CA : A Cancer Journal for Clinicians

Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

/pdf/small-molecules-in-targeted-cancer-therapy-advances-53fjqb1ed9.pdf

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.

Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients.

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(15)00210-2.pdf

Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism.

Esophageal cancer (EC) is one of the most lethal cancers in the world, and its morbidity and mortality rates rank among the top ten in China. Currently, surgical resection, radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer. However, outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments. As a new type of approach, targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer; these include cetuximab and bevacizumab, which target epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), respectively. In addition, other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed. For example, trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), has been approved by the Food and Drug Administration (FDA) as a first-line treatment of HER-2-positive cancer. Moreover, the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma (ESCC). These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients. Nevertheless, adverse events, optimal dosages and effective combinations still need further investigation. In this review, we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs, discuss their efficacy and safety, and provide a clinical rationale for precision medicine in esophageal cancer.

/pdf/advances-in-targeted-therapy-for-esophageal-cancer-3ooknk7eaz.pdf

Advances in targeted therapy for esophageal cancer.

Recent Advances on Reactive Oxygen Species-Responsive Delivery and Diagnosis System.

The mucus layer and cell membrane are two major barriers against pulmonary siRNA delivery. Commonly used polycationic gene vectors can hardly penetrate the mucus layer due to the adsorption of mucin glycoproteins that trap and destabilize the polyplexes. Herein, guanidinated and fluorinated bifunctional helical polypeptides were developed to synchronizingly overcome these two barriers. The guanidine domain and α-helix facilitated trans-membrane siRNA delivery into macrophages, whereas fluorination of the polypeptides dramatically enhanced the mucus permeation capability by ∼240 folds, because incorporated fluorocarbon segments prevented adsorption of mucin glycoproteins onto polyplexes surfaces. Thus, when delivering TNF-α siRNA intratracheally, the top-performing polypeptide P7F7 provoked highly efficient gene knockdown by ∼96% at 200 μg/kg siRNA and exerted pronounced anti-inflammatory effect against acute lung injury. This study thus provides an effective strategy for transmucosal gene delivery, and it also renders promising utilities for the noninvasive, localized treatment of inflammatory pulmonary diseases.

Fluorinated α-Helical Polypeptides Synchronize Mucus Permeation and Cell Penetration toward Highly Efficient Pulmonary siRNA Delivery against Acute Lung Injury.

Pro-Peptide-Reinforced, Mucus-Penetrating Pulmonary siRNA Delivery Mitigates Cytokine Storm in Pneumonia

Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance. Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively. Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p-EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs. Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system.

/pdf/biodegradable-nanoparticles-mediated-co-delivery-of-1v15706v41.pdf

Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway.

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.

/pdf/jak2-inhibitor-tg101348-overcomes-erlotinib-resistance-in-3v4g1isjjs.pdf

Shanzhou Duan

Papers

Recent Advances on Reactive Oxygen Species-Responsive Delivery and Diagnosis System.

Fluorinated α-Helical Polypeptides Synchronize Mucus Permeation and Cell Penetration toward Highly Efficient Pulmonary siRNA Delivery against Acute Lung Injury.

Pro-Peptide-Reinforced, Mucus-Penetrating Pulmonary siRNA Delivery Mitigates Cytokine Storm in Pneumonia

Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway.

JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor.