Anti-Cancer Drugs最新文献

The prognosis of advanced lung large-cell neuroendocrine carcinoma is poor, and the efficacy of targeted therapy is still being explored. A case of RET fusion mutation combined with ALK rearrangement positive advanced lung complex large cell neuroendocrine carcinoma was reported. The patient developed intrapulmonary and bone metastases 8 months after chemotherapy after lung cancer surgery, RET fusion mutations were detected by genetic testing, and intracranial progression occurred 1 year after pilatinib was applied. The comutation of RET and ALK was detected by genetic testing, and the pulmonary progression occurred 2 months after the application of aletinib, after being treated with pilatinib and aletinib, he progressed again in 9 months. We point out that large cell neuroendocrine carcinoma complex patients with RET gene mutation can benefit from targeted therapy, and when drug resistance is accompanied by ALK comutation, the patient can benefit from the treatment of the aletinib combined with pilatinib targeted therapy and the side effect is slight. At the same time, we further explore the resistance mechanism of targeted therapy in lung cancer.

The human papillomavirus (HPV) is implicated in multiple lethal cancers, although it is more sensitive to certain therapies than HPV-negative cancers. Therefore, the development of more targeted therapeutic strategies is imperative. The HPV oncogenes E6/E7 are ideal targets for HPV-positive cancer, but there are no clinical strategies that have been proven to effectively target E6/E7. Notably, metformin significantly inhibits E6/E7 expression; however, the underlying mechanism and therapeutic potential remain unclear, limiting its clinical translation. Cell Counting Kit-8, ethynyl-2'-deoxyuridine, and terminal-deoxynucleotidyl transferase-mediated Nick end labeling assays were conducted to evaluate the effects of metformin on cell viability, proliferation, and apoptosis. Quantitative real-time PCR, western blotting, and immunofluorescence assays were performed to determine changes in E6/E7 and p53 expression levels following metformin treatment. Patient-derived organoids and in-vivo xenograft models were constructed to evaluate the anticancer activity of metformin against HPV-positive cancer. Our research demonstrated enhanced sensitivity of HPV-positive cancer cells to metformin. Mechanistic studies have revealed that metformin exerts anticancer effects by inhibiting E6/E7 expression, which is associated with p53 reactivation. Furthermore, we substantiated the anticancer potential of metformin in HPV-positive patient-derived organoids and in-vivo tumor models. Our study focused on the mechanism underlying the enhanced responsiveness of HPV-positive cancer to metformin, highlighting the clinical potential of metformin as a targeted therapeutic strategy for HPV-positive cancer.

Herein, we report a case of occult epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma complicated by prostatic metastasis. A 75-year-old male with >30 years of smoking history presented with lower back pain as the initial symptom. Respiratory symptoms, including cough and sputum production, were absent. PET-computed tomography revealed the presence of bone and prostatic metastases, without any lung abnormalities. Biopsies of the space-occupying bone and metastatic lesions suggested that the metastases originated from primary lung adenocarcinoma. Genetic testing indicated EGFR 21L858R(+). The patient had an abnormal serum carcinoembryonic antigen level but a normal prostate-specific antigen level. Following a multidisciplinary discussion, a diagnosis of occult primary lung adenocarcinoma complicated by bone and prostatic metastases (TxN0M1b, Stage IVB) was considered. Following targeted therapy with oral osimertinib, the patient achieved a partial response, with alleviation of pain symptoms alleviated and normalization of carcinoembryonic antigen levels. In the absence of tissue biopsy, such cases can often be misdiagnosed as prostate cancer complicated by multiple bone metastases. Hence, the present case highlights the importance of comprehensive diagnostic testing, including tissue biopsy, to accurately identify the underlying cause of metastatic disease.

