Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process ...found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 VEGFR‐2) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet‐derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti‐VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors.
Implications for Practice:
Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF‐targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.
It is increasingly clear that there are many interconnected and compensatory pathways that can overcome vascular endothelial growth factor‐targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.
•RAS is the most frequently mutated oncogene in human cancers, accounting for approximately 30% of mutations in all human cancers.•Despite playing a distinct role in tumorigenesis, various attempts ...to inhibit K-RAS directly in the past were unsuccessful.•Additionally, inhibiting downstream Kras signaling through approaches such as inhibiting RAF, MEK and ERK have been unsuccessful.•Recently, a binding pocket (S-IIP) has been identified in K-RAS G12C that can be targeted by covalent inhibitors.•The K-RAS G12C mutation is present in about 13% of lung adenocarcinoma and 3% of colorectal cancer cases. Several inhibitors of this specific mutation have been developed, with initial evidence of impressive clinical activity.•Other approaches including, SHP2, SOS1 and eIF4 inhibition, are being evaluated to abrogate tumor growth in K-RAS mutant cells.
RAS is the most frequently mutated oncogene in human cancers, with mutations in about 30% of all cancers. RAS exists in three different isoforms (K-RAS, H-RAS and N-RAS) with high sequence homology. K-RAS is the most commonly mutated RAS isoform. The Ras protein is a membrane bound protein with inherent GTPase activity and is activated by numerous extracellular stimuli, cycling between an inactive (GDP-bound) and active (GTP-bound) form. When bound to GTP, it is switched “on” and activates intracellular signaling pathways, critical for cell proliferation and angiogenesis. Mutated RAS is constitutively activated and persistently turned “on” thereby enhancing downstream signaling and leading to tumorigenesis. Various attempts to inhibit Kras in the past were unsuccessful. Recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target K-RAS G12C. Additionally, various other approaches including, SHP2, SOS1 and eIF4 inhibition, have been utilized to abrogate tumor growth in K-RAS mutant cells, resulting in a renewed interest in this pathway. In this review article, we provide an overview on the role of K-RAS in tumorigenesis, past approaches to inhibiting Kras, and current and future prospects for targeting Kras.
Aberrant activation of the RAS-RAF-MEK-ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and ...inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a number of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clinical studies over the past decade. These agents are not efficacious in a broad range of unselected cancers, although single-agent antitumour activity has been detected mainly in tumours that harbour mutations in genes encoding the members of the RAS and RAF protein families, such as certain melanomas. Combinations of MEK1/2 inhibitors and cytotoxic chemotherapy, and/or other targeted agents are being studied to expand the efficacy of this class of agents. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for the future clinical development of MEK inhibitors. We discuss the clinical experience with MEK inhibitors to date, and consider the novel approaches to MEK-inhibitor therapy that might improve outcomes and lead to the wider use of such treatments.
Small-cell lung cancer (SCLC) is an aggressive disease with distinct pathological, clinical, and molecular characteristics from non-small-cell lung cancer. SCLC has high metastatic potential, ...resulting in a clinically poor prognosis. Early concurrent chemo-radiation is the standard of care for limited-stage SCLC (LS-SCLC). Prophylactic cranial irradiation (PCI) is recommended for patients with LS-SCLC without progression of disease after initial therapy. A combination of etoposide and cisplatin or carboplatin remains the mainstay of first-line treatment for ES-SCLC, with the addition of atezolizumab, now becoming standard. Most SCLCs initially respond to therapy but almost invariably recur. Topotecan and amrubicin (in Japan) remain the primary chemotherapy options for relapsed SCLC. Immunotherapy, including nivolumab with or without ipilimumab, is now available for refractory disease. In general, the poor prognosis of SCLC has not improved significantly for more than 3 decades. Recently, next-generation molecular profiling studies have identified new therapeutic targets for SCLC. A variety of proapoptotic agents, compounds capitalizing on DNA-repair defects, immunotherapy agents, and antibody-drug conjugates are being evaluated in SCLC, with a number of them showing early promise.
Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy. However, these patients continue to have ...a high risk of recurrence and death. Unfortunately, there has been little progress in the treatment of resectable NSCLC over the past several decades. Neoadjuvant therapy, which has been considered as an approach to improve survival in patients with resectable NSCLC, is a hotly debated topic. A systematic review of 32 randomized trials involving 10,000 patients revealed that there was no difference in survival between preoperative and postoperative chemotherapy. Because of such results and the theoretical concern about resectable tumors progressing on relatively ineffective neoadjuvant chemotherapy, and thus becoming unresectable, neoadjuvant chemotherapy fell out of favor, and many clinicians preferred adjuvant chemotherapy after surgery. However, neoadjuvant therapy has been revived in the past couple of years, with emerging data from various ongoing trials suggesting that neoadjuvant immunotherapy may have significant efficacy and could potentially improve the survival of patients with resectable NSCLC. In this review article, we discuss the evidence supporting the role of neoadjuvant immunotherapy in the multimodal management of resectable NSCLC. We summarize early results of ongoing clinical trials and highlight the challenges in adopting a uniform definition of treatment “success.” We address hurdles to be overcome for seeking regulatory approval for neoadjuvant immunotherapy and establishing it as a standard of care. Finally, we provide some perspectives for the future.
The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical ...outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.
Abstract The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients ...with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50–60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls – afatinib and dacomitinib – covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug–drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.
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