The Notch pathway is involved in cell proliferation, differentiation and survival. The Notch signaling pathway is one of the most commonly activated signaling pathways in cancer. Alterations include activating mutations and amplification of the Notch pathway, which play key roles in the progression of cancer. Accumulating evidence suggests that the pharmacological inhibition of this pathway can overcome chemoresistance. Efforts have been taken to develop Notch inhibitors as a single agent or in combination with clinically used chemotherapeutics to treat cancer. Some Notch inhibitors have been demonstrated to have therapeutic efficacy in preclinical studies. This review summarizes the recent studies and clinical evaluations of the Notch inhibitors in cancer.

CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.

The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.

Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.