Open-label trial to evaluate the efficacy of pre-emptive therapy with minocycline and multidisciplinary intervention for skin toxicity of anti EGFR antibody in colorectal cancer patient
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2625494 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Interventions: Vitamin K1 cream
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Primary outcome(s): The incidence of grade2-5 rash acneiform (CTCAE v4.0) of face whithin 4 weeks from starting cetuximab containing chemotherapy
Study Design: Parallel Randomized
| 2625669 | ecrin-mdr-crc
Project description:The Epidermal Growth Factor Receptor (EGFR)/ligand system is centrally involved in multiple homeostatic functions of the epithelia. Epithelial cells are the primary targets of humanized antibodies and small molecule inhibitors against this system, whereby the constellation of skin-specific side effects of these drugs stems from a profound disturbance of keratinocyte biology. So far, the molecular mechanisms underlying these toxic events have been investigated only broadly. Here we show that keratinocyte response to anti-EGFR drugs comprises the development of a type 1 interferon (IFN) molecular signature including enhanced expression of IFN-kappa. Mechanistically, nuclear accumulation of IRF1 precedes this signature as well as the enhanced expression of a chemokine cluster we previously identified as a relevant pro-inflammatory component of EGFR inhibition. In fact, either silencing of IRF1 transcript expression, or antibody-mediated blockade of type 1 IFN receptor function and consequent abrogation of STAT1 activation, leads to impairment of this gene transcription profile. High levels of IRF1 and IFN-kappa can be clearly observed in the early skin lesions of patients treated with cetuximab. Type 1 IFN signaling could be crucially implicated in the triggering of the inflammatory mechanisms active in the skin of patients under treatment with anti-EGFR drugs. Normal human keratinocyte cultures were treated with Tumor Necrosis Factor (TNF) alpha (50 ng/ml) alone (SAMPLES #4-6), or with the concomitant administration of the small-molecule EGFR inhibitor PD168393 (2 microM) (SAMPLES #7-9) for 6 hours. Cultures were performed in triplicate and include untreated controls (SAMPLES #1-3).
2016-07-31 | E-GEOD-74407 | biostudies-arrayexpress
Project description:EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation. Time course of human epidermal keratinocytes treated with Tyrphostin (AG1478) and untreated controls
2012-10-19 | E-GEOD-41680 | biostudies-arrayexpress
Project description:To search proteins that interact with EGFR, EGFR interactors were coimmunoprecipitated with anti-EGFR antibody from 5-8F cell extracts, separated on SDS-PAGE and stained with Coomassie blue, and non-immune IgG antibody instead of anti-EGFR antibody served as control. Interested bands were excised, and subjected to in gel trypsin digestion and liquid chromatography and high-throughput mass spectrometry (LC-MS/MS) analysis.As a result, a total of 268 proteins including ANXA1 and CBL were identified .
2024-09-18 | PXD056130 |
Project description:EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation.
2012-10-19 | GSE41680 | GEO
Project description:EGFR targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. Activating Ras mutations are a negative prognostic factor for response to EGFR ablation therapy in multiple cancer types. Furthermore, the major adverse consequence of this therapy is an acneiform papulopustular eruption on normal skin. To better understand Ras signaling in an EGFR depleted environment, we performed gene expression profiling on oncogenic Ras transformed and wildtype mouse keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment. We were able to identify a 25 gene signature specific to the Ras-EGFR ablation interaction and a distinct 19 gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wildtype Ras reduces ontologies favoring cell cycle control and transcription while ablation in the context of oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. The study showed substantial differences in ontologies between chronic EGFR ablation and acute pharmacological ablation, both with and without Ras activation. Pathway and biochemical analysis indicates that activation of p38α is a response to both acute and chronic abrogation of EGFR signaling under conditions of Ras activation. This was confirmed in oncogenic RAS transformed human keratinocytes and in tumors developing in orthografts of EGFR ablated mouse keratinocytes transformed by oncogenic Ras. EGFR ablation in the absence of oncogenic Ras revealed Erk and IL-1β related pathways. These findings reveal previously unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy.
