postnatal days 6 or 7) (n=46) were assigned to either a paired (simultaneous peppermint odor and stroking), unpaired (non‐simultaneous peppermint odor and stroking), or odor‐/stroke‐only condition. Brains were harvested 30 minutes after conditioning. Using Real‐time PCR, we found experience‐induced changes in gene expression profiles in both brain regions. For example, Bdnf exon IV gene expression in the olfactory bulb significantly increased in rats that received contiguous presentation of both stimuli; however, gene expression of HDAC2, HDAC5, TET1, and Gadd45B significantly decreased in the same subjects. In the anterior piriform cortex, there were significant increases in gene expression of Bdnf exons I and IV, DNMT3b, and Gadd45B in both paired and unpaired subjects. Understanding the unknown epigenetic modifications involved in attachment‐based learning may elucidate the mechanisms of the emotional connection an infant learns for the caregiver and its profound influence on neurological development.Support or Funding InformationSpecial thanks to Dr. Roth and Tiffany Doherty for their support and guidance along with Lauren Webb's and Tiffany's completion of odor‐stroke conditioning. This research is funded through grants P20GM103653, R01HD087509, and private donation funds to Dr. Roth.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.