The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
Cutaneous malignant melanoma (MM) is the most malignant type of all skin neoplasms. There is wide variability in the characteristics of MM between patients of different races. The aim of the present study was to investigate the clinicopathological characteristics of patients with MM in central China and to assess the value of specific hematological and biochemical indices for predicting metastasis. The data of 167 patients with MM from the First Affiliated Hospital of Zhengzhou University (Henan, China) were retrospectively analyzed and compared with the data of patients with MM available from cBioPortal for Cancer Genomics. Following analysis of the clinicopathological characteristics of the 167 patients, the median overall survival time was 50 months, and the median disease-free survival time was 35 months. Albumin/D-dimer prognosis score (ADPS), lactate dehydrogenase, sex, T stage, tumor-node-metastasis stage, Breslow thickness, Clark level, histological type, growth phase, ulceration and metastasis were all significantly associated with prognosis. An ADPS of <341.01 was identified as an independent predictor of metastasis. The trial registration no. is 2018-LW-037 and this clinical trial was registered in the
Background The benefit of adjuvant chemotherapy in invasive lobular carcinoma (ILC) is still unclear. The objective of the current study was to elucidate the effectiveness of adjuvant chemotherapy in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1b-c/N0–1/M0 ILC. Methods Based on Surveillance, Epidemiology, and End-Results (SEER) database, we identified original 12,334 HR-positive, HER2-negative, pT1b-c/N0–1/M0 ILC patients, who were then divided into adjuvant chemotherapy group and control group. End-points were overall survival (OS) and breast cancer-specific mortality (BCSM). Aiming to minimize the selection bias of baseline characteristics, Propensity Score Matching (PSM) method was used. Results In a total of 12,334 patients with HR-positive, HER2-negative, pT1b-c/N0–1/M0 ILC, 1785 patients (14.5%) were allocated into adjuvant chemotherapy group and 10,549 (85.5%) into control group. Used PSM, the 1785 patients in adjuvant chemotherapy group matched to the 1785 patients in control group. By Kaplan-Meier survival analyses, we observed no beneficial effect of adjuvant chemotherapy on OS in both original samples (P = 0.639) and matched samples (P = 0.962), however, ineffective or even contrary results of adjuvant chemotherapy on BCSM both in original samples (P = 0.001) and in matched samples (P = 0.002). In both original and matched multivariate Cox models, we observed ineffectiveness of adjuvant chemotherapy on OS (hazard ratio (HR) for overall survival = 0.82, 95% confidence interval (CI) [0.62–1.09]; P = 0.172 and HR = 0.90, 95%CI [0.65–1.26]; P = 0.553, respectively), unexpectedly promoting effect of adjuvant chemotherapy on BCSM (HR = 2.33, 95%CI [1.47–3.67]; P = 0.001 and HR = 2.41, 95%CI [1.32–4.39]; P = 0.004, respectively). Standard surgery was beneficial to the survival of patients. Lymph node metastasis was detrimental to survival and radiotherapy brought survival benefit in original samples, but two issues had unobvious effect in matched samples. Conclusion In this study, adjuvant chemotherapy did not improve survival for patients with HR-positive, HER2-negative pT1b-c/N0–1/M0 ILC.
Background : The benefit of adjuvant chemotherapy in invasive lobular carcinoma (ILC) is still unclear. The objective of the current study was to elucidate the effectiveness of adjuvant chemotherapy in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1b-c/N0-1/M0 ILC. Methods: Based on Surveillance, Epidemiology, and End-Results (SEER) database, we identified original 12334 HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC patients, who were then divided into adjuvant chemotherapy group and control group. End-points were overall survival (OS) and breast cancer-specific mortality (BCSM). Aiming to minimize the selection bias of baseline characteristics, Propensity Score Matching (PSM) method was used. Results : In a total of 12334 patients with HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC, 1785 patients (14.5%) were allocated into adjuvant chemotherapy group and 10549 (85.5%) into control group. Used PSM, the 1785 patients in adjuvant chemotherapy group matched to the 1785 patients in control group. By Kaplan-Meier survival analyses, we observed no beneficial effect of adjuvant chemotherapy on OS in both original samples ( P =0.639) and matched samples ( P =0.962), however, ineffective or even contrary results of adjuvant chemotherapy on BCSM both in original samples (P =0.001) and in matched samples ( P= 0.002). In both original and matched multivariate Cox models, we observed ineffectiveness of adjuvant chemotherapy on OS (hazard ratio (HR) for overall survival = 0.82, 95% confidence interval (CI) [0.62-1.09]; P =0.172 and HR=0.90, 95%CI [0.65-1.26]; P =0.553, respectively), unexpectedly promoting effect of adjuvant chemotherapy on BCSM (HR=2.33, 95%CI [1.47-3.67]; P =0.001 and HR=2.41, 95%CI [1.32-4.39]; P =0.004, respectively). Standard surgery was beneficial to the survival of patients. Lymph node metastasis was detrimental to survival and radiotherapy brought survival benefit in original samples, but two issues had unobvious effect in matched samples. Conclusion: In this study, adjuvant chemotherapy did not improve survival for patients with HR-positive, HER2-negative pT1b-c/N0-1/M0 ILC.
Background Tumor microenvironment plays pivotal roles in carcinogenesis, cancer development and metastasis. Composition of cancer immune cell subsets can be inferred by deconvolution of gene expression profile accurately. Compositions of the cell types in cancer microenvironment including cancer infiltrating immune and stromal cells have been reported to be associated with the cancer outcomes markers for cancer prognosis. However, rare studies have been reported on their association with the response to preoperative radiotherapy for rectal cancer. Methods In this paper, we deconvoluted the immune/stromal cell composition from the gene expression profiles. We compared the composition of immune/stromal cell types in the RT responsive versus nonresponsive for rectal cancer. We also compared the peripheral blood immune cell subset composition in the stable diseases versus progressive diseases of rectal cancer patients with fluorescence-activated cell sorting from our institution. Results Compared with the non-responsive group, the responsive group showed higher proportions of CD4+ T cell (0.1378 ± 0.0368 vs. 0.1071 ± 0.0373, p = 0.0215), adipocytes, T cells CD4 memory resting, and lower proportions of CD8+ T cell (0.1798 ± 0.0217 vs. 0.2104 ± 0.0415, p = 0.0239), macrophages M2, and preadipocytes in their cancer tissue. The responsive patients showed a higher ratio of CD4+/CD8+ T cell proportions (mean 0.7869 vs. 0.5564, p = 0.0210). Consistently, the peripheral blood dataset showed higher proportion of CD4+ T cells and higher ratio of CD4+/CD8+ T cells, and lower proportion of CD8+ T cells for favorable prognosis. We validated these results with a pooled dataset of GSE3493 and GSE35452, and more peripheral blood data, respectively. Finally, we imported these eight cell features including eosinophils and macrophage M1 to Support Vector Machines and could predict the pre-radiotherapy responsive versus non-responsive with an accuracy of 76%, ROC AUC 0.77, 95% confidential interval of 0.632–0.857, better than the gene signatures. Conclusions Our results showed that the proportions of tumor-infiltrating subsets and peripheral blood immune cell subsets can be important immune cell markers and treatment targets for outcomes of radiotherapy for rectal cancer.
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