Abstract Long-term outcome for patients with high-grade osteosarcoma has improved with the addition of systemic chemotherapy, but subsequent progress has been less marked. Modern, multiagent, dose-intensive chemotherapy in conjunction with surgery achieves a 5-year event-free survival of 60–70% in extremity localized, non-metastatic disease. A major, as yet unsolved, problem is the poor prognosis for metastatic relapse or recurrence, and for patients with axial disease. This article reviews the current state of the art of systemic osteosarcoma therapy by focusing on the experiences of cooperative osteosarcoma groups. Also, we shed light on questions and challenges posed by the aggressiveness of the tumor, and we consider potential future directions that may be critical to progress in the prognosis of high-grade osteosarcoma.
Summary Since the initial work, a decade ago that the combination of C-reactive protein and albumin, the Glasgow Prognostic Score (GPS), had independent prognostic value in patients with cancer, there have been more than 60 studies (>30,000 patients) that have examined and validated the use of the GPS or the modified GPS (mGPS) in a variety of cancer scenarios. The present review provides a concise overview of these studies and comments on the current and future clinical utility of this simple objective systemic inflammation-based score. The GPS/mGPS had independent prognostic value in (a) unselected cohorts (4 studies, >19,400 patients) (b) operable disease (28 studies, >8,000 patients) (c) chemo/radiotherapy (11 studies, >1500 patients) (d) inoperable disease (11 studies, >2,000 patients). Association studies (15 studies, >2,000 patients) pointed to an increased GPS/mGPS being associated with increased weight and muscle loss, poor performance status, increased comorbidity, increased pro-inflammatory and angiogenic cytokines and complications on treatment. These studies have originated from 13 different countries, in particular the UK and Japan. A chronic systemic inflammatory response, as evidenced by the GPS/mGPS, is clearly implicated in the prognosis of patients with cancer in a variety of clinical scenarios. The GPS/mGPS is the most extensively validated of the systemic inflammation-based prognostic scores and therefore may be used in the routine clinical assessment of patients with cancer. It not only identifies patients at risk but also provides a well defined therapeutic target for future clinical trials. It remains to be determined whether the GPS has prognostic value in other disease states.
Highlights • Current clinical and preclinical data of the abscopal effect is summarized. • The abscopal effect is linked with the immunogenic properties of irradiation. • Radiotherapy has a potential synergy with immune agents. • The issues that come with combining radiotherapy and immune agents are addressed.
Summary Interleukin-6 (IL-6) is a multifunctional cytokine which plays an important role in a wide range of biologic activities in different types of cell including tumor cells. IL-6 is involved in the host immune defense mechanism as well as the modulation of growth and differentiation in various malignancies. These effects are mediated by several signaling pathways, in particular the signal transducer and transcription activator 3 (Stat3). There exists abundant evidence demonstrating that deregulated overexpression of IL-6 was associated with tumor progression through inhibition of cancer cell apoptosis, stimulation of angiogenesis, and drug resistance. Clinical studies have revealed that increased serum IL-6 concentrations in patients are associated with advanced tumor stages of various cancers (e.g., multiple myeloma, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, prostate cancer, breast cancer and ovarian cancer) and short survival in patients. Therefore, blocking IL-6 signaling is a potential therapeutic strategy for cancer (i.e., anti-IL-6 therapy) characterized by pathological IL-6 overproduction. Preliminary clinical evidence has shown that antibody targeted IL-6 therapy was well tolerated in cancer patients. In this review, we detail the progress of the current understanding of IL-6 signaling pathway in cancer as well as an antibody targeted IL-6 therapy for human cancer.
Abstract Cancer metastasis is the major cause of cancer-related death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer formation or cancer progress. Evidence that phenolic compounds may have a potential inhibitory effect on cancer invasion and metastasis is increasingly being reported in the scientific literature. Curcumin, resveratrol, and their related derivatives are the most studied compounds in this topic so far; gallic acid, chlorogenic acid, caffeic acid, carnosol, capsaicin, 6-shogaol, 6-gingerol, and their corresponding derivatives are also suggested to be the active members of the phenolic family on anti-invasion and anti-metastasis. Because metastasis occurs through a multistep process, these bioactives might act on a variety of stages of the metastatic process to prevent tumor cells from metastasizing. This review summarizes the common protein targets and signaling pathways for the inhibition of invasion and metastasis as well as past publications on the in vitro and in vivo effects and molecular mechanisms of phenolic acids, monophenol, polyphenol, and their derivatives, except flavonoids, on cancer invasion and metastasis. Based on these data, we conclude that the daily consumption of natural dietary components that are rich in phenolics could be beneficial for the prevention of cancer metastasis.
