Project description:Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.
Project description:Molecular targets for the pathological vasculature are the vascular endothelial growth factor (VEGF)/VEGF receptor axis, integrins, angiopoietins, and platelet-derived growth factor receptor (PDGFR), as well as several intracellular or downstream effectors like protein kinase C beta and mammalian target of rapamycin (mTOR). Besides hypoxic damage or tumor cell starvation, preclinical models imply vessel independent tumor regression and suggest differential effects of anti-angiogenic treatments on tumorous and nontumorous precursor cells or the immune system. Despite compelling preclinical data and positive data in other cancers, the outcomes of clinical trials with anti-angiogenic agents in gliomas by and large have been disappointing and include VEGF blockage with bevacizumab, integrin inhibition with cilengitide, VEGF receptor inhibition with sunitinib or cediranib, PDGFR inhibition with imatinib or dasatinib, protein kinase C inhibition with enzastaurin, and mTOR inhibition with sirolimus, everolimus, or temsirolimus. Importantly, there is a lack of real understanding for this negative data. Anti-angiogenic therapies have stimulated the development of standardized imaging assessment and the integration of functional MRI sequences into daily practice. Here, we delineate directions in the identification of molecularly or image-based defined subgroups, anti-angiogenic cotreatment for immunotherapy, and the potential of ongoing trials or modified targets to change the game.
Project description:Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
Project description:Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12?years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.
Project description:Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.
Project description:Stem cell dysfunction is a hallmark of aging, associated with the decline of physical and cognitive abilities of humans and other mammals [Cell 2013;153:1194]. Therefore, it has become an active area of research within the aging and stem cell fields, and various techniques have been employed to mitigate the decline of stem cell function both in vitro and in vivo. While some techniques developed in model organisms are not directly translatable to humans, others show promise in becoming clinically relevant to delay or even mitigate negative phenotypes associated with aging. This review focuses on diet, treatment, and small molecule interventions that provide evidence of functional improvement in at least one type of aged adult stem cell.
Project description:Anti-angiogenic therapy has become an important component in the treatment of many solid tumors given the importance of adequate blood supply for tumor growth and metastasis. Despite promising preclinical data and early clinical trials, anti-angiogenic agents have failed to show a survival benefit in randomized controlled trials of patients with glioblastoma. In particular, agents targeting vascular endothelial growth factor (VEGF) appear to prolong progression free survival, possibly improve quality of life, and decrease steroid usage, yet the trials to date have demonstrated no extension of overall survival. In order to improve duration of response and convey a survival benefit, additional research is still needed to explore alternative pro-angiogenic pathways, mechanisms of resistance, combination strategies, and biomarkers to predict therapeutic response.
Project description:The increasing number of approved therapies for relapsed mantle cell lymphoma (MCL) provides patients effective treatment options, with increasing complexity in prioritization and sequencing of these therapies. Chemo-immunotherapy remains widely used as frontline MCL treatment with multiple targeted therapies available for relapsed disease. The Bruton's tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib achieve objective responses in the majority of patients as single agent therapy for relapsed MCL, but differ with regard to toxicity profile and dosing schedule. Lenalidomide and bortezomib are likewise approved for relapsed MCL and are active as monotherapy or in combination with other agents. Venetoclax has been used off-label for the treatment of relapsed and refractory MCL, however data are lacking regarding the efficacy of this approach particularly following BTKi treatment. Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective therapy for relapsed MCL, with the CAR-T treatment brexucabtagene autoleucel now approved for relapsed MCL. In this review the authors summarize evidence to date for currently approved MCL treatments for relapsed disease including sequencing of therapies, and discuss future directions including combination treatment strategies and new therapies under investigation.
Project description:Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating the immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review we summarize the current knowledge on HCC immunology and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives.