Efficacy of Definitive Radiotherapy for Patients with Clinical Stage IIIB or IIIC Lung Adenocarcinoma and Epidermal Growth Factor Receptor (EGFR) Mutations Treated Using First- or Second-Generation EGFR Tyrosine Kinase Inhibitors.

Background: The effectiveness of definitive radiotherapy (RT) for patients with clinical stage IIIB or IIIC lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutations who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) is unclear. Methods: Taiwan Cancer Registry data were used in this retrospective cohort study to identify adult patients diagnosed with EGFR-mutated stage IIIB or IIIC lung adenocarcinoma between 2011 and 2020. Patients treated with first- or second-generation EGFR TKIs were classified into RT and non-RT groups. Propensity score (PS) weighting was applied to balance covariates between groups. The primary outcome was overall survival (OS), and the incidence of lung cancer mortality (ILCM) was considered as a supplementary outcome. Additional supplementary analyses were conducted to assess the robustness of the findings. Results: Among 270 eligible patients, 41 received RT and 229 did not. After a median follow-up of 46 months, PS-weighted analysis showed the PS-weighted hazard ratio of death for the RT group compared to the non-RT group was 0.94 (95% CI: 0.61-1.45, p = 0.78). ILCM rates did not differ significantly between the two groups. Supplementary analyses yielded consistent results. Conclusion: The addition of definitive RT to first- or second-generation EGFR TKI treatment does not significantly improve OS of patients with EGFR-mutated stage IIIB or IIIC lung adenocarcinoma. NCT03521154NCT05167851.

Real-World Efficacy and Safety of Amivantamab for EGFR-Mutant NSCLC.

INTRODUCTION: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known. METHODS: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups. RESULTS: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib. CONCLUSIONS: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

Synthesis, antioxidant, antiproliferative activity, molecular docking and DFT studies of novel isoxazole derivatives of diosgenin, a steroidal sapogenin from Dioscorea deltoidea.

Diosgenin [25R-spirost-5-en-3ß-ol], isolated from Dioscorea deltoidea was used as a starting material for synthesizing its various isoxazole derivatives. A library of fifteen isoxazole analogues (DG1-DG15) were synthesised via modification at the C-3 hydroxyl group. The resulting analogues were fully characterized by spectral techniques and evaluated for their antioxidant and anticancer activity against four breast cancer cell lines; MDA-MB-231, MDA-MB-468, MCF-7, and 4 T1, using MTT assay. Molecular docking studies were carried out for all analogues with EGFR protein (PDB id: 6LUD) to check their activity by inhibiting EGFR protein, which is an effective strategy for cancer cell death. Furthermore, DFT studies were carried out for four analogues. Among all analogues, compound DG6 and DG9 showed the highest scavenging activity and compound DG9 exhibited a maximum cytotoxic effect on the MDA-MB-468 and MCF-7 cell lines with an IC50 value of 6.25 µg/mL and 6.81 µg/mL, while compound DG5 was the least potent (IC50 25.89 µg/mL). Molecular docking results revealed that DG8 and DG9 afforded the highest binding energy of -14.33 and - 14.71 kcal/mol, respectively for the target EGFR protein. These results demonstrate the potential of diosgenin analogues as drug candidates for breast cancer therapy. Furthermore, DFT studies revealed that the molecules are more polarizable and have smaller energy gap between their HOMO and LUMO orbitals, the smallest being of DG9 (3.221 eV) and hence are more reactive.

Formononetin Inhibits Microglial Inflammatory Response and Contributes to Spinal Cord Injury Repair by Targeting the EGFR/MAPK Pathway.

Zhenbao Pill contains many Chinese herbal medicinal ingredients and has been proven to have therapeutic effects on the repair of spinal cord injury (SCI). This study attempts to investigate the role of formononetin (FMN), an ingredient of Zhenbao Pill, in regulating neuroinflammation after SCI and the underlying mechanism. Primary microglia isolated from the spinal cord of newborn rats and human microglial clone 3 (HMC3) cells were stimulated with IL-1ß followed by FMN incubation. The cell viability and inflammatory cytokine levels were detected. The target of FMN was predicted and screened using databases. By silencing or overexpression of epidermal growth factor receptor (EGFR), the anti-neuroinflammatory effect of FMN was assessed in vitro. In vivo, FMN was intraperitoneally injected into rats after SCI followed by the neurological function and histopathology examination. The isolated microglia were in high purity, and the different concentrations of FMN incubation had no toxic effects on primary microglia and HMC3 cells. FMN reduced the inflammatory cytokine levels (TNF-α and IL-6) in a concentration-dependent manner. EGFR silencing or FMN incubation decreased p-EGFR and p-p38 levels and down-regulated inflammatory cytokine levels in IL-1ß-stimulated cells or supernatants. Nevertheless, the effects of FMN on microglial inflammation were reversed by EGFR overexpression. In vivo, FMN treatment improved the neuromotor function, repaired tissue injury, and inhibited EGFR/p38MAPK phosphorylation. Formononetin inhibits microglial inflammatory response and contributes to SCI repair via the EGFR/p38MAPK signaling pathway.

Saikosaponin-A Exhibits Antipancreatic Cancer Activity by Targeting the EGFR/PI3K/Akt Pathway.

BACKGROUND: A diagnosis of pancreatic cancer is pretty grim. Saikosaponin-A (SSA) is a Chinese herbal extract with anticancer activity. However, the therapeutic effect of SSA on pancreatic cancer remains elusive. AIM: The study aims to evaluate the antitumor effects of SSA on pancreatic cancer cells in vitro and in vivo. METHODS: After treatment with SSA, cell viability was measured using the CCK-8 assay, DAPI staining was performed to analyze the effect on nuclear morphology, propidium iodide (PI) staining was used to detect the cell cycle, and Annexin V/PI double staining was conducted to analyze apoptosis. Then, the expression of apoptosis-related proteins and EGFR/PI3K/Akt pathway-related proteins was determined using western blotting. The binding of SSA to EGFR was analyzed by performing molecular docking. The mouse pancreatic cancer model was established by subcutaneously injecting pancreatic cancer cells, and after 30 days of SSA gavage, the tumor volume was calculated. Tumor tissue sections were subjected to Ki67 immunohistochemical staining and HE staining. RESULTS: SSA inhibited the proliferation of pancreatic cancer cells. As the concentration of SSA increased, the proportions of BxPC-3 and MIA PaCa-2 cells in the G0/G1 phase increased, the proportions of early and late apoptotic cells also increased, and the apoptosis rate gradually increased. Apoptosis inhibitor experiments indicated that SSA promoted the activation of caspase 3 to induce apoptosis in pancreatic cancer cells. In addition, SSA treatment significantly reduced the levels of phosphorylated EGFR, Akt, and PI3K in the two cell lines. Molecular docking results showed that SSA may have potential binding sites in EGFR. Results of the xenograft experiment confirmed the antitumor effects of SSA, as evidenced by the decreased tumor weight and downregulated expression of Ki67. CONCLUSION: The results revealed that SSA exerted inhibitory effects on pancreatic cancer cells. These effects may be related to the inactivation of the EGFR/PI3K/Akt signalling pathway.

Identification of Molecular Targets and Underlying Mechanisms of Xiaoji Recipe against Pancreatic Cancer Based on Network Pharmacology.

Traditional Chinese medicine (TCM) is applied in the anticancer adjuvant therapy of various malignancies and pancreatic cancer included. Xiaoji recipe consists several TCM materials with anticancer activities. In our work, we intended to analyze the molecular targets as well as the underlying mechanisms of Xiaoji recipe against pancreatic cancer. A total of 32 active components and 522 potential targets of Xiaoji recipe were selected using the TCMSP and SwissTargetPrediction databases. The potential target gene prediction in pancreatic cancer was performed using OMIM, Disgenet, and Genecards databases, and totally, 998 target genes were obtained. The component-disease network was constructed using the Cytoscape software, and 116 shared targets of pancreatic cancer and Xiaoji recipe were screened out. As shown in the protein-protein interaction (PPI) network, the top 20 hub genes such as TP53, HRAS, AKT1, VEGFA, STAT3, EGFR, and SRC were further selected by degree. GO and KEGG functional enrichment analysis revealed that Xiaoji recipe may affect pancreatic cancer progression by targeting the PI3K/AKT and MAPK signaling pathways. Moreover, we performed in vitro assays to explore the effect of Xiaoji recipe on pancreatic cancer cells. The results revealed that Xiaoji recipe suppressed the viability and migration and promoted the apoptosis of pancreatic cancer cells via the inactivation of PI3K/AKT, MAPK, and STAT3 pathways. The findings of our study suggested the potential of Xiaoji recipe in the targeting therapy of pancreatic cancer.

Effect of Huaiqihuang Granules Combined with Comprehensive Nursing on Children with Primary Nephrotic Syndrome.

BACKGROUND: To observe the effect of Huaiqihuang granules combined with comprehensive nursing intervention on children with primary nephrotic syndrome (PNS) and its effect on renal function index. METHODS: A total of 104 patients were included, and the patients were randomly divided into two groups, with 52 cases in each group. The control group was treated with glucocorticoid, and the study group was treated with Huaiqihuang granules. The clinical efficacy of the two groups was observed. The levels of TG, TC, EGFR, 24 h UTP, BUN, Scr, IgA, IgG, IgM, IFN-γ and TNF-α were compared between two groups before and after treatment. The incidence of adverse reactions and recurrence rate after treatment were compared between the two groups. RESULTS: The effective rate of the study group (94.23%) was significantly higher than that of the control group (78.85%). Before treatment, there was no significant difference in TG and TC levels between the two groups. After treatment, the levels of TG and TC in both groups were decreased, and the decrease was more obvious in the study group. Compared with before treatment, the levels of 24 h UTP, BUN, Scr, IFN-γ, and TNF-α in both groups were significantly decreased after treatment, while EGFR, IgA, IgG, and IgM levels were significantly increased. Compared with the control group, the changes of each index in the study group were more obvious after treatment. After treatment, the incidence of adverse reactions and recurrence rate in the study group were significantly lower than those in the control group. CONCLUSIONS: Huaiqihuang granules combined with comprehensive nursing treatment in children with PNS can reduce the occurrence of recent recurrence and adverse reactions and improve the cellular immune function and renal function.

Alysicarpus vaginalis Bio-Actives as ESR Signaling Pathway Inhibitor for Breast Cancer Treatment: A Network Pharmacology Approach.

In our previous study Alysicarpus vaginalis (AV) has appeared as a promising target for breast cancer hence we have screened potential targets by in silico, In Vitro and In Vivo methods. A network pharmacology (NP) approach involves prediction and validating of targets via molecular modeling, western blotting and In Vivo MNU-induced mammary cancer. The PPI network showed the 573 edges between 214 nodes (targets) that are involved in breast cancer and important one are ESR-1, ESR-2, AR, EGFR, NOS3, MAPK, KDR, SRC and MET. Compound-target-pathway network involves 04 compounds and 221 interactive protein targets associated with breast cancer. GO and KEGG enrichment analysis predicted the ERR, c-MET, PDGFR-α/ß, EGFR, and VEGF as a key targets in the breast cancer treatment which are validated via molecular modeling. Expression of ER-α, AR and EGFR were significantly down regulated by AV in MCF-7 cell line. In addition, the immunoreactivity of ER-α was reduced significantly in MNU-induced mammary carcinoma, which is a key target in ER + breast cancer. Overall, this study scientifically light ups the pharmacological mechanism of AV in the treatment of breast cancer, strongly associated with the regulation of ESR signaling pathway.

Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. Activation of EGFR signal pathway increased monounsaturated fatty acids (MUFA) and lipid metabolism key enzyme Stearoyl-CoA Desaturase 1 (SCD1) expression. However the correlation between EGFR-TKI resistance and lipid metabolism remains to be determined. METHODS: In this study the differences in lipid synthesis between paired TKI-sensitive and TKI-resistant patient tissues and NSCLC cell lines were explored. Oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) was used to simulate a high lipid metabolic environment and detected the affection on the cytotoxic effect of TKIs (Gefitinib and osimertinib) in cell lines with EGFR-activating mutations. (20S)-Protopanaxatriol (g-PPT), an aglycone of ginsenosides, has been reported to be an effective lipid metabolism inhibitor, was used to inhibit lipid metabolism. Additionally, synergism in cytotoxic effects and signal pathway activation were evaluated using CCK-8 assays, Western blotting, flow cytometry, Edu assays, plate clone formation assays and immunofluorescence. Furthermore, two xenograft mouse models were used to verify the in vitro results. RESULTS: Gefitinib-resistant cells have higher lipid droplet content and SCD1 expression than Gefitinib-sensitive cells in both NSCLC cell lines and patient tissues. Additionally oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) abrogates the cytotoxic effect of both Gefitinib and osimertinib in cell lines with EGFR-activating mutations. As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of SCD1 in lung adenocarcinoma cells, and then down-regulated the content of intracellular lipid droplets. Combined treatment with Gefitinib and g-PPT reverses the resistance to Gefitinib and inhibits the activation of p-EGFR and the downstream signaling pathways. CONCLUSIONS: Our findings uncover a link between lipid metabolic reprogramming and EGFR-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance.

Bevacizumab for the first-line treatment of human epidermal growth factor receptor 2-negative advanced breast cancer.

PURPOSE OF REVIEW: Breast cancer is the most common cancer in women worldwide and its incidence is increasing as a result of the continued adoption of lifestyles associated with increased risk factors. Approximately, 75% of breast cancers do not express the human epidermal growth factor receptor 2 (HER2), including hormone receptor-positive and triple-negative tumors. HER2-negative breast cancers are resistant to, or eventually become resistant to, existing targeted treatments such as HER2-targeted agents and hormone therapies, and, as a consequence, are associated with poorer outcomes than HER2-positive breast cancer. Bevacizumab is a humanized monoclonal antibody that recognizes vascular endothelial growth factor-A, a rate-limiting step in pathological angiogenesis such as tumor growth. As angiogenic pathways become more complex as breast cancer progresses, angiogenesis inhibitors should be initiated earlier in the disease course. This review will discuss the evidence for bevacizumab as first-line therapy in metastatic breast cancer, with a particular focus on patients with HER2-negative disease. RECENT FINDINGS: Bevacizumab, when administered in combination with first-line standard chemotherapy, significantly increases progression-free survival and overall response rate in patients with metastatic breast cancer. SUMMARY: Novel targeted therapies that are appropriate to HER2-negative breast cancer, such as bevacizumab, may represent valuable therapeutic options in the clinical management of metastatic breast cancer.

Second-line treatments in non-small cell lung cancer. A systematic review of literature and metaanalysis of randomized clinical trials.

BACKGROUND: To assess the efficacy of second-line treatments in non-small cell lung cancer (NSCLC). METHODS: A systematic review of literature with metaanalysis of randomized clinical trials (RCTs) was independently performed by three authors. A primary analysis included all RCTs comparing any approach (chemotherapy or therapy with epidermal growth factor receptor [EGFR] inhibitors) with placebo; a secondary analysis included all RCTs comparing any treatment with docetaxel therapy every 3 weeks. The 1-year survival rate (SR) of the primary analysis was the primary outcome of the study; the 1-year SR of the secondary analysis, response rate (RR), and time to progression of primary and secondary analyses were the secondary end points. RESULTS: Fourteen RCTs met the selection criteria. The outcomes of 2,627 and 5,952 patients were analyzed in the primary and secondary analysis, respectively. A significant heterogeneity was documented in the primary analysis for 1-year SR with odd ratio [OR] = 0.763 (p = 0.029). No heterogeneity was documented for RR in the primary analysis, with OR = 0.165 (p < 0.001). A modest heterogeneity was documented in the secondary analysis for 1-year SR and RR, with 1-year SR OR = 0.924 (p = 0.122) and RR OR = 1.069 (p = 0.643). CONCLUSION: Second-line treatments in NSCLC seem to improve the main outcomes better than supportive care. Docetaxel administration every 3 weeks probably remains the "gold standard" because at present the data in literature are not enough to support a greater efficacy of other alternative options. Further trials are needed to identify a clinical and biological profile that could predict the response to treatments and a criterion to select the patients to be treated with chemotherapy or EGFR inhibitors.

Novel kinase inhibitors in renal cell carcinoma: progressive development of static agents.

The rapidly expanding knowledge regarding neoplastic diseases is providing a plethora of new targets for drug discovery and development as exemplified by recent data in renal cell carcinoma. The initial experience with molecularly "targeted" agents has demonstrated that development of the newer non-cytotoxic agents will provide unique challenges requiring modification of many traditional drug development concepts and methods. We discuss recently reported data from a few renal cell carcinoma trials with putative cytostatic agents and highlight issues that need to be addressed for efficient development of cytostatic agents during various phases of clinical development.