AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).
We evaluate the antitumor efficacy ...of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with
expression are enriched in EMT, migration, and invasion signaling pathways.
Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion.
stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (
, and
) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.
The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.
.
Purpose
Sexual quality of life (QoL) is affected during and after breast cancer (BC) treatment. The purpose was to investigate sexual and global QoL and patient-reported measures to address this ...issue in young women (< 51 years) with BC after the acute treatment phase, during adjuvant endocrine therapy.
Methods
Three EORTC questionnaires and an additional specific questionnaire, developed for the study, were used to assess sexual and global QoL and patient-reported supportive measures in BC patients who had received their endocrine therapy for at least 24 months. Among the 54 eligible patients, 45 (83%) agreed to participate in the study.
Results
We showed a deterioration in sexual QoL and poor communication with healthcare professionals. Most patients (88.9%) declared that it was important that sexuality should be discussed with caregivers and that the partner should also be involved. Most patients (60%) had taken at least one action to overcome their sexual problems. Most of these interventions (63%) originated from the patient herself.
Conclusions
Sexual QoL is a major issue in young BC patients and is poorly addressed by healthcare professionals. Most of the supportive methods used by the patients to overcome these side effects were on their own initiative. Communication and counseling on sexuality by healthcare professionals need to be improved during BC treatment. Patients suggested supportive measures they would find useful and appropriate to develop in the clinic. The final goal is to improve the sexual QoL of BC patients with the appropriate intervention and support.
Purpose
Sexual quality of life (QoL) is affected during and after breast cancer (BC) treatment and is not specifically evaluated with the general health-related quality-of-life questionnaires EORTC ...QLQ-C30 or QLQ-BR23. A specific questionnaire, the EORTC SHQ-C22, including physical, psychological, and social aspects of sexuality, was recently developed to address this issue in cancer patients.
Methods
A prospective bicentric study was conducted to evaluate the sexual QoL of women with BC during the first year of adjuvant hormonal treatment.
Results
A total of 106 women completed the 3 questionnaires at baseline and 92 of them, at 12 months. At baseline, we showed low sexual satisfaction and importance given to sexual activity and a very low communication with healthcare professionals about this issue. Twelve months later, the importance given to sexuality had increased. While the communication with professionals had improved, it remained at a very low level. We were unable to identify specific clinical factors (chemotherapy, menopausal status, type of surgery or radiotherapy) that would negatively affect the global sexual well-being in BC patients.
Conclusion
The analysis of sexual QoL of BC patients during the first year of hormonal treatment with a recently developed, cancer-dedicated, standardized tool pointed out the need for deeper communication between professionals and patients regarding sexual issues to fill the current gap in care of cancer patients and help patients with adequate intervention and support.
In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and ...proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5-25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients' ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.
Background
Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis ...(LCRA)
.
Methods
In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded.
Results
Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%;
p
= 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (
p
= 0.064), disease-free survival was 67.0% and 55.8%, respectively (
p
= 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (
p
= 0.084). The long-term, stoma-free rate was 89.1% overall.
Conclusions
Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.
Study results have shown that chronic exposure to cigarette smoke affects the taste function in humans. However, neither the quantitative impact on taste sensitivity nor the time-course of taste ...recovery on stopping smoking have been precisely examined.
The experimental design included 2 phases, (i) a case-control phase comparing the taste sensitivity level measured by Electrogustometric (EGM) thresholds from various parts of the tongue (locus) between smokers (
= 83) and non-smokers (
= 48), (ii) a follow-up study looking at the taste sensitivity recovery in smokers after smoking cessation (
= 24) and compared with non-smokers.
Smokers exhibited significantly lower taste sensitivity than non-smokers - the higher the nicotine dependence (Fagerström scores), the lower the taste sensitivity. After smoking cessation, EGM thresholds decreased progressively, and reached the taste sensitivity range of non-smokers depending on locus and time. After 2 weeks a recovery could be observed on the 3 Tip and the 2 edge loci; the recovery in the posterior loci was complete after 9 weeks, and in the dorsal loci recovery was observed only after 2 months or more.
Smoking cessation does lead to a rapid recovery of taste sensitivity among smokers, with recovery time found to differ based on the sensitivity of loci of the tongue. The use of EGM could potentially be explored as a motivational tool for smoking cessation.
We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 ...(monoclonal antibodies labeled with (125)I (125)I-mAbs).
We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-(125)Iiodo-2'-deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also.
Low-energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting.
Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.
Although many patients with colorectal cancer initially respond to the chemotherapeutic agent oxaliplatin, acquired resistance to this treatment remains a major challenge to the long-term management ...of this disease. To identify molecular targets of oxaliplatin resistance in colorectal cancer, we performed an shRNA-based loss-of-function genetic screen using a kinome library. We found that silencing of ataxia-telangiectasia mutated and RAD3-related (ATR), a serine/threonine protein kinase involved in the response to DNA stress, restored oxaliplatin sensitivity in a cellular model of oxaliplatin resistance. Combined application of the ATR inhibitor VE-822 and oxaliplatin resulted in strong synergistic effects in six different colorectal cancer cell lines and their oxaliplatin-resistant subclones, promoted DNA single- and double-strand break formation, growth arrest, and apoptosis. This treatment also increased replicative stress, cytoplasmic DNA, and signals related to immunogenic cell death such as calreticulin exposure and HMGB1 and ATP release. In a syngeneic colorectal cancer mouse model, combined administration of VE-822 and oxaliplatin significantly increased survival by promoting antitumor T-cell responses. Finally, a DNA repair gene signature discriminated sensitive from drug-resistant patients with colorectal cancer. Overall, our results highlight the potential of ATR inhibition combined with oxaliplatin to sensitize cells to chemotherapy as a therapeutic option for patients with colorectal cancer. SIGNIFICANCE: These findings demonstrate that resistance to oxaliplatin in colorectal cancer cells can be overcome with inhibitors of ATR and that combined treatment with both agents exerts synergistic antitumor effects.
http://cancerres.aacrjournals.org/content/canres/79/11/2933/F1.large.jpg.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic ...markers. We previously generated the nonligand competing anti‐HER3 antibody 9F7–F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7–F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody‐drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE‐based HER3 antibody‐drug conjugate (HER3‐ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3‐positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3‐ADC decreased the clonogenic survival of irradiated cells by increasing DNA double‐strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3‐ADC favored the inhibition of the AKT‐induced survival pathway, together with more efficient caspase 3/PARP‐mediated apoptosis. Incubation with HER3‐ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3‐ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient‐derived xenografts, and reduced proliferation (KI67‐positive cells). Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy is a new promising therapeutic strategy in PDAC.
What's new?
In pancreatic ductal adenocarcinoma (PDAC), chemoradiation is prescribed to patients with borderline resectable lesions to make surgery possible. The HER3 receptor is a key signaling hub in PDAC. Here, the authors developed a novel antibody‐drug conjugate targeting HER3 (HER3‐ADC) that enhanced radiosensitivity of PDAC by arresting cells in G2/M. HER3‐ADC increased radiation response in mice xenografted with PDAC cells, through inhibition of cell survival and induction of DNA break formation and apoptosis. Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy could help increase the rate of resection for patients with borderline resectable pancreatic cancer.
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