Tumor-infiltrating lymphocytes (TILs) often have upregulated expression of immune checkpoint receptors, such as programmed cell death 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3). Patients treated with antibodies targeting PD-1 or its ligand (PD-L1) can develop resistance or relapse, with LAG-3 upregulation on T cells being one possible mechanism. FS118 is a tetravalent, bispecific antibody comprising a full-length IgG 1 anti-PD-L1 antibody with bivalent LAG-3-binding capability in the fragment crystallizable region. Here we demonstrate how the structure of FS118 is important for its function. We generated variants of FS118 and tested their ability to mediate LAG-3 shedding using staphylococcal enterotoxin B assays, antigen recall assays, and soluble LAG-3 ELISAs. Mediated by metalloproteases ADAM10 and ADAM17, FS118 induced shedding of LAG-3 from the surface of both CD4 + and CD8 + T cells. We also determined the effect of surrogate antibodies on immune cell LAG-3 expression and proliferation in syngeneic mouse models. In vivo , the bivalent LAG-3 binding sites of a mouse surrogate of FS118 and their location in the fragment crystallizable region were important for eliciting maximal reduction in LAG-3 levels on the surface of TILs, as variants with a single LAG-3 binding site in the fragment crystallizable region, or with reversed orientation of the LAG-3 and PD-L1 binding sites, were less efficient at inducing shedding. We also show that PD-L1, not PD-1, binding drives the LAG-3 reduction on TILs. We hypothesize that the LAG-3 bivalency in the fragment crystallizable region of FS118 allows LAG-3 clustering, which optimizes cleavage by ADAM10/ADAM17 and thus shedding.

The biology of GZ17-6.02 alone and more so in combination with either of the standard-of-care agents etoposide or carboplatin killed MYCN overexpressing neuroblastoma (NB) cells is unknown. The methods involved in this study are in-cell immunoblotting, trypan blue exclusion, plasmid and siRNA transfection, assessment of autophagy using a plasmid expressing LC3-GFP-RFP. GZ17-6.02 (602) comprises, by mass, a ratio of curcumin (1.0), harmine (1.3), and isovanillin (7.7). In tumors dosed with 602, the ratio becomes curcumin (1.0), harmine (16), and isovanillin (6.1) (602NR). GZ17-6.02 activated ATM, AMPK, ULK1, ATG13, and PERK and inactivated ERBB1, ERBB2, ERBB3, ERBB4, AKT, mTORC1, mTORC2, SRC, NFκB, YAP, and eIF2α. 602 enhanced autophagosome formation and autophagic flux that was amplified when it was combined with etoposide or carboplatin. Compared with 602, 602NR caused significantly greater autophagosome formation that was also amplified when in combination with chemotherapy and which was reduced ~40% by knockdown of ATM or AMPKα and abolished by knockdown of Beclin1 or ATG5. Knockdown of ATM or AMPKα significantly reduced tumor cell death caused by 602 of 602NR, whereas endoplasmic reticulum stress (eIF2α) and macroautophagy (Beclin1, ATG5) were more effective at maintaining tumor cell survival. Combined knockdown of Beclin1 and the death receptor CD95 almost abolished the antitumor actions of 602 and 602NR. 602, and more so 602NR, kills MYCN NB cells and interacts with standard-of-care chemotherapeutics to cause further killing via autophagy and death receptor signaling.

The objective of this study is to explore the effect of adjuvant chemotherapy with toad venom injection in patients with intermediate and advanced colon cancer, in order to provide new reference drugs for clinical treatment. Prospectively, 148 patients with mid-stage to late-stage colon cancer in our hospital from January 2021 to May 2023 were selected for the study and randomly divided into two groups of 74 cases each. The control group was treated with FOLFOX4 chemotherapy, and the observation group was treated with four consecutive chemotherapy cycles based on the control group combined with toad venom injection. The treatment effects, adverse reactions, quality of life improvement rate, prognosis and cellular immune indexes [natural killer (NK) cells, CD4 + /CD8 + , CD4 + , CD3 + ], phosphatase tensin gene ( PTEN ), phosphatidylinositol-3-kinase (PI3k), and serine threonine protein kinase (pAKT) protein expression before and after treatment were counted in the two groups. The total effective rate of treatment in the observation group was 58.11% (43/74) after four cycles of chemotherapy, which was higher than that in the control group of 41.89% (31/74) ( P  < 0.05). After two cycles of chemotherapy and four cycles of chemotherapy, PTEN , CD4 + /CD8 + , CD4 + , CD3 + , and NK cells in peripheral blood were higher in the observation group than in the control group, and PI3k and pAKT were lower than in the control group ( P  < 0.05). There was no statistically significant difference in the rate of adverse reactions in the observation group compared with the control group ( P  > 0.05); the improvement rate of quality of life in the observation group was better than that in the control group after four chemotherapy cycles of treatment ( P  < 0.05); the survival rate was 75.00% (54/72) in the observation group compared with 54.29% (38/70) in the control group at 1-year follow-up. Toad venom injection adjuvant chemotherapy is effective in treating patients with intermediate and advanced colon cancer, which can upregulate PTEN level, inhibit PI3k and AKT expression, and improve immune function and quality of life of patients, thus improving prognosis.

