Anti-epithelial Growth Factor Receptor Research Articles

NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS258 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% v 12.3%) with mean PFS of 13.7 mos, with ~45% of pts in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data, which showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. A recent randomized trial subgroup analysis of 8 pts with dMMR metastatic colon cancer treated with FOLFOXIRI+bev+atezo, with the first patient having progression ~16 mos (AtezoTRIBE). Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy (48% PFS at 24 mos as assessed by site investigator), we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, and duration of response. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT05080673 .

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS3647 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% v 12.3%) with mean PFS of 13.7 mos, with ̃45% of pts in the IO arm progressed at 12 mos ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data, which showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. A recent randomized trial subgroup analyses of 8 pts with dMMR metastatic colon cancer treated with FOLFOXIRI+bev+atezo, with the first patient having progression ̃16 mos ( ESMO 2021, Abstt LBA20). Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy (48% PFS at 24 mos as assessed by site investigator), we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, and duration of response. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067. Clinical trial information: NCT02997228.

Efficacy and Safety of Tisotumab Vedotin in Patients with Head and Neck Squamous Cell Carcinoma: Results From a Phase II Cohort

<h3>Purpose/Objective(s)</h3> Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. <h3>Materials/Methods</h3> In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. <h3>Results</h3> Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. <h3>Conclusion</h3> TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209).

NRG-GI004/SWOG-S1610: Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS232 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean PFS of 13.7 months ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H (211 pts) to atezo monotherapy versus mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy, 48% PFS at 24 months, as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 months) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro.

Simple SummaryPhotodynamic priming is an emerging strategy that leverages subtherapeutic photochemistry for therapeutic benefits, often used as part of combination regimens. Our study aimed to couple photodynamically priming with antagonism of the prostaglandin E receptor 4, a therapeutic target linked to cancer-associated migration, invasion, angiogenesis, and immune evasion. Photodynamic priming and antagonism of the prostaglandin E receptor 4 independently attenuated OVCAR-5 ovarian cancer cell migration in a gap closure model, though their combination induced the most significant reductions. More potent combination effects were revealed when invasiveness was characterized using a transwell invasion model with CAOV3 ovarian cancer cells. Immunoblotting identified the epithelial growth factor receptor, cAMP-response element binding protein, and extracellular signal-regulated kinase 1/2 as potential mediators of these combinational effects. This work provides new evidence of a novel and clinically relevant combination strategy to address metastatic behavior, a major challenge in the treatment of cancer.The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are “photodynamically primed”, or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.

전이성 대장암의 새로운 표적치료

Over the past decade, substantial advances have been made in the individualization of therapeutic strategies for metastatic colorectal cancer (mCRC). Treatment strategies have been developed and classified according to their molecular and genetic characteristics based on predictive biomarkers such as microsatellite instability, RAS and BRAF mutations, HER2 amplification, or NTRK fusions. As molecular and genetic predictive tests are routinely performed, new challenges for mCRC treatment strategies are allowed. For patients responding to anti-epithelial growth factor receptor treatments, expanded biomarkers panels enable customized treatment to be selected and the optimal treatment can be determined. Patients with mCRC with the BRAFV600E mutation who did not have effective targeted treatments have effective therapeutic options. Attractive but rare targets, such as HER2 amplification and NTRK fusions, could be a breakthrough and the use of immune checkpoint inhibitors in patients with mismatch repair deficiency/microsatellite instability is the striking revolution. In this review, we summarize the current landscape of targeted therapies for mCRC patients, with a focus on new developments for epithelial growth factor receptor blockade and emerging biomarkers.

Dysregulated PDGFR alpha\xa0expression and\xa0novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor\xa0size

BackgroundPlatelet derived growth factor receptor alpha (PDGFRα) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFRα protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction.MethodsOur study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFRα expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls.ResultsPDGFRα staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFRα overexpression. This overexpression was significantly associated with mutations in exon 18 (P = 0.024), RAS wild type status (P < 10–3), tumor diameter (P = 0.048), whereas there was no association with tumor side (P = 0.13) and other clinicopathological features.ConclusionOverexpression of PDGFRα in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFRα overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.

KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician.

BackgroundColorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10–16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer.ConclusionsThere are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.

