A5079164225- Colorectal Cancer Treatments and Studies
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Cancer Research and Treatments
- Cancer Cells and Metastasis
- Cancer Treatment and Pharmacology
- Radiopharmaceutical Chemistry and Applications
- Chronic Lymphocytic Leukemia Research
- Gastric Cancer Management and Outcomes
- Glycosylation and Glycoproteins Research
- Nanoparticle-Based Drug Delivery
- Genetic factors in colorectal cancer
- Chemical Reactions and Isotopes
- Health Systems, Economic Evaluations, Quality of Life
- Pancreatic and Hepatic Oncology Research
- Radiomics and Machine Learning in Medical Imaging
- Radiation Therapy and Dosimetry
- Melanoma and MAPK Pathways
- Monoclonal and Polyclonal Antibodies Research
- Calcium signaling and nucleotide metabolism
- Hepatocellular Carcinoma Treatment and Prognosis
- Cardiac tumors and thrombi
- Antimicrobial Peptides and Activities
- Cholangiocarcinoma and Gallbladder Cancer Studies
Candiolo Cancer Institute
2013-2024
Istituti di Ricovero e Cura a Carattere Scientifico
2015-2022
University of Turin
2010-2019
Fondazione Piemontese per la Ricerca sul Cancro Onlus
2016
There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression ERBB3 receptor tyrosine kinase sensitizes KRAS lung and colon cancer cells to MEK inhibitors. We show inhibition results in MYC-dependent transcriptional upregulation ERBB3, which is responsible intrinsic drug resistance. Drugs targeting both EGFR ERBB2, each capable forming heterodimers can reverse unresponsiveness by...
Abstract The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction the S310F, L755S, V777L, V842I, L866M into colon epithelial cells increased signaling pathways anchorage-independent cell growth, indicating that they are activating mutations. these cancer lines produced resistance to cetuximab panitumumab by sustaining MAPK phosphorylation. mutants potently inhibited low nanomolar doses irreversible...
Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring mechanisms of this incomplete sensitivity devise efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated 125 independent samples that did not harbor...
Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response blockade identify alternative drug targets overcome resistance. Both tyrosine global...
Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is an effective treatment for patients RAS wild-type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC receive clinical benefits from anti-EGFR therapies, due to development resistance mechanisms. In this regard, HER2 has emerged as actionable target therapy.We have used SW48 and LIM1215 human colon cell lines, quadruple KRAS, NRAS, BRAF PI3KCA genes, their...
The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal (CRC), model availability is limited by a dearth large-scale collections patient-derived xenografts (PDXs) paired tumoroids from metastatic disease, where experimental therapies typically tested. Here we introduce XENTURION, an open-science resource offering platform 128 PDX patients with CRC, along matched PDX-derived tumoroids....
Abstract DNA sequence mutability in tumors with chromosomal instability is conventionally believed to remain uniform, constant, and low, based on the assumption that further mutational accrual a context of marked aneuploidy evolutionarily disadvantageous. However, this concept lacks robust experimental verification. We adapted principles mutation accumulation experiments, traditionally performed lower organisms, clonal populations patient-derived tumoroids empirically measured spontaneous...
Abstract Purpose: Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent tumor shrinkage correlates long-term outcome. We aimed find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on antiapoptotic molecules (BCL2, BCL-XL, MCL1). Experimental Design: Experiments were conducted in patient-derived...
ABSTRACT The breadth and depth at which cancer models are interrogated contribute to successful translation of drug discovery efforts the clinic. In colorectal (CRC), model availability is limited by a dearth large-scale collections patient-derived xenografts (PDXs) paired tumoroids from metastatic disease, setting where experimental therapies typically tested. XENTURION unique open-science resource that combines platform 129 PDX sister matched PDX-derived (PDXTs) patients with CRC,...
Abstract Rationale: The HERACLES A trial showed that a clinical sizeable subset of 3% metastatic colorectal cancers (mCRC), identifiable by the amplification HER2 gene, can be targeted for effective, durable and safe anti-HER2 treatment with combination small molecule kinase inhibitor lapatinib (L) monoclonal antibody trastuzumab (T) [Siena et al. J Clin Oncol 33, 2015.(suppl; abs 3508)]. As any other therapy, however, L+T was not active in all patients, even responders its efficacy limited...
Abstract Strong evidence supports the use of patient-derived xenografts (PDXs) as faithful models reflecting patient outcomes. Since not all research can support animals, exploiting in vitro such organoids (also know tumoroids) is essential. However, current biobanks metastatic colorectal cancer (mCRC) tumoroids have important limitations, small sample size and a lack systematic vivo validation with paired xenografts, which decreases translational value tumoroid-based pipelines. Here we...
Abstract HER2 amplification occurs in about 5% of colorectal cancers (CRC) and is only partially associated with clinical response to combined HER2/EGFR targeted treatment. An alternative approach, based on Adoptive Cell Therapy (ACT) using T cells engineered anti-HER2 Chimeric Antigen Receptor (CAR), proved toxic due "on-target off-tumor" activity. Therefore, we developed a combinatorial ACT strategy safely target CRC synNotch-based artificial regulatory network. A synthetic Notch receptor...
Abstract In the precision medicine era, multi-parametric interrogation of tumors in cancer patients has enabled rationally refined clinical trials and considerably improved response rates. Nevertheless, incomplete mass obliteration late relapse invariably emerge. This also relates to metastatic colorectal (mCRC), as massive tumor regression upon anti-EGFR therapy with cetuximab is relatively infrequent. Clinical evidence suggests that recurrence may be endorsed by a population lingering...
Abstract Background: Cancer genome sequencing is identifying new genetic alterations and driver events in human cancers. The Genome Atlas (TCGA) colorectal cancer project found that 7% of (CRC) patients have HER2 somatic mutations or gene amplification. amplification CRC known to produce resistance the EGFR monoclonal antibodies, cetuximab panitumumab. However, impact has not been studied it open question as whether are clinically important CRC. Results: Introduction mutations, S310F, L755S,...
Results Xenopatients retained the histological and genomic features of original counterparts, responded to anti-EGFR antibody cetuximab similarly clinical observations, could be prospectively stratified as responders or nonresponders based on predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset cetuximab-resistant, KRAS/ NRAS/BRAF/PIK3CA wild-type cases. In this subset, combined HER2/EGFR inhibition induced long-lasting tumor regression....
RiassuntoGli AA. hanno ricercato il numero di cellule, isolate dal sarcoma da benzopirene, necessario a riprodurre tumore nel polmone del ratto, quando le cellule vengono inoculate per via endovenosa; e l'istogenesi dei noduli sarcomatosi così provocati. Si è avuta la riproduzione soltanto in qualche animale dopo inoculazione 5000-7500 nella maggior parte degli animali con 30 mila cellule. Notevoli sono state differenze individuali.L'inizio stato visto –- una latenza variabile 5 45 giorni...