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Capecitabine induced toxicities such as hand-foot syndrome (HFS) and progression of metastatic cancer are both treatable with concurrent celecoxib as shown in the ADAPT (Activating ...Cancer Stem Cells from Dormancy And Potentiate for Targeting) trial. In the present study, five commonly used NSAIDs, including celecoxib were compared for their pro-oxidative capacities as cytotoxic drugs against human and mouse metastatic melanoma or breast cancer cells in vitroand the source of cellular ROS production induced by celecoxib was examined in greater detail.
Celecoxib was unique among the NSAIDs in that it showed particular potency as a cytotoxic drug against the metastatic cancer cells with IC50 values in the low micromolar range. Celecoxib rapidly enhanced mitochondrial superoxide production in situ from cancer cells within minutes, leading to a decrease in cellular respiration and dissipation of the mitochondrial transmembrane potential (Δψm), followed by extensive ROS-dependent apoptosis of the metastatic cancer cells. Celecoxib also showed rapid and direct effects on isolated mitochondria, inducing extensive ROS production in a dose-dependent manner, whilst it inhibited respiration via Complex I or Complex II when tested in whole cells. Mitochondrial ROS production was necessary for the celecoxib induced cell death.
These novel findings for direct effects of celecoxib on mitochondria to induce metastatic cancer cell death via a ROS-dependent pro-oxidative mechanism provide supportive evidence for its combinatorial use as a chemosensitizing agent complementing chemotherapies to improve response rates in patients with advanced metastatic cancers.
Colorectal cancer represents an important oncological challenge both for its incidence, which makes it an important health problem, and for its biological complexity, which has made clinical results ...very difficult in terms of outcome for this category of patients. To date these diseases should not be treated as a single entity but it is necessary to distinguish colorectal cancers based on characteristics that nowadays are essential to have greater therapeutic benefits. These include the sideness of the disease, the state of microsatellites, the presence of prognostic and predictive mutations of response to treatments currently available in clinical practice, which are associated with new therapeutic targets. The greatest challenge in the future will be to circumvent the resistance mechanisms that make this disease very difficult to treat with good long-term results by studying effective combination treatments with a good toxicity profile. Once such combinations or targeted treatments are consolidated, it will be desirable to shift the best therapies to the first line treatment to make them immediately accessible to the patient. It will also be essential to refine the selection of patients who can benefit from these treatments.
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•Histidine-functionalized carbon nanodots as photo-oxidative nanozymes were developed.•The ability of nanozyme for cancer theranostics was proved on B16-F10 melanoma cells.•The ...biocompatibility of nanozyme was demonstrated by MTT assay.
Ultra-small histidine-functionalized carbon nanodots (His C-dots) with engineered modality as photo-oxidative nanozymes for cancer theranostics were prepared by one step microwave-assisted pyrolysis. The role of chemically embedded imidazole ring into nanoparticle aromatic domains was to enhance the absorbance, fluorescence, and phosphorescence intensities in aqueous solution at room temperature. It contributed to the increase of pyrrolic nitrogen, which was responsible for the higher oxygen adsorption and better photosensitization under visible irradiation. The ability of nanozyme as theranostics was demonstrated on illuminated with visible light B16-F10 mouse melanoma cells with high metastatic potential under normoxic condition. The inhibition of cell migration was measured by wound healing assay after scratching confluent monolayer of the breast cancer cells. The microscopic data revealed that the metastatic migration could be controlled by the applied nanozyme dosage, which was responsible for the production of singlet oxygen and the causing of effective photo-induced cytotoxicity. The biocompatibility of the illuminated His C-dots was proved on ATPase activity of intact mitochondria and sub-mitochondrial particles, on diamine oxidase activity of liver and kidney fractions in dark mode, MTT assay as well as on non-illuminated adenocarcinomic human alveolar basal epithelial cells (A549) and human liver cancer cells (HepG2). The satisfactory ability of the reported nanoparticles as fluorescence anticancer agents makes them a promising platform for the development of oxidize-mimicking nanozymes with application in the photodynamic therapy.