Anti-claudin-4 extracellular domain antibody enhances the antitumoral effects of chemotherapeutic and antibody drugs in colorectal cancer.

Claudin-4 (CLDN4) is a major epithelial tight junction protein overexpressed in many cancers to maintain the tumor environment. In this report, we aimed to determine the efficacy of targeting CLDN4 in colorectal cancer (CRC) using an anti-CLDN4 extracellular domain antibody, 4D3. CLDN4 was upregulated in CRC metastatic foci. CLDN4 expression in CRC cells was reduced by upregulation of TNFα, which was induced by Clostridium perfringens enterotoxin produced by gut flora. In a nude mouse liver metastasis model, inhibition of metastasis was increased by combination treatment with 5-fluorouracil (FU) and 4D3 compared to that with 5-FU alone. Moreover, combination treatment with 4D3 and anti-epithelial growth factor receptor (EGFR) antibody C225 resulted in more pronounced inhibition of in vitro sphere formation and tumor growth in nude mice compared to that observed with C225 alone. Moreover, the time interval between the administration of 4D3 and that of C225 was important for maximizing the C225-induced inhibition of EGFR phosphorylation. In a nude mouse model, sequential treatment with 4D3 and C225 with a 6-h time interval resulted in more pronounced inhibition of tumor growth than concurrent treatment. These findings suggest that the targeting of CLDN4 enhances the antitumoral effects of chemotherapeutic agents and molecular targeting antibodies when used in combination.

Panitumumab Provides Better Survival Outcomes Compared to Cetuximab for Metastatic Colorectal Cancer Patients Treated with Prior Bevacizumab within 6 Months

Objective: Anti-epithelial growth factor receptor (EGFR) antibodies cetuximab (Cmab) and panitumumab (Pmab) have shown survival benefit for metastatic colorectal cancer (mCRC) patients. This study aimed to compare Pmab and Cmab according to the interval between bevacizumab discontinuation and anti-EGFR antibody initiation (bevacizumab-free interval; BFI). Methods: We retrospectively evaluated mCRC patients who received Cmab or Pmab in combination with irinotecan at two institutions. Inclusion criteria were histologically confirmed mCRC, with KRAS exon 2 wild-type tumor, refractory or intolerant to fluoropyrimidines, oxali platin, and irinotecan. Results: One-hundred-seventy-eight patients fulfilled the eligibility criteria. Among them, there was no significant difference in overall survival (OS) and progression-free survival (PFS) between the Pmab (n = 44) and Cmab groups (n = 134). Of 132 patients with BFI < 6 months, the median OS was 13.3 and 11.5 months in the Pmab (n = 39) and Cmab (n = 93) groups, respectively (p = 0.043). The median PFS was 5.8 and 4.9 months in the Pmab and Cmab groups, respectively (p = 0.055). Multivariate analysis for OS confirmed the superiority of Pmab. Conclusion: Pmab showed more favorable outcomes in patients treated with bevacizumab within the last 6 months. The interval between prior bevacizumab and subsequent anti-EGFR therapy may be useful for determining the optimal anti-EGFR therapy.

Technical Validation of a Reverse-Transcription Quantitative Polymerase Chain Reaction In Vitro Diagnostic Test for the Determination of MiR-31-3p Expression Levels in Formalin-Fixed Paraffin-Embedded Metastatic Colorectal Cancer Tumor Specimens.

MiR-31-3p expression has been shown to be a predictive biomarker for response to anti-epithelial growth factor receptor therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). To aid in the quantification of miR-31-3p expression in formalin-fixed paraffin-embedded (FFPE) primary tumor samples from patients with mCRC, a reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay was developed and validated. Assay development included the identification of a microRNA reference standard and the determination of an appropriate relative quantification cutoff for differentiating low versus high miR-31-3p expression. Sample specimens for the validation studies included both FFPE slides and shavings. Polymerase chain reaction (PCR) efficiency and linearity, analytical sensitivity and specificity, assay robustness, reproducibility, and accuracy were demonstrated across a number of test conditions and differing quantitative PCR platforms. The data from this study provide evidence as to the feasibility of quantifying the expression of miR-31-3p from FFPE tumor tissue using a standardized RT-qPCR assay.

