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Mashup Score: 58RAS G12C Inhibitors: Three Birds with One Stone - 4 day(s) ago
Summary:. In this issue, Rubinson, Tanaka, and colleagues demonstrate that differences among G12C inhibitors rely on their ability to covalently bind not only G12C mutant KRAS but also NRAS and HRAS, proposing sotorasib as a potent NRAS G12C inhibitor.See related article by Rubinson et al., p. 727 (6).
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Mashup Score: 3Highlighted research articles - 4 day(s) ago
In this study, Rubinson, Tanaka, and colleagues reveal that a subset of switch-II pocket-binding KRASG12C inhibitors can target all RASG12C proteins. In contrast to KRASG12C-specific compounds, which depend on binding to histidine 95 in the KRAS protein, these pan-RASG12C inhibitors bind within the switch-II pocket in a manner that is independent of position 95, thus allowing binding to HRASG12C and NRASG12C, which harbor distinct amino acids at this position. Furthermore, clinical efficacy of sotorasib plus panitumumab was demonstrated in a patient with NRASG12C-mutant colorectal cancer. Together, these results indicate that pan-RASG12C inhibitors, such as sotorasib, represent a new treatment option for patients with HRASG12C and NRASG12C-mutant cancers.See article, p. 727.Somatic alterations that activate JAK2 signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN); however, current clinical JAK inhibitors fail to reduce mutant clonal fraction and are l
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Mashup Score: 2Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers - 9 day(s) ago
Sotorasib and other selected KRASG12C inhibitors leverage differential dependence on switch-II pocket binding at amino acid position 95 to target all RASG12C isoforms, which has critical implications for the treatment of NRASG12C- or HRASG12C-mutant tumors.
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Mashup Score: 10
Cancer Discovery | 14 | 5 | May 2024
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Mashup Score: 17Accelerating Drug Development Using Spatial Multi-omics - 9 day(s) ago
Summary:. Spatial biology approaches enabled by innovations in imaging biomarker platforms and artificial intelligence–enabled data integration and analysis provide an assessment of patient and disease heterogeneity at ever-increasing resolution. The utility of spatial biology data in accelerating drug programs, however, requires balancing exploratory discovery investigations against scalable and clinically applicable spatial biomarker analysis.
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Mashup Score: 12Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer - 9 day(s) ago
AbstractPancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstr
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Mashup Score: 51
AbstractThe tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senoly
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Mashup Score: 22Condensate-promoting ENL mutation drives tumorigenesis in vivo through dynamic regulation of histone modifications and gene expression - 9 day(s) ago
Abstract. Gain-of-function mutations in the histone acetylation ‘reader’ ENL, found in AML and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in
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Mashup Score: 8Cancer and the Metaorganism - 9 day(s) ago
Summary: . Pathogenic shifts in the gut microbiota are part of the “ecological” alterations that accompany tumor progression and compromise immunosurveillance. The future management of health and disease including cancer will rely on the diagnosis of such shifts and their therapeutic correction by general or personalized strategies, hence restoring metaorganismal homeostasis.
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Mashup Score: 16The Virtual Child - 10 day(s) ago
Summary: . We are building the world’s first Virtual Child–a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will “develop cancer” that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.
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In the Spotlight— RAS G12C Inhibitors: Three Birds with One Stone, by Tessa Seale and @Sandra_Misale. https://t.co/ySMLXJ3M3p @hopkinskimmel @HopkinsMedicine https://t.co/tub5jUy5JN