Abstract The present contribution reports childhood cancer incidence and survival rates as well as time trends and geographical variation. The report is based on the databases of population-based cancer registries which joined forces in cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE. According to these data, which refer to the International Classification of Childhood Cancer, leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, represent the largest diagnostic groups among the under 15-year-olds. The most frequent single diagnoses are: acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the mid of the last century. In Europe, the yearly increase averages 1.1% for the 1978–1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas. The probability of survival has risen considerably over the past decades, with the EUROCARE data showing an improvement of the relative risk of death by 8% when comparing the 2000–2002 time span to the 1995–1999 period. Regarding the years 1995–2002, the data show an overall 5-year survival probability of 81% for Europe and similar values for the USA. The data presented here describe the cancer situation with a specific, European focus. They are drawn from population-based cancer registries that ensure excellent data quality, and as a consequence represent the most valid European population-based data existing at present. It is also apparent that not all countries have data available from nationwide childhood cancer registries, a situation which warrants further improvement.
Summary Alterations of signal transduction pathways leading to uncontrolled cellular proliferation, survival, invasion, and metastases are hallmarks of the carcinogenic process. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the Raf/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are critical for normal human physiology, and also commonly dysregulated in several human cancers, including breast cancer (BC). In vitro and in vivo data suggest that the PI3K/AKT/mTOR and Raf/MEK/ERK cascades are interconnected with multiple points of convergence, cross-talk, and feedback loops. Raf/MEK/ERK and PI3K/AKT/mTOR pathway mutations may co-exist. Inhibition of one pathway can still result in the maintenance of signaling via the other (reciprocal) pathway. The existence of such “escape” mechanisms implies that dual targeting of these pathways may lead to superior efficacy and better clinical outcome in selected patients. Several clinical trials targeting one or both pathways are already underway in BC patients. The toxicity profile of this novel approach of dual pathway inhibition needs to be closely monitored, given the important physiological role of PI3K/AKT/mTOR and Raf/MEK/ERK signaling. In this article, we present a review of the current relevant pre-clinical and clinical data and discuss the rationale for dual inhibition of these pathways in the treatment of BC patients.
Summary Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options. Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE. Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients.
Highlights • Resistance to anti-PD1 therapy affects up to ∼70% of patients treated. • Resistance can be primary or acquired. • Tumor intrinsic mechanisms that limit the induction of tumor-specific T cells or their efficacy within tumor tissue may promote resistance. • Logical therapeutic combinations might prove effective to prevent, or to treat resistant tumors.
Abstract Telomeres are protective caps at the ends of human chromosomes. Telomeres shorten with each successive cell division in normal human cells whereas, in tumors, they are continuously elongated by human telomerase reverse transcriptase (hTERT). Telomerase is overexpressed in 80–95% of cancers and is present in very low levels or is almost undetectable in normal cells. Because telomerase plays a pivotal role in cancer cell growth it may serve as an ideal target for anticancer therapeutics. Inhibition of telomerase may lead to a decrease of telomere length resulting in cell senescence and apoptosis in telomerase positive tumors. Several strategies of telomerase inhibition are reviewed, including small molecule inhibitors, antisense oligonucleotides, immunotherapies and gene therapies, targeting the hTERT or the ribonucleoprotein subunit hTER. G-quadruplex stabilizers, tankyrase and HSP90 inhibitors targeting telomere and telomerase assembly, and T-oligo approach are also covered. Based on this review, the most promising current telomerase targeting therapeutics are the antisense oligonucleotide inhibitor GRN163L and immunotherapies that use dendritic cells (GRVAC1), hTERT peptide (GV1001) or cryptic peptides (Vx-001). Most of these agents have entered phase I and II clinical trials in patients with various tumors, and have shown good response rates as evidenced by a reduction in tumor cell growth, increased overall disease survival, disease stabilization in advanced staged tumors and complete/partial responses. Most therapeutics have shown to be more effective when used in combination with standard therapies, resulting in concomitant telomere shortening and tumor mass shrinkage, as well as preventing tumor relapse and resistance to single agent therapy.
Highlights • Dysregulation of the cyclin D–CDK4/6–INK4–Rb pathway frequently occurs in cancer. • Inhibition of CDK4/6 is a promising strategy for anticancer treatment. • Addition of CDK4/6 inhibitors to other agents may overcome resistance.
