A5078182587- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Mechanisms of cancer metastasis
- ATP Synthase and ATPases Research
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Genetic factors in colorectal cancer
- Colorectal Cancer Treatments and Studies
- Cancer-related gene regulation
- RNA modifications and cancer
- Immune Cell Function and Interaction
- Cancer-related Molecular Pathways
- interferon and immune responses
- Biochemical and Molecular Research
- Peptidase Inhibition and Analysis
- Wnt/β-catenin signaling in development and cancer
- Cardiac pacing and defibrillation studies
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Digestive system and related health
- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- Atrial Fibrillation Management and Outcomes
Revolution Medicines (United States)
2021-2025
University of California, Berkeley
2020-2022
Ludwig-Maximilians-Universität München
2014-2018
Helmholtz Zentrum München
2013
Institute e-Austria Timisoara
2003
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of KRAS(G12C) oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small cell lung 2,3 Nevertheless, G12C account only around 15% -mutated cancers 4,5 there no approved majority tumours containing other...
Abstract RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor the active, GTP-bound state both mutant and wild-type variants canonical RAS isoforms with broad therapeutic potential for aforementioned unmet medical need. exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 KRAS. Notably, oral administration was tolerated in vivo drove profound tumor regressions...
Abstract Cancer cell lines are not homogeneous nor they static in their genetic state and biological properties. Genetic, transcriptional phenotypic diversity within contributes to the lack of experimental reproducibility frequently observed tissue-culture-based studies. While cancer line heterogeneity has been generally recognized, there no studies which quantify number clones that coexist distinguishing characteristics. We used a single-cell DNA sequencing approach characterize cellular...
Abstract About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation MAPK signaling, which promotes tumor invasion and progression. Here, we report that signaling shows strong intratumoral heterogeneity unexpectedly remains regulated cancer irrespective mutation status. Using primary tissues, xenograft models, reporter constructs, showed cells with high activity resided specifically at the leading edge, ceased to proliferate, underwent epithelial–mesenchymal...
Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (STING) protein has yielded mixed results, perhaps because it initiates potently but does not provide signals sustain activation proliferation activated cytotoxic lymphocytes. To improve efficacy, we...
Abstract Mutant RAS is common in pancreatic carcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal (CRC) exists predominantly the GTP-bound (RAS(ON)) state, leading to excessive downstream oncogenic signaling. KRASG12C(OFF) inhibitors have provided clinical proof of concept for targeting mutant KRAS. Preclinical data suggests inhibition RAS(ON) may be a superior therapeutic strategy. In addition, KRASG12 mutations such as KRASG12D KRASG12V remain unserved.RMC-6236...
Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression putative stem and differentiation antigens. While in normal colonic mucosa, clonal repopulation occurs along gradients from crypt base toward apex, the architecture colon cancer relevance for outgrowth poorly understood. Using a multicolor lineage tracing approach xenografts that reflect primary architecture, we here demonstrate is mainly driven by cells located at leading edge axis...
Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression TALE transcription factor PBX3 in cells undergoing epithelial-mesenchymal transition (EMT), analyze regulation, and determine clinical associations colorectal cancer.Experimental design: We used transcriptomic situ analyses to cancer biology approaches its regulation function. Clinical were analyzed independent tissue...
Abstract Major epithelial tumors harboring the cancer driver KRASG12D, most common oncogenic KRAS mutation1, remain an outstanding unmet medical need. While RAS primarily promotes tumor progression through sustained cellular proliferation, there is also increasing evidence that it adversely shapes microenvironment (TME) induction of immuno-suppressive cytokines2, downregulation MHCI, and modulation checkpoint proteins3. KRASG12D oncoproteins can be selectively targeted with covalent...
Abstract KRASG12V mutant cancers represent a significant unmet medical need with nearly 44,000 new diagnoses annually in the US. The mutation occurs frequently multiple tumor histotypes; incidence NSCLC, CRC and pancreatic is 6%, 10% 26%, respectively. RAS proteins are small GTPases that drive cell proliferation survival when bound to GTP. Mutant exist predominantly GTP-bound (RAS(ON)) state, leading excessive downstream signaling via interaction effectors such as RAF. intrinsic GTP...
Abstract Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but resistance develops rapidly. Here we an inhibitor, (RMC-4998) that targets RAS its active, GTP-bound form, to treat mutant cancer various immune competent mouse models. pathway reactivation after RMC-4998 treatment could be delayed using combined with a SHP2 which not only impacts tumour cell signalling also remodels microenvironment less immunosuppressive. In...
Abstract Colorectal cancer (CRC) is the third most commonly diagnosed in United States. About 40% of colorectal cancers have mutations KRAS, with KRAS G12D representing largest population. Targeted therapies, as well immune checkpoint inhibitor limited efficacy monotherapies for patients microsatellite stable (MSS) CRC. However, recent clinical evidence BRAF mutant MSS CRC showed that inhibitors combination MEK or EGFR and anti-PD-1 resulted significantly longer overall survival a higher...
Abstract Oncogenic RAS promotes carcinogenesis by sustaining cell proliferation and orchestrating immune escape. We others have shown that inhibition combined with checkpoint blockade (ICB) prolongs durability of response in immunogenic, RAS-driven preclinical models. Clinical data most patients treated KRAS G12C(OFF) inhibitors develop resistance through reactivation the pathway. previously demonstrated combination a RAS(ON) G12C-selective inhibitor multi-selective can overcome mechanisms...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that driven by oncogenic RAS mutations in >90% of cases. Daraxonrasib (RMC-6236) orally bioavailable RAS(ON) multi-selective tri-complex inhibitor with broad-spectrum activity against mutant and wild-type variants N, H KRAS. We reported encouraging efficacy daraxonrasib at tolerated dose levels 160 to 300 mg daily as a data cutoff 23 Jul 2024 patients previously treated, metastatic PDAC, median progression free...
In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH is found in most tumors. Here, we demonstrate that high activity marks a distinct colon cancer cell subpopulation with low levels pronounced epithelial phenotype. Therapeutic targeting had limited effects on growth caused expansion cells activity, whereas upon prevailed. Lineage-tracing experiments indicated plasticity between both...
Purpose: Constitutively active WNT signaling is a hallmark of colorectal cancers and driver malignant tumor progression. Therapeutic targeting difficult due to high pathway complexity its role in tissue homeostasis. Here, we identify the transcription factor ADNP as pharmacologically inducible repressor colon cancer.Experimental Design: We used transcriptomic, proteomic, situ analyses expression cancer cell biology approaches determine function. induced xenografts by low-dose ketamine vivo...
Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal phenocopy architecture thus preserve structural organization of the normal intestinal epithelium. A subset colon showed crypt-like compartments high WNT activity nuclear β-Catenin at leading tumor edge,...
// Christine Woischke 1, * , Cristina Blaj Eva Marina Schmidt Sebastian Lamprecht 1 Jutta Engel 2 Heiko Hermeking 3, 4 Thomas Kirchner David Horst Pathologisches Institut, Ludwig-Maximilians-Universität München, Germany Tumorregister Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, 3 German Cancer Consortium (DKTK), Heidelberg, Research Center (DKFZ), These authors have contributed equally to this work Correspondence to: Horst, email:...
Abstract Background The p53 protein is the best studied target in human cancer. For decades, has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, complex diverse function of attracted more attention. Using several molecular approaches, we impact different variants on extrinsic intrinsic apoptosis signaling. Results We reproduced previously published results within induction: while wild-type promoted cell death, mutations reduced sensitivity....
<p>Supplementary Figure 1 shows RMC-6236 crystal structure in tri-complex, as well biophysical and cellular potencies of by genotype. Supplementary 2 demonstrates dose-dependent anti-tumor activities at tolerable doses; pharmacodynamic effects on RAS signaling NCI-H441 xenograft tumors assessed IHC, relatively refractory KP-4 NCI-H2122 human DUSP6 mRNA expression vivo. 3 genotype dependent response across NSCLC, PDAC CRC; potential modifiers to the durability KRASG12C NSCLC models upon...
ABSTRACT Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but responses are short-lived due to rapid development resistance. In this study we a novel covalent tri-complex inhibitor, RMC-4998, that targets RAS its active, GTP-bound investigate treatment mutant cancer various immune competent mouse models. While (ON) inhibitor was more potent than (OFF) adagrasib, pathway reactivation still observed. This could be delayed...
Abstract Mutant KRAS is present in more than 80% pancreatic cancer, promotes cancer cell survival, and protects cells from immune recognition attack. We have shown that inhibitors of the active state RAS (RAS(ON)) promote neoantigen synergize with immunotherapy preclinical immunogenic models. 1 evaluated impact RMC-6236, an investigational RASMULTI(ON) inhibitor on anti-tumor activity tumor microenvironment (TME) remodeling two congenic KRASG12D/+ GEMM-derived PDAC models resistant to...