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Trametinib: a MEK inhibitor for management of metastatic melanoma.

This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-

Trametinib: A Targeted Therapy in Metastatic Melanoma.

Trametinib is a MEK inhibitor approved both as a single agent and in combination with dabrafenib for the treatment of BRAF V600E or V600K mutated melanoma. It is a once-daily oral medication that was approved based on progression-free survival and overall survival advantage compared to chemotherapy. Most common side effects include rash, diarrhea, peripheral edema, and fatigue. When used in combination with dabrafenib, pyrexia and nausea are also common. Most side effects can be managed effectively with dose interruptions, supportive care, and/or dose reductions. Ongoing trials are investigati

Targeting MDM2, RAS, and PCNA for cancer targeted therapy: pan-cancer approaches vs. cancer-specific strategies.

Cancer therapy and cancer drug discovery and development have been historically focused on specific cancers (tissue/organ of origin). However, with advances in molecular biology and multi-omics of cancer, there is a trend to develop pan-cancer therapeutic modalities. In targeted therapy, pan-cancer strategies target common molecular alterations across different cancer types and specific cancer strategies are tailored to the unique biological characteristics of individual tumor types. Each approach offers distinct advantages and limitations, and understanding these differences is critical in th

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… Mutations in RAS lock it in an active GTP-bound state, leading to dysregulated signaling through multiple downstream effectors, including rapidly accelerated fibrosarcoma (RAF) kinases, phosphoinositide 3-kinases (PI3K), the RAS association domain family (RASSF), T lymphoma invasion and metastasis protein … In its GTP-bound active state, RAS recruits RAF kinases to the plasma membrane, triggering their activation. Once activated, RAF phosphorylates MEK1/2, which subsequently phosphorylates and activates ERK1/2 ( Ullah et al., 2022 ). …

Ранняя реакция на рост Gene 1 Выгоды Аутоиммунная болезнь путем поощрения дифференциации ячеек в качестве регулятора Foxp3.

Foxp3+ Регулирующие T (Treg) клетки, как один из подтипов CD4+T клеток, являются важнейшим сторожем в патогенезе самоантигенных реактивных заболеваний. В этом контексте мы продемонстрировали, что выборочная абляция гена раннего реагирования роста 1 (Egr-1) в CD4+T клеток усугубила экспериментальный аутоиммунный энцефаломиелит (EAE) в мюриновых моделях. Отсутствие Egr-1 в клетках CD4+T, полученное из мышей EAE и наивных клеток CD4+T, препятствовало дифференциации и влиянию Treg. Важно то, что в CD4+T клеток нескольких склерозных пациентов как Egr-1, так и Foxp3 было обнаружено снижение. Дальней

Targeting vascular endothelial growth receptor-2 (VEGFR-2): structural biology, functional insights, and therapeutic resistance.

Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of

A systematic review of ongoing clinical trials in optic pathway gliomas.

INTRODUCTION: Optic pathway gliomas (OPGs), also known as Visual Pathway Gliomas, are insidious, debilitating tumours. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of OPGs within the optic pathway typically precludes complete resection or optimal radiation dosing, hence outcomes remain poor compared to many other low-grade gliomas. The aim of this systematic review was to formulate a comprehensive list of all current ongoing clinical trials that are specifically looking at clinical care of OPGs in order t

Keyword Index for Volume 104

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

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-mol

Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV), a type 4 γ herpes virus, is recognized as a causative agent in nasopharyngeal carcinoma (NPC). Incidence of EBV-positive NPC have grown in recent decades along with worse outcomes compared with their EBV-negative counterparts. Latent membrane protein 1 (LMP1), encoded by EBV, induces NPC progression. The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases (RTK), is a driver of tumorigenesis, including for NPC. Little data exist on the relationship between EGFR and EBV-induced NPC. In our initial review, we found that LMP1

Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures.

Chemotherapy and targeted therapy have opened new avenues in clinical oncology. However, there is a lack of response in a substantial percentage of cancer patients and diseases frequently relapse in those who even initially respond. Resistance is, at present, the major barrier to conquering cancer, the most lethal age-related pathology. Identification of mechanisms underlying resistance and development of effective strategies to circumvent treatment pitfalls thereby improving clinical outcomes remain overarching tasks for scientists and clinicians. Growing bodies of data indicate that stromal

Медицинский каннабис и признаки рака: критический обзор.