•Colorectal cancer (CRC) incidence and mortality rates have been increasing among adults under the age of 50-years (young patients, YP) and for uncertain reasons.•YP with CRC were more likely to be ...female, good performance status and with left-sided primary. No standard molecular features were found to differ significantly between YP and OP.•YP with CRC had a more aggressive treatment approach, signified by increased rates of surgical management and more aggressive chemotherapy regimens.•Median OS was significantly longer in YP, which is consistent with a tendency for YP to have favorable prognostic variables and a more aggressive treatment approach. Median PFS did not differ between the two groups.•It remains unclear whether there is a distinct tumor biology in YP and based on current evidence, a modified treatment approach is not warranted.
Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP).
We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years).
Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0–1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP.
Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.
HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal ...transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.
Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks.
All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels.
HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies.
NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 .
When evaluating metastatic tumor response to systemic therapies, dissociated response is defined as the coexistence of responding and non-responding lesions within the same patient. Although commonly ...observed on interim whole-body imaging, the current response criteria in solid cancer do not consider this evolutive pattern, which is, by default, assimilated to progression. With targeted therapies and chemotherapies, dissociated response is observed with different frequencies, depending on the primary cancer type, treatment, and imaging modality. Because FDG PET/CT can easily assess response on a lesion-by-lesion basis, thus quickly revealing response heterogeneity, a PET/CT dissociated response has been described in up to 48% of women treated for a metastatic breast cancer. Although some studies have underlined a specific prognostic of dissociated response, it has always ended up being described as an unfavorable prognostic pattern and therefore assimilated to the “Progressive Disease” category of RECIST/PERCIST. This dichotomous imaging report (response vs. progression) provides a simple information for clinical decision-support, which probably explains the relatively low consideration for the dissociated response pattern to chemotherapies and targeted therapies until now. With immune checkpoint inhibitors, this paradigm is quickly changing. Dissociated response is observed in around 10% of advanced lung cancer patients and appears to be associated to treatment efficiency. Indeed, for this subset of patients, a clinical benefit of immunotherapy and favorable prognosis are usually observed. This specific pattern should therefore be considered in the future immunotherapy-adapted criteria for response evaluation using CT and PET/CT, and specific clinical managements should be evaluated for this response pattern.
A quintessential setting for precision medicine, theranostics refers to a rapidly evolving field of medicine in which disease is diagnosed followed by treatment of disease‐positive patients using ...tools for the therapy identical or similar to those used for the diagnosis. Against the backdrop of only‐treat‐when‐visualized, the goal is a high therapeutic index with efficacy markedly surpassing toxicity. Oncology leads the way in theranostics innovation, where the approach has become possible with the identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels or warheads for imaging and therapy. Radiotheranostics—using radiopharmaceuticals—is becoming routine in patients with prostate cancer and neuroendocrine tumors who express the proteins PSMA (prostate‐specific membrane antigen) and SSTR2 (somatostatin receptor 2), respectively, on their cancer. The palpable excitement in the field stems from the finding that a proportion of patients with large metastatic burden show complete and partial responses, and this outcome is catalyzing the search for more radiotheranostics approaches. Not every patient will benefit from radiotheranostics; but, for those who cross the target‐detected line, the likelihood of response is very high.
The unique profile of upregulated glycosylation in metastatic cancer cells may form the basis for the development of new biomarkers for the targeting and diagnosis of specific cancers. This study ...introduces a pancreatic cancer cell-derived exosome detection technology, which is based on the specific binding of lectins to distinctive glycan profiles on the surface of exosomes. Lectins with a high and specific affinity for sialic acid or fucose were attached to bifunctional Janus nanoparticles (JNPs), which facilitated interactions with pancreatic cancer cell-derived exosomes in a microfluidic device. Here, we show that pancreatic cancer cell-derived exosomes from two cell lines and plasma samples collected from patients diagnosed with pancreatic cancer were successfully captured on the lectin-conjugated JNPs with affinities that were comparable to those of CA19-9, a conventional antibody. In addition, exosome detection using our platform could differentiate between metastatic and nonmetastatic pancreatic cancer cells. This study opens the possibility to achieve a new early diagnosis marker based on the glycan properties of pancreatic cancer cell-derived exosomes.
•The use of specific glycan moieties allows the development of clinical diagnostics with high ensitivity and selectivity.•Lectin-glycan interactions have the inherent potential to capture exosomes derived from cancer cells without antibodies.•The relative fluorescence evaluation of exosomes presents an opportunity for evaluating cancer metastasis.
This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody.
TSA mouse breast carcinoma cells were ...injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.
In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the inhibition of the secondary tumor.
Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
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