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In-depth understanding of the mechanism of targeted cancer therapy will help deepen the understanding of targeted therapy and help clinical decision-making and treatment. Let's Know about The Principles of Targeted Therapy for Cancer Treatment.
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Huateng Pharma https://en.huatengsci.com The Principles of Targeted Therapy for Cancer Treatment With the rapid development of tumor molecular biology, tumor molecular targeted therapy has been applied clinically, and its importance in medical oncology treatment has been increasingly recognized. However, targeted therapy is still in its infancy, and its clinical application still needs continuous exploration and summary. In-depth understanding of the mechanism of targeted cancer therapy will help deepen the understanding of targeted therapy and help clinical decision-making and treatment. What Are Targeted Cancer Therapies? Targeted cancer therapy is a treatment that acts on specific molecular targets to intervene in the process of cell canceration, such as inhibiting tumor cell proliferation, interfering with cell cycle, inducing tumor cell differentiation, inhibiting tumor cell metastasis, inducing tumor cell apoptosis, and inhibiting tumor angiogenesis, etc. It mainly acts on tumor cells, but has little effect on normal cells. Tumor growth factor receptors, signal transduction molecules, cyclins, apoptosis regulators, proteolytic enzymes, vascular endothelial growth factor and more can all be used as molecular targets for cancer treatment. Targeted therapies are currently the focus of much anticancer drug development. They are a cornerstone of precision medicine, a form of medicine that uses information about a person's genes and proteins to prevent, diagnose, and treat disease.
Huateng Pharma Types of Targeted Therapy https://en.huatengsci.com Many different targeted therapies have been approved for use in cancer treatment. 1. Treatment for tumor cells themselves Targeted therapy for growth factor receptors and cell membrane differentiation antigens on the cell membrane Most of these targeted therapies are monoclonal antibodies (mAbs). The specific binding of mAbs to growth factor receptors or antigens induces tumor immune response by blocking cell proliferation signals, and produces antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), thereby achieving the purpose of killing tumor cells . According to different target molecules, mAbs can be divided into two types: mAbs acting on cell growth factor receptors and mAbs acting on cell membrane differentiation antigens, such as EGFR\VEGFR\IGFR. mAbs against cell membrane differentiation antigen Cell membrane differentiation antigens refer to cell surface markers that appear during cell differentiation, maturation, and activation, and are usually represented by cluster of differentiation (CD). After mAbs bind to leukocyte differentiation antigens, they kill tumor cells through ADCC and CDC effects. Some differentiation antigen mAbs together with chemical drugs and radionuclides form monoclonal antibody conjugates, so that the active substances that kill tumor cells can specifically act on tumor cells. Currently, the differentiation antigen mAbs used in clinical applications include: rituximab, alemtuzumab, ibritumomab tiuxetan, and tositumomab, etc. 2. Targeted Therapy for Intracellular Signal Transduction Molecules Cell signal transduction refers to the process in which the cell membrane or intracellular receptors are stimulated by information molecules and converted by the intracellular signal transduction system, thereby affecting the biological behavior of cells. In tumor cells, gene mutation or overexpression of growth factors or receptors leads to excessive activation of receptors, activation of intracellular kinases, and downstream signal pathways to promote tumor growth. The key molecules in tyrosine kinase and its downstream signal transduction pathway are the current research focus. At present, the representative drugs of this type of main pathway include: Signal pathway Representative drugs Gefitinib, erlotinib, icotinib, lapatinib, sunitinib, sorafenib, imatinib Norine kinase inhibitor Key molecular inhibitors of tyrosine kinase and its downstream signal transduction pathway everolimus