Онкология остаётся сложным и гетерогенным заболеванием, вызывающим значительную morbidity и mortality по всему миру, несмотря на продвижение в диагностике и лечении. Характерные черты онкологии раскрывают биологические механизмы, поддерживающие развитие опухолей и злокачественное эволюцию, а также помогают выявить потенциальные мишени для терапии. Медикаментозный кресс-масло в основном используется в онкологии для поддерживающей терапии, но растущее предклиническое доказательство указывает на взаимодействие с сигнальными путями, связанными с онкологией. Этот обзорный материал обобщает текущие

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st-3rd, 2022-Naples, Italy).

Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have se

COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity.

The COVID-19 pandemic has been the focus of research the past two years. The major breakthrough was made by discovering pathways related to SARS-CoV-2 infection through cellular interaction by angiotensin-converting enzyme (ACE2) and cytokine storm. The presence of ACE2 in lungs, intestines, cardiovascular tissues, brain, kidneys, liver, and eyes shows that SARS-CoV-2 may have targeted these organs to further activate intracellular signalling pathways that lead to cytokine release syndrome. It has also been reported that SARS-CoV-2 can hijack coatomer protein-I (COPI) for S protein retrograde

Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders.

In the category of mature B-cell neoplasms, splenic B-cell lymphoma and leukemia were clearly identified and include four distinct entities: hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), splenic diffuse red pulp lymphoma (SDRPL) and the new entity named splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN). The BRAFV600E mutation is detected in nearly all HCL cases and offers a possibility of targeted therapy. BRAF inhibitors (BRAFi) represent effective and promising therapeutic approaches in patients with relapsed/refractory HCL. Vemurafenib and dabrafenib were

Clinical development of targeted and immune based anti-cancer therapies.

Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to

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… The Raf kinases have long been associated with cancer [ 241 ]. BRAF mutations have been extensively reported in numerous cancers, including melanomas (50–66%), papillary thyroid tumors (45–50%), CRCs (10%), prostate tumors (10%), and NSCLCs (3%) [ 238 , 242 – 245 ]. …

Multifunctionality of Calebin A in inflammation, chronic diseases and cancer.

Chronic diseases including cancer have high case numbers as well as mortality rates. The efficient treatment of chronic diseases is a major ongoing medical challenge worldwide, because of their complexity and many inflammatory pathways such as JNK, p38/MAPK, MEK/ERK, JAK/STAT3, PI3K and NF-κB among others being implicated in their pathogenesis. Together with the versatility of chronic disease classical mono-target therapies are often insufficient. Therefore, the anti-inflammatory as well as anti-cancer capacities of polyphenols are currently investigated to complement and improve the effect of

Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis.

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway,

Полнотрансформатная ретиноидальная кислота в гематологическое расстройство: не только острая промиелоцитическая лейкемия.

Всетранс-ретиноиновая кислота (ATRA) играет определенную роль в развитии тканей, нейронной функции, воспроизводстве, зрение, росте и дифференциации клеток, иммунитете от опухоли и апоптозе. АТРА может действовать, вызывая автофагическую сигнализацию, ангиогенез, клеточную дифференциацию, апоптоз и иммунную функцию. В крови ATRA впервые с большим успехом использовалась в острой промиелоцитической лейкемии (APL), где ATRA дифференцировала клетки лейкемии на зрелые гранулоциты. АТРА может играть определенную роль не только в ППН, но и в других гематоологических заболеваниях, таких, как иммунная т

Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium.

The medical history of cancer began millennia ago. Historical findings of patients with cancer date back to ancient Egyptian and Greek civilizations, where this disease was predominantly treated with radical surgery and cautery that were often ineffective, leading to the death of patients. Over the centuries, important discoveries allowed to identify the biological and pathological features of tumors, without however contributing to the development of effective therapeutic approaches until the end of the 1800s, when the discovery of X-rays and their use for the treatment of tumors provided the

Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma.

Recurrence of disease due to chemotherapy drug resistance remains a major obstacle to a more successful survival outcome of multiple myeloma (MM). Overcoming drug resistance and salvaging patients with relapsed and/or refractory (R/R) MM is an urgent and unmet medical need. Several new personalized treatment strategies have been developed against molecular targets to overcome this drug resistance. There are several targeted therapeutics with anti-MM activity in clinical pipeline, including inhibitors of anti-apoptotic proteins, monoclonal antibodies, antibody-drug conjugates, bispecific antibo