A Novel Small Molecule Targeting Oncogenic miR-10b in Gastric Cancer

https://openworks.mdanderson.org/sumexp21/1206/thumbnail.jp

Characterization of a novel oncogenic miRNA inhibitor in cancer therapy

As cancer research continues to move towards more personalized methods, targeted inhibitors of oncogenic drivers of cancer are found to be an innovative and promising therapeutic approach. Previously thought to be undruggable regions of the genome, RNA has become an area of increasing interest in cancer due to the identification of more targetable regions and their relationship to tumor growth and progression. This work reports on the development of IACS-13743, a novel small molecule found to directly bind and inhibit microRNA-10b. Oncogenic miR-10b has been found to be overexpressed in several malignant cancer types, making it an attractive biomarker for targeted inhibitor therapy. IACS-13743 is found to impede tumor progression and proliferation in brain cancer, gastric cancer and pancreatic cancer in vitro. This effect is also shown in a cerebral organoid model. Using a multidisciplinary approach, this study identifies a relationship between oncogenic miR-10b and the dysregulation of the PI3K/AKT pathway in cancer, along with putting forth a compound that can mitigate these effects. These findings provide a fundamental step in moving forward a targeted therapeutic for a known oncogenic RNA driver and unique biomarker in multiple malignant cancer types

The Effects of Exercise on Neurocognitive Impairments in a Translational Model of Pediatric Radiotherapy

Cranial radiation therapy (CRT) is used as a treatment for brain malignancies that are not easily accessible and would provide significant risk to the patient through invasive methods like surgery. While CRT has been shown to be effective as a treatment, healthy areas surrounding the irradiation sites are detrimentally affected. Frontal lobe functions are impaired, particularly the domains of attention, processing speed and inhibition control. These deficits often manifest months to years after radiation and significantly impair quality-of-life over time. Exercise is proposed as an adjuvant therapy to ameliorate the deleterious effects of radiation. We established a rodent model of the neurocognitive effects of CRT. Adolescent Fischer rats were irradiated with a fractionated dose of 20Gy (4Gy x 5 days). We showed lasting neurocognitive impairments in the 5-Choice Serial Reaction Time Task (5-CSRTT), a test that simultaneously measures several cognitive modalities. We investigated whether voluntary exercise could ameliorate these impairments by having physical activity groups exercise from the week after irradiation until behavioral training. We found that exercise significantly ameliorated performance at both 3 months and 6 months post-RT in accuracy, premature responses, and latency to correct responses, along with the number of trials taken to complete stages during training. Our data suggests that exercise significantly mitigates neurocognitive deficits sustained by cranial radiation therapy in our translational model of pediatric radiotherapy.Psychology, Department o

Radiation-induced growth retardation and microstructural and metabolite abnormalities in the hippcampus

Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT

Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer

The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to cancer. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are widely appreciated as pervasive regulators of gene expression, governing the evolution of metabolic disorders, including DM and cancer. The ways ncRNAs affect the development of DM complicated with cancer have only started to be revealed in recent years. Insulin-like growth factor 1 receptor (IGF-1R) signaling is a master regulator of pathophysiological processes directing DM and cancer. In this review, we briefly summarize a number of well-known miRNAs and lncRNAs that regulate the IGF-1R in DM and cancer, respectively, and further discuss the potential underlying molecular pathogenesis of this disease association