Ontosight^® Newsletter Issue 14

Ontosight^® – Newsletter
November 18^th – December 1^st, 2024 – Issue 14

Welcome to the 14^th edition of the Ontosight^® Newsletter! This issue highlights advances in cancer research, neurological health, immunotherapy, and metabolic care, along with innovative technologies like nanovaccines and key regulatory updates on groundbreaking therapies. Stay informed on the latest in healthcare and life sciences!

Featured Articles

1. Advances in Cancer Research and Treatment

• Cancer cells impair monocyte-mediated T cell stimulation to evade immunity

The tumour microenvironment influences anti-tumour immune responses, with inflammatory monocytes playing a key role in stimulating CD8+ T cells via cross-dressing antigen presentation. However, hyperactivation of MAPK signaling in cancer cells disrupts this process by reducing type I interferon (IFN-I) production and increasing prostaglandin E2 (PGE2) secretion. Restoring IFN-I levels and blocking PGE2 can re-sensitize tumors to T cell-mediated immunity, offering potential strategies to enhance immunotherapies. [Article]

• Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective therapies, with PRMT5 identified as a key target. Using PROTAC technology, the study developed YZ-836P, a potent degrader of PRMT5, which effectively reduced tumor growth and induced apoptosis in TNBC cells, organoids, and xenograft models. YZ-836P shows promise as a novel therapeutic candidate for TNBC treatment. [Article]

• CTCF enhances pancreatic cancer progression via FLG-AS1-dependent epigenetic regulation and macrophage polarization

CTCF, upregulated in pancreatic ductal adenocarcinoma (PDAC), promotes tumor progression by interacting with HNRNPU via FLG-AS1, activating IGF2BP2, and inducing histone lactylation. This drives cell proliferation and M2 polarization of tumor-associated macrophages (TAMs) via the IGF2BP2/CSF1/CSF1R axis. Targeting CTCF, combined with curaxin and gemcitabine, shows potential for PDAC immunotherapy. [Article]

• Identification of VISTA regulators in macrophages mediating cancer cell survival

Resistance to immune checkpoint blockade (ICB) therapies is often driven by immune-suppressive macrophages in the tumor microenvironment (TME). This study identifies AhR and IRAK1 as key regulators of VISTA, an immune suppressor, using CRISPR screening and a microfluidic platform. Targeting AhR and IRAK1 in mouse models reduced VISTA, reprogrammed macrophages, and enhanced infiltration of cytotoxic immune cells, overcoming ICB resistance. [Article]

• Breast Cancer Subtype-Specific Organotropism is Dictated by FOXF2-Regulated Metastatic Dormancy and Recovery

FOXF2 regulates breast cancer subtype-specific organotropism by promoting metastasis in the bone and inhibiting it in the lung. In luminal breast cancer (LumBC) and basal-like breast cancer (BLBC), FOXF2 activates NF-κB and BMP pathways in the bone, while repressing TGF-β signaling in the lung. Targeting these pathways could offer potential strategies to prevent subtype-specific metastasis and improve treatment precision. [Article]

• Integration of eQTL and Multi-Omics Comprehensive Analysis of Triacylglycerol Synthase 1 (TGS1) as a Prognostic and Immunotherapeutic Biomarker Across Pan-Cancer

This study identifies Trimethylguanosine Synthase 1 (TGS1) as a potential cancer susceptibility gene through Mendelian randomization (MR), linking its overexpression to impaired telomere elongation and tumor progression. A pan-cancer analysis revealed higher TGS1 expression across 33 tumor types, correlating with poor prognosis and immune cell infiltration. The findings highlight TGS1’s oncogenic roles, its involvement in apoptosis, and its potential as a biomarker and therapeutic target in cancer. [Article]

• FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer

KRAS G12C-targeted therapies like sotorasib show limited efficacy due to resistance mechanisms involving ERK reactivation, which requires wild-type HRAS and NRAS. The dual inhibitor FGTI-2734 blocks WT RAS membrane localization and prevents sotorasib-induced ERK feedback, overcoming resistance. Combining FGTI-2734 with sotorasib enhances anti-tumor activity, reduces ERK reactivation, and significantly improves tumor regression in KRAS G12C lung cancer models, offering a potential strategy to improve treatment outcomes. [Article]

2. Neurological and Brain Health Innovations

• Elevated expression of the retrotransposon LINE-1 drives Alzheimer’s disease-associated microglial dysfunction

This study highlights a potential role of the retrotransposable element LINE-1 in late-onset Alzheimer’s disease (LOAD). Elevated LINE-1 activity was found in microglia from LOAD brains, correlating with disease-associated morphology. In iPSC-derived microglia, LINE-1 activation altered morphology, impaired amyloid-beta phagocytosis, and induced transcriptomic changes affecting antigen presentation, lipid metabolism, and Alzheimer’s-related genes. These findings suggest LINE-1-driven microglial dysregulation as a contributor to LOAD pathogenesis. [Article]

• Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer’s disease models

This study explores the role of mitochondrial dysfunction in Alzheimer’s disease (AD) by analyzing proteomic changes in a fly model expressing toxic amyloid β (Aβ-Arc). Results reveal disruptions in complex I and mitochondrial one-carbon (1C) metabolism, critical for cellular function. Enhancing 1C metabolism via Nmdmc or folinic acid supplementation improved mitochondrial health and neuroprotection in fly and mammalian models. Genetic and Mendelian randomization analyses suggest that boosting folate-dependent 1C metabolism could mitigate AD risk, presenting a promising therapeutic strategy. [Article]

• Persistence of Spike Protein at the Skull-Meninges-Brain Axis May Contribute to the Neurological Sequelae of COVID-19

This study links SARS-CoV-2 to persistent neurological symptoms by detecting spike protein accumulation in the skull-meninges-brain axis of COVID-19 patients and mice long after viral clearance. The spike protein induced neuroinflammation, proteomic alterations, and worsened outcomes in stroke and brain injury models, while vaccination reduced but did not completely prevent accumulation. These findings suggest persistent spike protein may drive neurodegenerative changes in long COVID. [Article]

• Hypoxia is Linked to Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

This study identifies hypoxia as a key driver of acquired resistance (AR) to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Resistant tumors showed reduced T cell infiltration and MHC expression and were associated with poor progression-free survival. Targeting hypoxic regions with a hypoxia-activated pro-drug delayed AR, suggesting a combined therapeutic approach could enhance ICI efficacy. [Article]

3. Innovations in Immunotherapy and Inflammatory Diseases

• Exploring the global impact of obesity and diet on dementia burden: the role of national policies and sex differences

This study examines the global impact of obesity on dementia prevalence and mortality, highlighting sex-specific differences. It finds that higher obesity prevalence is associated with increased dementia mortality, with males more vulnerable. National obesity management strategies and healthier diets were linked to lower dementia rates, emphasizing the need for integrated public health interventions. [Article]

• JAK Inhibitors: A Double-Edged Sword in Immune-Mediated Diseases Management

JAK inhibitors, used to treat immune-mediated inflammatory diseases, carry safety risks, including a nearly doubled risk of gastrointestinal perforations (GIPs) in rheumatoid arthritis (RA) patients compared to biologics. The FDA’s ORAL Surveillance study linked tofacitinib to higher cancer and cardiovascular events, leading to regulatory restrictions. These findings stress the need for careful risk assessment and monitoring to optimize the use of JAK inhibitors. [Article]

• Protection against Clostridioides difficile disease by a naturally avirulent strain

This study demonstrates that an avirulent Clostridioides difficile strain, ST1-75, protects mice from colitis caused by a virulent strain (R20291) by rapidly depleting amino acids, which limits the growth of the virulent strain. Supplementing amino acids counteracts this effect, highlighting nutrient depletion as a potential therapeutic mechanism. The ST1-75 strain may serve as a biotherapeutic agent to prevent recurrent C. difficile infection in high-risk patients. [Article]

• Blocking Virus Infection with BacMam Virus Delivery Bovine Interferon-α Gene

This study explores the use of the BacMam system to deliver bovine interferon-α (BoIFNα) for antiviral applications. The recombinant BacMam-BoIFNα virus effectively secreted BoIFNα in HEK293T cells and exhibited antiviral activity against multiple viruses in bovine-derived cells, including VSV, BPIV3, BEV, and BVDV. The virus inhibited viral replication in MDBK cells via the JAK-STAT pathway and also reduced BPIV3 replication in mice, demonstrating its potential as an efficient tool for combating bovine viral infections. [Article]

4. Metabolic & Cardiovascular Health

• Association of coffee consumption and caffeine metabolism with arrhythmias and cardiac morphology

This study investigates the impact of coffee consumption and caffeine metabolism on cardiac structure and arrhythmias using data from the UK Biobank. Coffee intake was linked to increased left ventricular mass, larger ventricular and atrial volumes, and reduced risks of atrial fibrillation and sinus rhythm with a short PR interval. Caffeine metabolism, influenced by CYP1A2 or polygenic scores, showed no significant effect on these associations. The findings suggest that moderate coffee consumption may not require restriction to mitigate arrhythmia risk. [Article]

• Ergothioneine Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) by Enhancing Autophagy, Inhibiting Oxidative Damage, and Inflammation

This study explores the therapeutic potential of ergothioneine, a natural antioxidant from mushrooms, in treating metabolic dysfunction-associated steatosis liver disease (MASLD). Ergothioneine reduced body weight, improved lipid metabolism and insulin resistance, and alleviated liver damage in high-fat diet mice. Mechanistically, it promoted autophagy, reducing oxidative stress, inflammation, and apoptosis, effects reversed by an autophagy inhibitor. These findings suggest ergothioneine as a promising candidate for MASLD treatment via autophagy activation. [Article]

• Effects of intermittent fasting on body composition, clinical health markers, and memory status in the adult population

This study analyzed prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR) in a large international cohort. Measured PPM (PPMm) was more prevalent than predicted PPM (PPMp), with limited correlation between the methods. Severe PPMm initially showed worse survival, but neither PPMm nor PPMp significantly impacted 2-year mortality after adjustments. Valve selection should prioritize a comprehensive patient-centered approach over isolated hemodynamic considerations. [Article]

5. Novel Therapeutics and Emerging Technologies

• A novel pan-epitope based nanovaccine self-assembled with CpG enhances immune responses against flavivirus

This study presents the TBT-CpG nanovaccine (NaVs), a self-assembled pan-epitope vaccine for flaviviruses, which demonstrated robust immunogenicity and safety. The nanovaccine enhanced antigen presentation via the MHC II pathway, promoted dendritic cell maturation, and triggered targeted immune responses, effectively protecting against Dengue and Zika virus infections. These findings highlight its potential as a safe and effective vaccine platform. [Article]

• High-throughput single-cell analysis reveals Omp38-specific monoclonal antibodies that protect against Acinetobacter baumannii infection

This study highlights the therapeutic potential of monoclonal antibodies (mAbs) targeting the outer membrane protein Omp38 of Acinetobacter baumannii. Omp38-specific mAbs demonstrated broad-spectrum binding, reduced bacterial loads, minimized inflammatory responses, and improved survival in mouse infection models. These findings suggest Omp38-specific mAbs as a promising targeted treatment for A. baumannii infections, addressing global concerns of antibiotic resistance. [Article]

• A hypoxia-activated and microenvironment-remodeling nanoplatform for multifunctional imaging and potentiated immunotherapy of cancer

This study presents a nanoplatform integrating hypoxia-activated NIR-II fluorescence/photoacoustic imaging with phototherapy to treat cancer. It triggers immunogenic cell death, activates the STING pathway, and engages adaptive immunity, suppressing tumors and preventing rechallenge in a 4T1 mouse model. The approach offers precise tumor targeting and robust immunotherapy. [Article]

