Focal adhesion kinase inhibitors, a heavy punch to cancer

Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

Trojan-Like Peptide Drug Conjugate Design and Construction for Application in Treatment of Triple-Negative Breast Cancer

Clinical treatment of triple negative breast cancer (TNBC) is very poor for lack of effective treatment combination selection. Protein C receptor (PROCR) is a novel cancer stem marker in TNBC patients tumor tissues. Developed based on peptide BP10 with affinity to PROCR as a targeting element, constructing a peptide drug conjugate of BP10 covalently coupling doxorubicin with disulfide bonds. This study demonstrated that the constructed BP10-DOX can selectively target Triplenegative breast cancer cells expressing PROCR and controlled release of DOX in response to the GSH environment. Moreover, BP10-DOX improves the therapeutic efficiency on MDA-MB-231 cells in vitro. Further evidence obtained from in vivo xenograft experiments revealed that administration of BP10-DOX enhanced the antitumor efficacy. This study developed a promising chemotherapy strategy for TNBC.

Comparative Efficacy of Traditional Conservative Treatment and Ct-guided Local Chemotherapy for Mild Spinal Tuberculosis

Background: There are considerable differences in the treatment strategy for spinal tuberculosis, inclouding conservative or surgical procedures. Conservative treatment is always suitable for most patients. This study aimed to compare the clinical efficacy of traditional conservative treatment with CT-guided local chemotherapy strategy of mild spinal tuberculosis.Methods: This research retrospectively analysed 120 patients with spinal tuberculosis between January 2005 and January 2016 according to the diagnostic criteria of mild spinal tuberculosis. In total, 89 patients underwent traditional conservative treatment, 31 underwent CT-guided local chemotherapy. Clinical outcome, laboratory indexes, and radiological results were analysed to provide a clinical basis for the choice of mild spinal tuberculosis treatment.Results: All cases achieved a clinical cure with 24 to 50 months followed up. Cobb angle of the two groups spinal tuberculosis segments was 6.25 ± 3.11°, 5.69 ± 2.58° before treatment and 12.36 ± 6.31°, 14.87 ± 7.26° after treatment, respectively. VAS scores were significantly decreased post-treatment. There was no obvious kyphosis, symptoms or neurological deficits at the final follow-up.Conclusions: For mild spinal tuberculosis, traditional conservative treatment can achieve satisfactory results. The strategy combined with CT-guided local chemotherapy treatment is minimally invasive, beneficial for the drainage of paravertebral abscesses and pain relief.

Supporting drug development for neglected tropical diseases using mathematical modelling

Drug-based interventions are at the heart of global efforts to reach elimination as a public health problem (trachoma, soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis) or elimination of transmission (onchocerciasis) for five of the most prevalent neglected tropical diseases tackled via the World Health Organization preventive chemotherapy strategy. While for some of these diseases there is optimism that currently available drugs will be sufficient to achieve the proposed elimination goals, for others—particularly onchocerciasis—there is a growing consensus that novel therapeutic options will be needed. Since in this area no high return of investment is possible, minimizing wasted money and resources is essential. Here, we use illustrative results to show how mathematical modelling can guide the drug development pathway, yielding resource-saving and efficiency payoffs, from the refinement of target product profiles and intended context of use, to the design of clinical trials.

HER2-Positive Breast Cancer Patients with Pre-Treatment Axillary Involvement or Postmenopausal Status Benefit from Neoadjuvant Rather than Adjuvant Chemotherapy Plus Trastuzumab Regimens

Background: No survival benefit has yet been demonstrated for neoadjuvant chemotherapy (NAC) against HER2-positive tumors in patients with early breast cancer (BC). The objective of this study was to compare the prognosis of HER2-positive BC patients treated with NAC to that of patients treated with adjuvant chemotherapy (AC). Materials and methods: We retrospectively analyzed disease-free (DFS) and overall survival (OS) in 202 HER2-positive patients treated with NAC and 701 patients treated with AC. All patients received trastuzumab in addition to chemotherapy. Patient data were weighted by a propensity score to overcome selection bias. Results: After inverse probability of treatment weights (IPTW) adjustment, no difference in DFS (p = 0.3) was found between treatments for the total population. However, after multivariate analysis, an interaction was found between cN status and chemotherapy strategy (IPTW-corrected corrected Hazard ratio cHR = 0.52, 95% CI (0.3–0.9), pinteraction = 0.08) and between menopausal status and chemotherapy (CT) strategy (cHR = 0.35, 95%CI (0.18–0.7)) pinteraction < 0.01). NAC was more beneficial than AC strategy in cN-positive patients and in postmenopausal patients. Moreover, after IPTW adjustment, the multivariate analysis showed that the neoadjuvant strategy conferred a significant OS benefit (cHR = 0.09, 95%CI [0.02–0.35], p < 0.001). Conclusion: In patients with HER2-positive BC, the NAC strategy is more beneficial than the AC strategy, particularly in cN-positive and postmenopausal patients. NAC should be used as a first-line treatment for HER2-positive tumors.