2012-01-11 | GSE29415 | GEO
Project description:Background and rationale: EGFR represents the main and more studied signal activation pathway in the development of colorectal carcinoma. KRAS, NRAS, BRAF and PI3KA mutations and ERBB2 and MET amplification are responsible for most of the cases of primary resistance to anti-EGFR antibody treatments. Despite the identification of these resistance mechanisms, a primary resistance to the therapy was detected in a certain percentage of cases, in which tumour bio-molecular characteristics would suggest a possible response to anti-EGFR antibody treatment. In these cases, pathway activation mechanisms should exist, which act in an alternative, complementary or parallel way than the EGFR one, allowing tumour progression despite of EGFR pharmacological deactivation. Skin toxicity is a characteristic of drugs having EGFR as a target and it shows itself mainly as a sterile acneiform folliculitis together with neutrophils perifollicular infiltrates but also as skin xerosis and paronychia starting from the earliest cycles of treatment. This skin toxicity seems to be closely related to EGFR activation of pro-inflammatory cytokines able to activate specific inflammatory activators, which induce neutrophils granulocytes chemotaxis. Lycopene is a compound belonging to carotenoid group, largely contained in tomatoes and their derivatives, which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in general and of lycopene in particular in the diet showed to be effective in skin protection from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin and thus contribute to reduce free radicals and inflammation effects. Moreover, lycopene ability to induce apoptosis and to inhibit cell cycle progression in some types of tumour cells, both in vitro and in vivo, has already been described. Lycopene seems to be able to suppress significantly PCNA (Proliferating cell nuclear antigen, cofactor of DNA polymerase-β) and β-catenin nuclear expression in neoplastic cells, essential substrate of WNT/β-catenin pathway, which is itself closely connected to activating pathways often involved in carcinogenesis of some kinds of tumours, in particular of colorectal carcinoma, like Akt/GSK3β/β-catenin and Hippo pathways. For its proved skin anti-inflammatory activity as powerful free radicals scavenger, lycopene, which accumulates itself specifically in skin, could be effective in reducing anti-EGFR drugs toxicity. Contemporary use of lycopene could have a positive effect on anti-EGFR drugs treatment effectiveness in patients with metastatic colorectal carcinoma due to its ability to interfere with pathways involved in neoplastic cells proliferation.
Estimated population:100 patients (50 for each of the two groups of treatment)
Study Framework: In this study, patients suffering from metastatic colorectal cancer and submitted to therapy with panitumumab would be enrolled. According to indications, panitumumab would be used:
in first line combined with Folfox or Folfiri;
in second line combined with Folfiri or treatments containing Irinotecan
in monotherapy in any therapeutic line in patients resistant to Fluoropyrimidines, Oxaliplatin and Irinotecan or intolerant to these drugs.
Standard schedules of these treatments would be used.
This is a phase-II, randomized, double-blind study between experimental prophylactic treatment with Lycopene vs placebo:
* Treatment A - lycopene tablets 20 mg
* Treatment B - placebo tablets
Patients should take orally Lycopene/placebo after dinner (to promote its absorption), starting the day before the beginning of treatment with panitumumab for the entire duration of the therapy, until progression of the disease or definitive drug suspension for toxicity.
Objectives of the study
Primary objective: to assess the effectiveness of lycopene versus placebo in reducing skin toxicity induced by panitumumab in patients treated for metastatic colorectal carcinoma.
Secondary objective: to assess lycopene pharmacokinetics
Exploratory objectives: to assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Disease Control (DC), Objective Response (OR) and Stabilisation of the Disease (SD). To assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Progression Free Survival (PFS).
As far as randomization is concerned, the two groups will be balanced according to sex, therapeutic line and institution in which patients will be treated.
| 2245461 | ecrin-mdr-crc
Project description:The Epidermal Growth Factor Receptor (EGFR)/ligand system is centrally involved in multiple homeostatic functions of the epithelia. Epithelial cells are the primary targets of humanized antibodies and small molecule inhibitors against this system, whereby the constellation of skin-specific side effects of these drugs stems from a profound disturbance of keratinocyte biology. So far, the molecular mechanisms underlying these toxic events have been investigated only broadly. Here we show that keratinocyte response to anti-EGFR drugs comprises the development of a type 1 interferon (IFN) molecular signature including enhanced expression of IFN-kappa. Mechanistically, nuclear accumulation of IRF1 precedes this signature as well as the enhanced expression of a chemokine cluster we previously identified as a relevant pro-inflammatory component of EGFR inhibition. In fact, either silencing of IRF1 transcript expression, or antibody-mediated blockade of type 1 IFN receptor function and consequent abrogation of STAT1 activation, leads to impairment of this gene transcription profile. High levels of IRF1 and IFN-kappa can be clearly observed in the early skin lesions of patients treated with cetuximab. Type 1 IFN signaling could be crucially implicated in the triggering of the inflammatory mechanisms active in the skin of patients under treatment with anti-EGFR drugs.
2016-07-31 | GSE74407 | GEO
Project description:Bispecific anti-EGFR/EPHA2 antibody displays strong tumor-suppressing activity
2023-01-30 | PXD023087 | Pride
Project description:Profiling the skin microbiota composition from the face of healthy women. Exploring the differences between three age groups and between dry skin and not dry.
2023-02-24 | GSE225848 | GEO