Surgical treatment of colorectal liver metastases

Surgical resection of the metastases offers the only opportunity for long-term survival in colorectal liver metastases. However, only 10% to 20% of patients present with resectable disease, and so how to increase surgical patients has been a clinical hotspot. In addition to expanding surgical indications, two-stage hepatectomy and convertible therapy are optional. In convertible therapy, initial treatment regimen decides long-term benefit, and it is important to select appropriate patient population in addition to Ras status when anti-epithelial growth factor receptor monoclonal antibody is used. Minimally invasive surgery can also be used for liver resection and simultaneous resection, and it is safe and effective. For patients with colorectal cancer and unresectable asymptomatic liver metastases, the debate continues over the efficacy of primary resection compared to chemotherapy alone, limited by lack of prospective evidence. Therefore, multidisciplinary team assessment is essential to optimize outcomes in colorectal liver metastases.

Dual targeting of solid lipid nanoparticles grafted with 83-14 MAb and anti-EGF receptor for malignant brain tumor therapy

AimsSolid lipid nanoparticles (SLNs) conjugated with surface 83-14 monoclonal antibody (8314MAb) and anti-epithelial growth factor receptor (AEGFR) were synthesized and applied to permeate the blood–brain barrier (BBB) and inhibit the growth of glioblastoma multiforme (GBM). Main methods8314MAb and AEGFR were crosslinked on SLNs to carry etoposide (ETP) across human brain-microvascular endothelial cells (HBMECs) and to treat U87MG cells. Key findingsAn increase in the 8314MAb concentration increased the permeability for propidium iodide (PI) and ETP across the BBB, however, decreased the 8314MAb grafting efficiency and transendothelial electrical resistance of the monolayer of HBMECs. In addition, an increase in the AEGFR concentration enhanced the viability of HBMECs and human astrocytes (HAs), however, reduced the AEGFR grafting efficiency and ETP release rate. An incorporation of both 8314MAb and AEGFR increased the particle size, however, decreased the zeta potential, ETP release rate, and viability of HBMECs and HAs. SignificanceThe conjugation of 8314MAb and AEGFR on ETP-loaded SLNs can be a promising strategy to deliver antitumor ETP to the brain and restrain the propagation of GBM.

A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer.

Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy. We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months). Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43-0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41-0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012). A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy.

Rare RAS Mutations in Metastatic Colorectal Cancer Detected During Routine RAS Genotyping Using Next Generation Sequencing.

Overall survival of metastatic colorectal cancer (mCRC) patients has been improved with the addition of targeted therapy such as anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR mAbs) to standard chemotherapy. Retrospective studies and randomized trials showed that the presence of RAS mutations was linked to the absence of clinical response to anti-EGFR mAbs. Patients harboring KRAS and NRAS mutations on exons 2, 3 or 4 have little or no benefit from anti-EGFR therapies. Polymerase chain reaction (PCR)-based assays are routinely used to assess KRAS and NRAS status, whereas deep sequencing with next generation sequencing (NGS) currently represents an alternative method. The objective of our study was to identify KRAS and NRAS non-hotspot mutations using NGS of mCRC tumor samples. DNA was extracted from 188 consecutive formalin-fixed paraffin embedded samples of histologically proven colorectal cancer tumor tissue from patients with mCRC. Following amplification, DNA was sequenced by ultra-deep pyrosequencing. Non-hotspot mutations identified by NGS (frequency of mutated allele range [1.8-70.6%]) were confirmed by Sanger direct-sequencing when possible. NGS procedure was applicable in 94% of the cases and detected mutations in 62% of the samples. Nine uncommon mutational profiles were found with a frequency of mutated allele > 1%. Silent mutations were found in 3.6% of the samples. Mutations at or near functional domains of RAS proteins, other than defined hotspots, were found in 3.6%. NGS proved to be accurate, sensitive and suitable for routine RAS genotyping. Clinical responses to anti-EGFR mAbs are potentially impaired in the presence of these uncommon RAS mutations.

Immunotargeted photodynamic therapy for cholesteatoma: in vitro results with anti-EGFR-coated indocyanine green nanocapsules.

