Animesh Acharjee’s Post

interesting paper - the link between metabolism and cGAS-mediated immunity!

Collab🚨: CRI's McBrayer Lab contributed to a discovery published in Science Magazine from the Manguso Lab & Bardeesy Lab at Mass General Hospital Cancer Center that defines a new #cancer-causing mechanism associated with IDH1 mutations (the most commonly mutated metabolic gene across cancers). From Sam McBrayer, Ph.D.: "They found that IDH1 mutations repress expression and sensing of transposable viral elements in the genome that can trigger innate immune signaling in brain and liver cancers. "Drugs that inhibit IDH1 mutant enzymes can reverse this process, leading to anti-tumor immune responses. These findings provide new insights into how IDH1 mutations, as well as drugs that target these mutations, regulate cancer growth." Read it here: https://lnkd.in/gheTrga8 #relentlessdiscovery #CancerResearch

A concise summary of what is going on, the major concerns and what is at stake in cancer immunotherapy, including Checkpoint Inhibitors, vaccines, ADC, CAR-T and gene editing. https://lnkd.in/ePHjNP-A

Topic #ICI and #autoimmune diseases! Little is understood about the pathogenic mechanisms driving irColitis (#CheckpointInhibitor #Colitis). The #BroadInstitute used single-cell multi-omics to profile cells from the colon mucosa and blood of cancer patients treated with anti-PD-1 or anti-CTLA-4 monotherapy and dual therapy who developed irColitis. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Luminal epithelial cells in patients with irColitis expressed genes associated with apoptosis, increased cell turnover and malabsorption. https://lnkd.in/enPAQ5qY

There is a small percentage of certain cancers where the cells start to lose their identity..and seem to take on the identity of other cells. So how does this happen? Well…researchers are still trying to tease apart the mechanisms, but have found a few answers…which are leading to more questions. About 25 years ago, researchers at Cold Spring Harbor Labs ‘discovered’ that a gene (p63) was important not only for the formation of normal basal cells (the small cells in the lower part of the epidermis), but also that this protein cased pancreatic cancer cells to become more basal-like. Fast-forward to today…and researchers are building on that research foundation. Now, p63 is a difficult protein to target with drugs, so they needed a different method of trying to ‘screen’ how p63 helped cells turn from ‘normal’ to basal-like. What they did—they screened the genomes of basal-like cancer cells and then ranked the genes needed to help these cells maintain their new identity. The top protein: MED12. MED12 is a subunit of the mediator complex—which is responsible for transcription regulation. In addition, they showed that MED12 & p63 could bind directly to each other…raising the question if both are needed to ‘switch’ cells to the basal-like? More research is needed…especially considering the mediator complex is essential for normal cellular activity—but if the interaction between the two could be disrupted? Also…more research is needed to see if there are other proteins that also play a part in switching the ‘identity’ of cells from their normal to ‘basal-like’. #cancerresearch #proteins #proteinproteininteractions #transcriptionalcontrol #mediatorcomplex

Zhang, D., Wang, M., Ma, S. et al. Phosphoglycerate mutase 1 promotes breast cancer progression through inducing immunosuppressive M2 macrophages. Cancer Gene Ther (2024). https://lnkd.in/dAiqxzsJ "Abstract Immunosuppressive tumor microenvironment (TME) contributes to tumor progression and causes major obstacles for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme involved in cancer metabolism while its role in remodeling TME remains unclear. In this study, we reported that PGAM1 suppression in breast cancer (BC) cells led to a decrease in M2 polarization, migration, and interleukin-10 (IL-10) production of macrophages. PGAM1 regulation on CCL2 expression was essential to macrophage recruitment, which further mediated by activating JAK-STAT pathway. Additionally, the CCL2/CCR2 axis was observed to participate in PGAM1-mediated immunosuppression via regulating PD-1 expression in macrophages. Combined targeting of PGAM1 and the CCL2/CCR2 axis led to a reduction in tumor growth in vivo. Furthermore, clinical validation in BC tissues indicated a positive correlation between PGAM1, CCL2 and macrophage infiltration. Our study provides novel insights into the induction of immunosuppressive TME by PGAM1 and propose a new strategy for combination therapies targeting PGAM1 and macrophages in BC."

🧙♂️ Ever wondered how a tiny gene can have such a big impact on cancer? Let's dive into the fascinating world of SFRP1! 🔎 What's SFRP1? It's like a superhero gene, fighting cancer in two different ways! 😎 First, it acts as a "Tumor Suppressor." That means it's like a guardian, keeping cancer at bay. But in some cases, it can switch sides and become a "Tumor Promoter," making things tricky. 🗡 SFRP1's secret weapon? Epigenetics! This gene gets silenced by tiny molecular tags, leading to all sorts of trouble like cell misbehavior, disease progression, and resistance to treatment. 💫 But here's the exciting part: we can awaken SFRP1 with special "demethylating drugs." It's like giving our superhero a power boost to fight cancer! 🌐 Scientists are also looking at SFRP1 for guiding cancer treatments. It's like having a GPS for therapy! 🚗 This gene's journey is so promising that it's catching the attention of researchers, doctors, and even the folks in white coats who create new drugs. 💪 So, stay tuned for more thrilling updates on SFRP1, the gene with a dual role in the battle against cancer! https://lnkd.in/gcYdDw78 #cocofrancyblog #researchlife #sharingiscaring

✨ #Vandetanib is an #Orally Active #TKI for Medullary Thyroid #Cancer Research 🎈 Receptor #tyrosine #kinases (#RTKs) are a subclass of tyrosine kinases that play imporrtant role in mediating cell-to-cell communication and controlling a wide range of complex biological functions, including #cell #growth, motility, #differentiation, and #metabolism. Dysregulation of RTK signaling leads to an assortment of human #diseases, most notably, #cancers. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and/or autocrine activation. The #VEGF/ #VEGFR system is an important target for anti-#angiogenic therapy in cancer and for pro-angiogenic therapy in neuronal degeneration and ischemic diseases. 🔔 #Vandetanib (#D6474) is a potent, orally active inhibitor of #VEGFR2/ #KDR tyrosine kinase activity. #Vandetanib acts as a tyrosine kinase inhibitor (TKI) of cell receptors including #EGFR, #VEGFR and #RET-tyrosine kinase. Vandetanib inhibits non-small cell #lung #cancer (#NSCLC) cell line Calu-6 cell #migration and #invasion. Vandetanib also induces #autophagy through reactive #oxygen species (#ROS) to antagonize the inhibitory effects on tumor cell growth. Inhibition of ROS or autophagy enhances the sensitivity of Calu-6 cells to Vandetanib. Vandetanib can directly inhibit #RET activity, which influences the #Rho-#JNK pathway. All in all, Vandetanib (D6474) is a potent, orally active inhibitor of VEGFR2/KDR tyrosine kinase activity for NSCLC research. 👉 https://lnkd.in/dXX_XU8H 👉 For more detailed information: https://lnkd.in/dDdX_nja

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). Non-randomized, open label, single site Phase 1 study to define the appropriate dose of CARv3-TEAM-E and evaluate its safety for the treatment of recurrent or newly diagnosed glioblastoma. The study was divided in 4 arms: 1- Safety Run-In Phase 2- Recurrent Glioblastoma (GBM), EGFRvIII Positive 3- Newly Diagnosed GBM, EGFRvIII Positive 4- Recurrent GBM, EGFRvIII Negative Primary endpoints: 1- Incidence of Adverse Events (AEs) [ Time Frame: From Day 0 to 2 years post-treatment ] 2- Number of Dose-Limiting Toxicities (DLTs) [ Time Frame: up to 6 months ] Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. My thoughts: With this design, we can get limited information about Safety, efficacy between virgin treatment of CART cell treatment vs recurrent patient, and EGFRvIII receptor influence. The limitant toxicity would be influenced by how "normally" the target gene is incorporated into CART-cell, and it not generating new secuence of proteins which can be recognized by host immune cells. The article: https://lnkd.in/g3r3q29p The trial: https://lnkd.in/gFa3QuEa

Vitamin D availability influences our gut microbiome, impacting our body's response to cancer therapies. 🌱💊 Low vitamin D levels have been correlated with tumor development, while gene signatures of vitamin D activity are associated with improved patient responses to immunotherapy. 🧬💡 #CancerResearch #Immunotherapy #GutHealth #VitaminD #CancerAwareness #Microbiome #HealthTech