Highlights • Bladder cancer incidence and mortality have changed little over the past 20 years. • Immunotherapy offers improved efficacy and tolerability over other modalities. • Checkpoint inhibitors offer an effective alternative for patients with few options. • Recent data on PD-L1 inhibitors have proven their benefit in bladder cancer.
Abstract There is increasing interest in cancer stem cells (CSCs) and their role in cancer progression. Recently, CSCs have been identified in brain, skin, and intestinal tumors and it has been suggested that these CSCs are responsible for tumor growth and metastasis. In breast cancer fatality is often due to the development of metastatic disease (MBC). Almost 30% of early breast cancer patients eventually develop MBC and in 90% of these multi-drug resistance (MDR) occurs. This could be attributed to the presence of breast cancer stem cells (BCSCs). Epithelial-to-mesenchymal transition (EMT) is a process known to contribute to metastasis in cancer and it is mainly characterized by loss of E-cadherin expression. The TGF-β signaling pathway has an established role in promoting EMT by down-regulating E-cadherin via a number of transcription factors, such as Twist, Snail and Slug. EMT has also been reported to produce cells with stem cell-like properties. Definition of the exact molecular mechanisms that are involved in the generation of stem cells through EMT could lead to the identification of new potential therapeutic targets and enable the development of more efficient strategies for particular patient groups. In this review we discuss what is known about the relationship between EMT, BCSCs and MDR.
Abstract Epithelial cell adhesion molecule (EpCAM, CD326) is a pleiotropic molecule that potentially offers therapeutic applications in cancer treatment. Initially described as a dominant surface antigen on human colon carcinoma, it is a transmembrane glycoprotein mediating epithelial-specific intercellular cell–adhesion. Recent data suggest that EpCAM is also involved in cell signaling, migration, proliferation and differentiation. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker. Testing for EpCAM is based on morphology and phenotypical staining and can be performed with primary carcinoma tissue and cells harvested from malignant effusions. Stable or highly expressed EpCAM has been detected in most adenocarcinomas and has also been found in metastases, malignant effusions, and cancer stem cells. EpCAM may thus be an ideal tumor antigen candidate to detect circulating and metastasizing cancer cells by microchip technologies. In certain tumor types overexpression was linked to advanced stage of disease and worse overall survival, suggesting EpCAM as a potential prognostic marker. In addition to its diagnostic and prognostic role, EpCAM’s broad expression and apparent involvement in tumorigenesis and metastasis point to its potential as a target for immunotherapeutic strategies. The first EpCAM targeting, trifunctional antibody catumaxomab (Removab®) has shown clear clinical benefits in treatment of malignant ascites associated with EpCAM positive carcinomas. Further research and clinical studies should unravel EpCAM’s complex role in oncological processes, and expand potential therapeutic applications of EpCAM targeted strategies.
Highlights • p53 is the most frequently mutated gene in human cancer, but until recently was believed to be “undruggable”. • p53 is particularly frequently mutated (>80%) in difficult to treat tumors (TNBC, HGS ovarian, squamous lung cancer). • Several drugs are now available that can reactivate mutant p53 to a form exhibiting wild-type properties (e.g., PRIMA-1MET). • Other compounds are available that block the degradation of wild-type p53 (e.g., nutlins). • p53-targeting drugs currently undergoing clinical trials include PRIMA-1MET (APR-246) and nutlin derivatives.
Abstract Approximately 70−75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key intracellular signaling system that drives cellular growth and survival; hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer and in resistance to endocrine therapy. Moreover, preclinical and clinical evidence show that PI3K/AKT/mTOR pathway inhibition can augment the benefit of endocrine therapy in ER+ breast cancer, from the first-line setting and beyond. This article will review the fundamental role of the PI3K/AKT/mTOR pathway in driving ER+ breast tumors, and its inherent interdependence with ER signaling. In addition, ongoing strategies to combine PI3K/AKT/mTOR pathway inhibitors with endocrine therapy for improved clinical outcomes, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway, will be evaluated.
Highlights • Synchronous CRC liver metastases should be defined as ‘synchronously detected’. • Prognosis is poorer for synchronously detected metastases than for metachronous ones. • A multidisciplinary team approach is key to optimizing outcomes. • Advances in diagnosis, systemic treatment and surgery have improved outcomes. • Management depends on resectability and symptoms of liver metastases and primary tumour.
Abstract Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell–cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity.
The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog. (C) 2017 Elsevier Ltd. All rights reserved.