Exploring the Optimal Chemotherapy Strategy for Locoregionally Advanced Children and Adolescent Nasopharyngeal Carcinoma Based on Pretreatment Epstein-Barr Virus DNA Level in the Era of Intensity Modulated Radiotherapy

BackgroundThe present study aimed to explore the optimal chemotherapy strategy for locoregionally advanced children and adolescent nasopharyngeal carcinoma (LcaNPC), based on the level of pretreatment plasma Epstein-Barr virus DNA (pEBV-DNA) in the era of intensity modulated radiation therapy (IMRT).MethodsThis real-world, retrospective study consecutively reviewed locoregionally advanced nasopharyngeal carcinoma patients younger than 22 years old from 2006 to 2016 in the Sun Yat-sen University Cancer Center. The Kaplan–Meier method with the log-rank test and the Cox regression model were used to investigate the survival outcomes of different chemotherapy intensities and pEBV-DNA. Treatment-related toxicity was also evaluated using the chi-squared test or Fisher’s exact test.ResultsA total of 179 patients were enrolled, including 86 patients in the high-risk group (pEBV-DNA ≥7,500 copies/ml) and 93 patients in the low-risk group (pEBV-DNA &lt;7,500 copies/ml). Among all patients, those receiving low intensity induction chemotherapy (IC courses = 2) had a better 5-year overall survival (OS) than those receiving no IC (P = 0.025) and high intensity IC (IC courses &gt;2) (P = 0.044). In the high-risk group, receipt of low intensity IC showed significant 5-year OS (P = 0.032), progression-free survival (PFS) (P = 0.027), and 5-year distant metastasis-free survival (DMFS) (P = 0.008) benefits compared with not receiving IC. Multivariate analyses identified that not receiving IC was a risk factor compared with low intensity IC for OS (hazard ratio (HR) = 10.933, P = 0.038) among all patients. Moreover, in the high-risk group, not receiving IC was a risk factor for 5-year OS (HR = 10.878, P = 0.038), 5-year PFS (HR = 5.705, P = 0.041), and 5-year DMFS (HR = 10.290, P = 0.040) compared to low intensity IC. There were no differences in survival for patients treated with or without concurrent chemotherapy.ConclusionTwo courses of platinum-based IC might be the optimal induction chemotherapy intensity to reduce risk of death, progression, and distant metastasis in patients with high pEBV-DNA levels.

Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy

Cell therapy is a promising strategy for cancer therapy. However, its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments. In this study, the “cell-chemotherapy” strategy was presented to enhance antitumor efficacy. M1-type macrophages, which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability, carried sorafenib (SF)-loaded lipid nanoparticles (M1/SLNPs) were developed. M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously. M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide, and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP. Tumor accumulation of M1/SLNP was increased compared with SLNP (p < 0.01), which proved M1/SLNP could enhance tumor targeting of SF. An increased ratio of M1-type macrophages to M2-type macrophages, and the CD3+CD4+ T cells and CD3+CD8+ T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments. The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group (p < 0.01), indicating M1/SLNP exhibited enhanced antitumor efficacy. Consequently, M1/SLNP showed great potential as a novel cell-chemotherapeutic strategy combining both cell therapy and targeting chemotherapy.

Effective Treatment of a Malignant Breast Phyllodes Tumor with Doxorubicin-Ifosfamide Therapy

Malignant phyllodes tumors of the breast occur infrequently and are difficult to treat with chemotherapy. Here, we present an effective chemotherapy strategy for recurrent malignant breast phyllodes tumors. A 48-year-old woman was diagnosed with a malignant phyllodes tumor in her right breast and underwent total right mastectomy. One year later, the tumor recurred in the right (a 2.2 cm mass) and left (a 10 cm mass) lungs; pleural effusion was also observed in the left lung. Eight courses of doxorubicin-ifosfamide (AI) therapy were administered. After treatment, the right lung mass and pleural effusion regressed completely and the left lung mass regressed to 2 cm. In conclusion, AI therapy is useful for treating recurrent malignant breast phyllodes tumors.

Multiorgan involvement by amyloid light chain amyloidosis

Amyloid light chain (AL) amyloidosis is a protein conformational disease. AL amyloidosis results from aggregation of misfolded proteins that are deposited in tissues as amyloid fibrils. Diagnosis of AL amyloidosis can be challenging due to its low incidence and clinical complexity. Therapy requires a risk-adapted approach involving dose reductions and schedule modifications of chemotherapy regimens along with close monitoring of hematologic and organ responses. We herein describe a patient whose condition was diagnosed as systemic AL amyloidosis and presented with splenic rupture as the initial symptom. Congo red staining of the kidney biopsy was positive. The normal structure of the liver and spleen had been replaced by amyloid deposition. The chemotherapy strategy involved a combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone.