Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Valerio Voliani in Nanomaterials and Neoplasms, 2021
Tyrosine kinases that are responsible for activation of signal transduction cascades can be inhibited by tyrosine kinase inhibitors. These are used as anticancer drugs by competing with ATP [211]. About 15%–20% of patients with early-stage breast cancer have tumors that overexpress or amplify HER2 genes, which is associated with increased proliferation of cancer cells and poor prognosis [390–394]. When HER2 binds to the ligands (preferably forming dimers), the HER2 pathway can initiate the mitogen-activated protein kinase pathway as well as the PI3K/Akt pathway, which in turn activates the nuclear factor kappa B pathway. When growth factors bind to their receptors on the cell surface, the receptors give a signal causing cell division. However, if growth factor receptor inhibitors bind to their receptors, the receptors no longer cause uncontrolled cell proliferation. Trastuzumab (Herceptin) is a HER2-specific mAb and the only approved HER2-targeted drug. Cells targeted with trastuzumab experience cell cycle arrest in the G phase; thus, cell proliferation is reduced by downregulation of HER2/neu [383, 384]. When cancer develops it requires generation of neovasculature for nutrient and oxygen supply. Trastuzumab suppresses angiogenesis, formation of new blood vessels, by both induction of antiangiogenic factors and repression of proangiogenic factors. Cetuximab (Erbitux), an EGFR inhibitor, binds to EGFR and inhibits uncontrolled growth of cancers with EGFR mutations [215, 216, 395–400].
Specific Therapy for Leukemias
Tariq I Mughal, John M Goldman, Sabena T Mughal in Understanding Leukemias, Lymphomas, and Myelomas, 2017
The demonstration that imatinib durably blocks the kinase activity of the BCR–ABL1 oncoprotein provided a major incentive for the development of the next generation of kinase inhibitors. The next (second) generation tyrosine kinase inhibitors, dasatinib (Sprycel), and nilotinib (Tasigna; AMN107), appear to be more potent than imatinib and are now in the clinic, for treatment of imatinib-resistant/refractory CML. Other candidate drugs include bosutinib (SKI-606), a third generation tyrosine kinase with similarities to dasatinib, and homohar-ringtonine (omacetaxine, Myelostat), a drug developed from a Chinese evergreen yew tree Cephalotaxus harringtonia that enhances apoptosis of CML cells and may also have some activity against a subclone (subtype) of CML, known as T315I CML, which is a mutant form resistant to all currently available tyrosine kinase inhibitors.
Endocrine and Neuroendocrine Tumors
Pat Price, Karol Sikora in Treatment of Cancer, 2020
RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system/neural crest and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands requires additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. RET fusion proteins have been reported in papillary thyroid and non-small cell lung adenocarcinomas. There has been much recent interest and clinical benefit from the use of the RET inhibitors in the therapy of metastatic medullary thyroid cancer. Vandetanib and cabozantinib have been licensed and are of proven efficacy; recently, a more potent agent, Blue-667, has become available and looks more promising still. This last drug has activity in the brain (of more importance in the RET-driven lung cancers than medullary carcinoma of thyroid). Side-effects such as hypertension, ECG changes, and blood test abnormalities are usually minor but close monitoring is required—as for all cancer patients on tyrosine kinase inhibitors.
Investigational drugs in early stage clinical trials for the treatment of HER2+ breast cancer
Published in Expert Opinion on Investigational Drugs, 2019
Andrea Gombos, Maria Alice Franzoi, Ahmad Awada
With such efficacious systemic treatment options, possibly prolonging the survival of advanced cancer patients, the prevention and management of brain metastases are becoming an even more challenging and urgent topic to be addressed. Despite the continuous development of really exciting and promising new drugs in the HER2-targeting field, so far few of them are crossing the blood-brain barrier and are able to address this population of really bad prognosis. Probably the most promising tyrosine kinase inhibitor in this regard is tucatinib given in combination. Neratinib is a drug potentially effective in this setting as well. The initiative of investigators developing these drugs to include even in advanced phase trials patients diagnosed with progressive brain metastases is exemplary.
Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore
Published in Journal of Medical Economics, 2020
Mohamed Ismail Abdul Aziz, Wayne Yong Xiang Foo, Chee Keong Toh, Wan-Teck Lim, Kwong Ng
In the absence of local data, health state utility values were obtained from an international, prospective health-related quality of life (HRQoL) survey using the EQ-5D instrument on patients (mean age 64.7 years) with advanced NSCLC receiving first-, second- or subsequent-line treatments or best supportive care20. The utility values were consistent with an earlier cost-effectiveness analysis evaluating tyrosine kinase inhibitors for metastatic NSCLC in Singapore21. Utilities were weighted by the proportion of time spent in each health state stratified by treatment arms. Disutilities associated with AEs were sourced from a UK study22 (Table 2). The disutility associated with interstitial lung disease was omitted as the underlying cause could not be definitively determined to be treatment induced or disease related.
Tumor reduction and symptom relief after electrochemotherapy in a patient with aggressive fibromatosis – a case report
Published in Acta Oncologica, 2018
Joanna Vitfell-Rasmussen, Rikke Mulvad Sandvik, Karin Dahlstrøm, Gina Al-Farra, Anders Krarup-Hansen, Julie Gehl
Aggressive fibromatosis also known as desmoid tumors constitute 3% of soft tissue tumors and 0.03% of all cancers [1]. They most commonly occur in women after childbirth and the gender ratio is 1.5–2.5:1 for females versus males [2]. It is a monoclonal (myo-) fibroblastic proliferation derived from mesenchymal progenitor cells [3]. These tumors commonly develop in the fibrous (connective) tissue of the body that forms tendons and ligaments, usually in the arms, legs or midsection and also the head and neck area. Superficial desmoid tumors tend to be less aggressive than deep desmoids (abdominal, extra abdominal, mesenteric). Desmoid tumors may present sporadically or as a manifestation of a hereditary syndrome called familial adenomatous polyposis (FAP) or familial infiltrative fibromatosis [4,5]. They never metastasize but they might be multifocal. Previously, the primary treatment was surgery but as the recurrence rate often is as high as 50% or more, surgery is now more restricted to non-harmful locations or emergencies. Other therapies include watchful waiting, radiotherapy, antiestrogens (e.g. tamoxifen), non-steroidal anti-inflammatory drugs (NSAIDs) or chemotherapy and tyrosine kinase inhibitors (e.g. imatinib, sorafenib) [6]. Radiotherapy is only advised if all other treatment options have been applied and the clinical condition needs to be solved, i.e., nerve damage, obstruction, etc., this is due to the risk of secondary malignancies [7].
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