The objective was to test the hypothesis that immunotargeted photodynamic therapy (IT-PDT) using anti-epithelial growth factor receptor (EGFR)-coated indocyanine green (ICG) nanocapsules would selectively kill cholesteatoma-derived keratinocytes while sparing middle ear-derived mucosa cells in vitro. Rates of residual cholesteatoma caused by incomplete microsurgical removal are unacceptably high; thus, development of an adjuvant therapy to safely destroy undetected residual cholesteatoma cells would be desirable. IT-PDT is a possible means to achieve this end. ICG nanocapsules coated with anti-EGFR were synthesized and applied to cholesteatoma-derived keratinocytes and middle ear mucosa cells in vitro. Selective binding to keratinocytes was evaluated by fluorescence microscopy. Activation of ICG was undertaken by applying near-infrared light (810 nm) at an applied energy dose of 1,080 J/cm. Cell death was evaluated 2 hours after treatment with trypan blue staining. Selective and robust nanocapsule binding to keratinocytes, but not mucosa cells, was confirmed by preapplication and postapplication fluorescence measurements. A keratinocyte cell death rate of 70.12% ± 2.50% was achieved, whereas negligible mucosa cell death was observed. Negligible cell death was also observed for both cell types with application of the nanocapsules alone or with application of near-infrared light alone. Anti-EGFR ICG nanocapsules applied topically and activated as part of an IT-PDT scheme results in a high rate of cholesteatoma-derived keratinocyte cell death while negligibly affecting middle ear mucosal cells in vitro. These preliminary findings suggest that this is a feasible concept and that further investigation is warranted.

Electrolyte disorders assessment in solid tumor patients treated with anti-EGFR monoclonal antibodies: a pooled analysis of 25 randomized clinical trials.

The role of anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) in treatment-related electrolyte disorders is still controversial. Therefore, we conducted a meta-analysis of published randomized controlled trials (RCTs) to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events. We searched relevant clinical trials from PubMed, EMBASE, and Web of Knowledge databases, meeting proceedings of American Society of Clinical Oncology and the European Society of Medical Oncology, as well as ClinicalTrials.gov. Eligible studies included phases II, III, and IV RCTs. Statistical analysis was performed to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) using fixed effects or random effects models based on the heterogeneity of included studies. A total of 16,411 patients from 25 RCTs were included in this meta-analysis. The all-grade incidence of hypomagnesemia related to anti-EGFR MoAbs was 34.0 % (95 % CI 28.0–40.5 %), and that for hypokalemia and hypocalcemia were 14.5 % (95 % CI 8.2–24.4 %) and 16.8 % (95 % CI 14.2–19.7 %), respectively. Compared with chemotherapy alone in colorectal cancer, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia and grade 3/4 hypokalemia with RRs of 7.14 (95 % CI 3.13–16.27, p < 0.001) and 2.19 (95 % CI 1.14–4.23, p = 0.019). Additionally, colorectal cancer patients in panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia and hypokalemia (RR 18.29, 95 % CI 7.29–48.41, p < 0.001, and RR 3.3, 95 % CI 1.32–8.25, p = 0.011). Treatment with anti-EGFR MoAbs is associated with significantly higher risks of electrolyte disorders such as hypomagnesemia, hypomagnesemia, and hypocalcemia, especially in colorectal cancer. Rigorous monitoring and early treatment of electrolyte disorders are proposed.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-014-2983-9) contains supplementary material, which is available to authorized users.

Small Molecule Agonists of PPAR-γ Exert Therapeutic Effects in Esophageal Cancer

The transcription factor PPAR-γ plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-γ agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-γ agonist that selectively activates PPAR-γ target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-γ status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-γ was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-γ expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-γ agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, the combination of efatutazone with the antiepithelial growth factor receptor antibody cetuximab synergized to negatively regulate the phosphoinositide 3-kinase-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC.

Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab

RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.

Identification of K-ras Mutation in a Patient With Non-small Cell Lung Cancer Treated With Chemoradiation Therapy and Panitumumab: A Possibility to Personalize Cancer Therapy

RTOG 0839 is a Phase II study of pre-operative chemoradiation therapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigatory agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody. Although K-ras mutations have been shown to be predictive to anti-EGFR therapy in colorectal cancer, it is unknown if they predict benefit to anti-EGFR therapy in combination with chemoradiation for Stage III NSCLC. The purpose of this report is to identify a NSCLC patient with a KRAS mutation who had a partial pathologic response, with disappearance of K-ras mutant clone.