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Drug Targeting to Tumors: Principles, Pitfalls and (Pre-) Clinical Progress
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Twan Lammers, Fabian Kiessling, Wim E. Hennink, Gert Storm
In the past few decades, significant progress has been made in understanding the molecular principles of many different diseases. In the case of cancer, these improved insights into the genetic and (patho-) physiological processes contributing to malignant transformation and tumorigenesis have resulted in the development of several novel (classes of) chemotherapeutic drugs. Such “molecularly targeted therapeutics,” like the growth factor receptor inhibitor Herceptin, the proteasome inhibitor Velcade, the histone deacetylase inhibitor Vorinostat and the antiangiogenic agent Avastin, more selectively interfere with certain “hallmarks of cancer” [1, 2], like with the overexpression of growth factors and growth factor receptors, with the altered balance between apoptosis and anti-apo-ptosis, with the numerous genetic and epigenetic changes that are present in cancer cells, and with the development of a dense vascular network, needed to provide tumors with oxygen and nutrients. By means of their pharmacologically and/or physiologically more optimal mechanism(s) of action, “molecularly targeted therapeutics” have been shown to be able to more preferentially kill cancer cells, both in vitro and in vivo, and to improve the balance between the efficacy and the toxicity of systemic anticancer therapy [3–5].
Cancer
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Agents such as interferons, immunomodulators, tumor antigens, and lymphokines/cytokines are being investigated as means of enhancing the immune system response of individuals with cancer. Monoclonal antibodies have also been studied as a highly specific means of delivering chemotherapeutic drugs directly to cancer cells or as a means of blocking specific pathways in cancer cells that might be essential for replication or survival. Two monoclonal antibodies currently used for the treatment of cancer are, bevacozumabTM (AvastinTM, an angiogenesis receptor inhibitor), and cetuximabTM (ErbituxTM, a growth factor receptor inhibitor).
Malignancy following lung transplantation
Published in Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell, LUNG Transplantation, 2016
Katherine M. Vandervest, Martin R. Zamora
Management of skin carcinoma in transplant recipients depends on the type of lesion and its extent. Precancerous lesions or very superficial NMSC may be treated with cyclic topical therapies, such as cryotherapy, 5-fluorouracil, imiquimod, topical retinoid, and photodynamic therapy. More infiltrative but uncomplicated instances of SCC and BCC require prompt excision or Mohs micrographic surgery with histologic examination to verify clear margins and determine tumor stage. Adjuvant radiation therapy is often recommended if lymph node infiltration or extracapsular spread is present. Chemotherapy with bleomycin, fluorouracil, and cisplatin is generally reserved for metastatic disease.30 Multiple novel therapies are under investigation. One such agent is cetuximab, an endothelial growth factor receptor inhibitor that is used for metastatic SCC in the head and neck. Another is ingenol mebutate, a topical medication for treating actinic keratosis.51
Overcoming challenges in refining the current generation of coronary stents
Published in Expert Review of Cardiovascular Therapy, 2021
Masayuki Mori, Atsushi Sakamoto, Yu Sato, Rika Kawakami, Kenji Kawai, Anne Cornelissen, Biniyam Abebe, Saikat Ghosh, Maria E. Romero, Frank D. Kolodgie, Renu Virmani, Aloke V. Finn
Based on prior pre-clinical and clinical evidences, mTOR inhibitors (e.g. sirolimus and its analogues) have clear-cut advantages over paclitaxel in coronary PCI in terms of safety and efficacy [90,91]. Therefore, limus drugs are the current major pharmacologic agent used in DES. However, since mTOR inhibitors inhibit the proliferation and function not only of vascular smooth muscle cells (the target of DES) but also of endothelial cells, disturbing healthy endothelial functional recovery is unavoidable. For further reduction of the risk of in-stent neoatherosclerosis, vascular smooth muscle cell-specific anti-proliferative agents (which do not disturb endothelial function) need to be considered. Some attempts are ongoing, such as Mithramycin A (specificity protein-1 inhibitor), Rhosin (RhoA inhibitor), and Sorafenib (platelet-derived growth factor receptor inhibitor) in preclinical studies [112–114]. To confirm the feasibility of these new DESs, further evaluation is warranted.
An evaluation of olaparib for the treatment of pancreatic cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Proving the role of targeted therapies in pancreas cancer has been challenging. The epithelial growth factor receptor inhibitor, erlotinib was evaluated in combination with gemcitabine and even received FDA approval based on a statistically significant, but clinically irrelevant difference in median OS of 2 weeks [5]. The toxicities with erlotinib therapy are not trivial and need to be considered, especially given the limited benefit. Attempts to identify a subset that would benefit from erlotinib were unsuccessful. Multiple other targeted therapies such as antiangiogenic therapy, hyaluran inhibitors, and BRAF inhibitors were evaluated with minimal success [6]. High incidence of KRAS mutations has been noted in advanced pancreas cancer. Potent inhibitors of KRASG12C mutation are under current drug development, and evaluation in early phase clinical trials is ongoing [7]. These have demonstrated preliminary promising responses however the incidence of these mutations in pancreas cancer is about 2%. Germline DNA repair mutations are noted to have an incidence of about 7% in advanced pancreas cancer [8]. The success of specific targeted therapies in germline DNA repair mutation cancers, led to evaluation of this strategy in advanced pancreas cancer.
The prognostic role of NK cells and their ligands in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis
Published in OncoImmunology, 2020
Sangeeta K. Bisheshar, Emma J. De Ruiter, Lot A. Devriese, Stefan M. Willems
Roughly 60% of HNSCC patients have an advanced stage disease at the time of diagnosis, due to limited awareness and knowledge of alarm symptoms, and the characteristic rapid proliferation of HNSCC.8 Currently, treatment methods are insufficient; locoregional recurrence occurs in 15-50% of patients,9 and for all clinical stages combined, five-year survival rates are between 56%-62%.10,11 This calls for reliable prognostic biomarkers that enable clinicians to stratify patients in risk groups and treating them accordingly, improving personalized medicine. Cancer development is facilitated by the inability of the immune system to recognize and eliminate tumor cells. In HNSCC, an immunogenic cancer type, immune escape mechanisms are key to tumor initiation and progression. Since the host immune system plays an important role in the development of cancer, the scientific necessity arose to further employ the immune system for the treatment of HNSCC. Currently, cetuximab, an EGFR (endothelial growth factor receptor) inhibitor, is used in case a contradiction for chemotherapy exists.12,13 The antitumor effect of cetuximab is strengthened by binding the FcY receptor on NK cells enabling antibody-dependent cellular cytotoxicity (ADCC).14