Goal
Decision-making individuals in the Biotech, pharmaceutical, and healthcare industries do not have time to read long articles and instead require brief summaries that highlight key results. Here, I will write summaries of translationally relevant findings for those with more advanced scientific knowledge.
Posted: 9/9/24
Combination of pimozide and inhibitors of glutamine metabolism to treat glioblastoma
Development of a brain-penetrant and effective treatment strategy for glioblastoma (GBM) could significantly improve outcomes in patients afflicted by this deadly form of brain cancer.
A recently published study found that an anti-psychotic drug, pimozide, upregulates glutamine metabolism in GBM cells, which causes resistance to pimozide.
OMICs and qPCR data demonstrated that a glutamine transporter, ASCT2, was more highly expressed and more active in pimozide-treated GBM cells. Pimozide does this by inhibiting lysosomal hydrolysis of lipid droplets, thereby reducing the amount of available cholesterol and activating a transcription factor, SREBP-1, which directly upregulates ASCT2 expression.
Pimozide combined with ASCT2 inhibitors (GPNA, DON, CB-839) reduced SREBP-1 and ASCT2 expression. Use of pimozide with these inhibitors caused significant cell death in GBM cell lines, and increased lifespan of mice intracranially injected with GBM cells. Lastly, this combination was also effective in GBM patient-derived organoids.
Overall, pimozide combined with one or multiple ASCT2 inhibitors is a promising GBM treatment strategy that will be interesting to test in clinical trials.
Reference: Zhong, Y. et al., Cell Rep Med, 2024. doi: 10.1016/j.xcrm.2024.101706
Posted: 9/3/24
A new target for the treatment of Alzheimer’s Disease
The development of an effective treatment for Alzheimer’s Disease (AD) could significantly reduce a major healthcare burden, while helping millions of patients and those close to them.
A study published in Science found that IDO1, an enzyme involved in the production of kyneurine (KYN) from tryptophan (TRP), is more highly expressed and more active in astrocytes and microglia in response to amyloid and tau oligomers, leading to increased production of KYN.
Increased amounts of KYN impeded glycolytic and oxidative phosphorylation activity in cultured astrocytes and neurons, as well as in AD mouse models (APP and PS1).
Inhibition of IDO1 via genetic and pharmacological (PF-0680003) methods reduced KYN production, restored normal glycolytic and oxidative phosphorylation activity, and improved cognitive abilities in AD models.
Mechanistically, increased KYN production via IDO1 activity in astrocytes appears to reduce lactate production, which is normally transferred to neurons to sustain glycolysis and proper neuronal function.
Reference: Minhas, P.S. et al., Science, 2024. doi: 10.1126/science.adm6131
Posted: 8/26/24
A micropatterned platform to improve measurement of metastasis potential
Enhanced sensitivity and streamlined measurement of metastasis potential could improve treatment plan design and provide a high-throughput system for drug discovery.
A recent study in Science Advances described a novel micropatterned platform with narrow openings (5 mm vs. 8 mm in current technology) to assess cancer cell invasiveness, a critical measure of metastatic potential.
Using LM2-4 (highly invasive cell line) and MCF-7 breast cancer cells (noninvasive cell line), the authors demonstrated that the platform can detect changes in cell morphology, track cellular movement, and measure invasiveness with high resolution and reproducibility.
Using the same cell lines, this platform proved to be significantly more sensitive than the currently used scratch (3.5-fold increased sensitivity) and Transwell (10-fold increased sensitivity) assays.
The micropatterned platform is compatible with 96-well plates, permitting high-throughput drug discovery experiments. Further, the micropatterned platform can be paired with biophysical imaging technology to delineate the specific part of the metastatic mechanism a particular drug inhibits, such as nuclear deformability.
Reference: Bhattacharya, S. et al., Sci Adv, 2024. doi: 10.1126/sciadv.adk0015
Posted: 8/19/24
OLAH expression as a biomarker for severity of respiratory infection
The identification of biomarkers for severity of respiratory infection could rapidly improve strategy and provide new drug targets to treat respiratory diseases.
Oleoyl-ACP hydrolase (OLAH), a protein that drives oleic acid production, is more highly expressed in patients with severe respiratory infections, such as avian A(H7N9) influenza, COVID-19, seasonal flu, RSV, and MIS-C compared to healthy or mildly infected patients.
CRISPR-Cas9 knockout of OLAH in mice significantly improved resilience to lethal flu infection; mice survived longer, and tissue damage, lung viral load, and inflammation were all reduced. Feeding mice oleic acid, a major product of OLAH, caused increased viral replication and inflammation.
Transplantation of wild type or OLAHKO bone marrow into irradiated wild type or OLAHKO mice (immune-cell deficient) demonstrated that OLAH expression specifically in immune cells is critical for the protective effects observed in OLAHKO mice.
Analysis of specific types immune cells identified macrophages as the primary drivers of severe infection upon infection and treatment with oleic acid.
Reference: Jia, X. et al., Cell, 2024. doi: 10.1016/j.cell.2024.07.026
Posted: 8/12/24
Synthetic antibiotic targeting resistant gram-positive bacteria
PS757, a newly synthesized compound that is bactericidal against gram-positive bacteria at stationary and exponential growth phases, could be part of the solution to the antibiotic resistance problem.
Streptococcus Pyogenes, bacteria frequently associated with skin and soft tissue infection (SSTI), treated with PS757 exhibit significant damage to the cell wall, failure to form a biofilm, and even biofilm destruction when applied after biofilm formation.
In mouse models of S. pyogenes SSTI, PS757 caused significant subcutaneous ulcer regression, reduced circulation of TNFa and IL-6, but not IL-1b, and accelerated tissue healing compared to vehicle controls.
Transcriptomic analyses on stationary phase S. pyogenes cells treated with a non-growth-inhibiting dose of PS757 indicated a significant reduction in the expression of two virulence factors, emm5 and spe5.
Reference: Zou, Z. et al., Sci Adv, 2024 doi: 10.1126/sciadv.adn7
Butsch Science Communication 