Immune checkpoint blockage (ICB) therapy has shown minimal effectiveness in anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC) regardless of Programmed death-ligand 1 expression. ALK fusion accompanied by mismatch repair deficiency or microsatellite instability-high (MMRd/MSI-H) and high tumor mutation burden (TMB-H) are extremely rare in NSCLC, and the efficacy of ALK inhibitors or ICB-based therapies is unclear. Here, we report the case of a 60-year-old female patient with metastatic lung adenocarcinoma accompanied by EML4-ALK fusion, TMB-H, MMRd/MSI-H, and pathogenic mutations in TP53, MLH1, and STK11. The patient experienced progression on initial iruplinalkib and subsequent alectinib therapy within 5 months. After the failure of third-line therapy with cisplatin-pemetrexed combined with bevacizumab, she received sintilimab plus anlotinib which led to a progression-free survival of 6.5 months. She received sintilimab combined with albumin-paclitaxel plus carboplatin and achieved partial response after 6 months. She developed adverse events after one cycle of sintilimab plus albumin-paclitaxel treatment. Then she was continued with sintilimab plus anlotinib as a maintenance therapy due to intolerance to chemotherapy. After progression on ICB-based therapy, the patient was treated with lorlatinib and still under follow-up with overall survival of more than 3 years. Our findings highlight the therapeutic potential of ICB-based regimens in patients with MSI-H and ALK-rearranged NSCLC.

FOLFOX combined with cetuximab is a recommended first-line treatment regimen for RAS/BRAF wild-type metastatic colorectal cancer (mCRC). CAPEOX combined with cetuximab differs from the FOLFOX regimen by using oral capecitabine instead of continuous infusion of fluorouracil, offering greater convenience and cost-effectiveness with higher patient acceptance. However, the comparative efficacy of these two regimens remains debatable, necessitating further evidence to explore any differences in their efficacy. This study collected medical records of mCRC patients who were treated with CAPEOX or FOLFOX combined with cetuximab from 1 October 2021 to 16 October 2023 at Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University. Eligible patients were selected based on inclusion criteria and followed up through the hospital's follow-up system and telephone interviews. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were used to assess patients' progression-free survival (PFS) and overall survival (OS). A total of 71 eligible patients were enrolled in this study; 43 patients received CAPEOX combined with cetuximab (Group A, n  = 43), and 28 patients received FOLFOX combined with cetuximab (Group B, n  = 28). The two groups achieved similar median PFS (mPFS) and median OS (mOS), with mPFS of 18 months and 12 months, respectively ( P  = 0.23), and mOS of 33 months and 20 months, respectively ( P  = 0.21), with no statistically significant differences. The results of this study demonstrated that CAPEOX combined with cetuximab is an equally viable option for first-line treatment of RAS/BRAF wild-type mCRC as FOLFOX combined with cetuximab.

Anlotinib, a tyrosine kinase inhibitor, has shown encouraging antitumor activity in platinum-resistant/refractory ovarian cancer. The efficacy of anlotinib as maintenance therapy in advanced ovarian cancer remains unclear. Therefore, we designed this study to evaluate the efficacy and safety of anlotinib maintenance therapy following first-line treatment with paclitaxel and platinum-based chemotherapy in advanced ovarian cancer. In this single-arm, phase II clinical trial, patients with newly diagnosed advanced ovarian cancer were received anlotinib monotherapy as maintenance therapy once after a response to platinum-based chemotherapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival. From April 2020 to June 2021, 24 patients were enrolled in this study. The median follow-up was 40.17 months (interquartile range, 32.40-47.93 months). Of 21 patients with efficacy value, the median progression-free survival and median overall survival were 15.8 months (95% confidence interval, 6.8-24.8 months) and 43.8 months (95% confidence interval, 25.45-62.15 months). The quality-adjusted progression-free survival was 14.4 months and there were no observed treatment-related deaths or serious treatment-emergent adverse events, demonstrating the safety of anlotinib in maintenance therapy. Anlotinib shows significant potential as a first-line maintenance therapy for advanced ovarian cancer, extending survival and providing a reliable treatment option.