Additional Highlights

Explore more groundbreaking research and regulatory updates in our biweekly newsletter:

• Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein [Article]
• Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging [Article]
• Bactericidal Antibiotic Treatment Induces Damaging Inflammation via TLR9 Sensing of Bacterial DNA [Article]
• Elevated blood pressure variability is associated with an increased risk of negative health outcomes in adults aged 65 and above [Review]
• KM Biologics Receives WHO Emergency Use Listing for its Mpox Vaccine [News]
• Zai Lab Announces the Inclusion of AUGTYRO® (repotrectinib) for ROS1+ NSCLC and Other Updates in China’s National Reimbursement Drug List [News]
• Blenrep combinations accepted for review by the US FDA for the treatment of relapsed/refractory multiple myeloma [News]
• Johnson & Johnson seeks U.S. FDA approval for subcutaneous induction regimen of TREMFYA® (guselkumab) in ulcerative colitis, a first for an IL-23 inhibitor News]
• Soleno Therapeutics Announces FDA Extension of Review Period for DCCR (Diazoxide Choline) Extended-Release Tablets in Prader-Willi Syndrome [News]
• Applied Therapeutics Receives Complete Response Letter from U.S. FDA Regarding New Drug Application for Govorestat for Classic Galactosemia [News]
• ADVANZ PHARMA’s response to the reversal of the suspension of the European Commission decision on the OCALIVA® conditional marketing authorisation in Europe [News]
• Tris Pharma Secures Additional ex-US Approvals to Expand Global Availability of Quillivant XR and QuilliChew ER for the Treatment of Attention Deficit Hyperactivity Disorder [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
AstraZeneca	Tagrisso (osimertinib)	EMA’s CHMP	Approval Recommended	Unresectable EGFR-mutated lung cancer	Link
Samsung Bioepis & Biogen	OPUVIZ™ (aflibercept biosimilar)	European Commission	Marketing Approval	Wet AMD, macular oedema (RVO/DME), myopic choroidal neovascularization	Link
AbbVie	ELAHERE® (mirvetuximab soravtansine)	European Commission	Marketing Approval	Platinum-resistant ovarian cancer	Link
BridgeBio	Attruby™ (acoramidis)	FDA	Marketing Approval	ATTR-CM to reduce cardiovascular death/hospitalization	Link
Astellas	IZERVAY™ (avacincaptad pegol)	FDA – sNDA	Supplemental New Drug Application	Geographic atrophy secondary to age-related macular degeneration	Link
Pfizer	HYMPAVZI™ (marstacimab)	European Commission	Marketing Approval	Severe hemophilia A or B without inhibitors	Link
AOP Health	Rapiblyk™ (landiolol)	FDA	Marketing Approval	Atrial fibrillation and flutter in critical care	Link
Shorla Oncology	JYLAMVO™ (methotrexate)	FDA	Expanded Approval	Pediatric indications in oncology and autoimmune conditions	Link
Amneal	DHE Autoinjector	FDA	Marketing Approval	Acute migraine and cluster headache	Link
Jazz Pharmaceuticals	Ziihera® (zanidatamab-hrii)	FDA	Marketing Approval	Previously treated HER2-positive metastatic biliary tract cancer	Link
UCB	BIMZELX® (bimekizumab-bkzx)	FDA	Marketing Approval	Moderate-to-severe hidradenitis suppurativa	Link
GSK	Menveo (MenACWY vaccine)	European Commission	Marketing Approval	Invasive meningococcal disease caused by bacterial serogroups A, C, W, Y	Link
GSK	Arexvy	Japan’s MHLW	Approval expanded	Prevention of RSV disease in adults aged 50-59 at increased risk	Link
Novo Nordisk	Wegovy® (semaglutide)	Health Canada	Marketing Approval	Reducing risk of non-fatal myocardial infarction	Link
CervoMed	Neflamapimod	FDA	Orphan Drug Designation	Frontotemporal dementia	Link

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