Huateng Pharma 3. Targeted Therapy for Cyclin https://en.huatengsci.com Cell cycle regulation is a very complex and delicate regulation process, which is closely related to cell differentiation, growth and death. Cyclin-dependent kinase/cyclin (CDK/cyclin) is the core of the cell cycle regulatory network, which controls the start, progress and end of the cycle. Aurora kinase is an important regulatory kinase for cell mitosis. Targeted therapy targeting CDK/cyclin and Aurora kinase is the current research focus. 4. Targeted Therapy for Apoptosis Regulators Apoptosis is an autonomous cell death mode controlled by genes under certain physiological or pathological conditions, following its own procedures. Apoptosis-promoting genes include: P53 gene, MYC gene, TRAIL gene, etc.; apoptosis-inhibiting genes include: BCL-2 gene, IAP family, COX-2 gene, etc. Targeting apoptosis-related regulatory genes to induce tumor cell apoptosis is an important research direction for tumor molecular targeted therapy. For example, mapatumumab is an anti-TRAIL receptor 1 protein mAb, which can induce apoptosis of tumor cells expressing the TRAL receptor 1 protein. 5. Targeted Therapy for Cell Epigenetics Tumor cells often have epigenetic abnormalities, including abnormal DNA methylation, abnormal histone deacetylation and the resulting abnormal chromatin structure. Abnormal epigenetics can affect the transcription of many genes, including genes related to cell growth, differentiation, apoptosis, transformation, and tumorigenesis and development. DNA methylation plays an important role in DNA repair, gene stabilization, differentiation and gene suppression. Under the action of certain carcinogenic factors, the over-expression of methyltransferase in the cell makes the tumor suppressor gene hypermethylated, leading to tumorigenesis. Methyltransferase inhibitors can restore the function of tumor suppressor genes, that is, demethylation, so as to achieve the purpose of treating cancer. For example, decitabine (decitabine) is a DNA demethylation drug. 6. Treatment for The Microenvironment of Tumor Growth Anti-VEGF drugs: Among many angiogenic factors, VEGF has the strongest effect, and it plays a vital role in angiogenesis. VEGF and VEGFR are highly expressed in tumor cells and tumor vascular endothelium, and are the most ideal targets for anti-cancer angiogenesis. Bevacizumab is a humanized anti-VEGF mAb used for the treatment of colorectal cancer, breast cancer and non-small cell lung cancer. Sunitinib can bind to phosphorylated VEGFR tyrosine residues to inhibit signal transduction. It can directly inhibit tumor cell proliferation and tumor angiogenesis. Drugs that inhibit the degradation of extracellular matrix: Matrix metalloproteinases (MMP) can degrade the extracellular matrix and allow endothelial cells to enter the tumor stroma, thereby promoting tumor cell migration and tumor blood vessel formation. Natural and synthetic matrix metaloproteinase inhibitors (MMPI) can block MMP from degrading extracellular matrix components, thereby inhibiting tumor metastasis and angiogenesis.
Huateng Pharma There are a variety of synthetic MMPIs, such as batimastat, tanomastat, marimastat, prinomastat and so on. https://en.huatengsci.com Drugs that directly inhibit endothelial cells: New blood vessels are mainly composed of endothelial cells, pericytes and basement membrane. The activation, migration and proliferation of endothelial cells are the key steps of angiogenesis. Endostatin is a 184 amino acid fragment of the C-terminal non-collagen region domain of collagen VIII, which can inhibit the proliferation of vascular endothelial cells, thereby inhibiting angiogenesis. Clinical Application Strategy of Molecular Targeted Drugs Separate application: Gefitinib, erlotinib or icotinib have a total effective rate of more than 70% in the treatment of advanced non-small cell lung cancer with sensitive mutations, which is far superior to traditional chemotherapy. Imatinib, for the treatment of chronic myelogenous leukemia patients, has a complete hematological remission rate of more than 90%. Combined application: ① combined with chemotherapy ② combined with radiotherapy ③ combined with molecular targeted drugs Huateng Pharma, professional pharma APIs and intermediates supplier in China, offers high-quality drug APIs and intermediates' process development and scale-up production with capacities varying from gram to kilograms and multi tons. References: [1] Osmani L, Askin F, Gabrielson E, Li Q K. Semin Cancer Biol(Seminars in cancer biology), 2018, 52(Pt 1):103-109. [2] Deberardinis R J, Chandel N S. Sci Adv(Science advances), 2016, 2(5):e1600200. [3] Wargo J A, Reuben A, Cooper Z A, Oh K S, Sullivan R J. Semin Oncol(Seminars in oncology), 2015, 42(4):601-616. [4] Krajewski K M, Braschi-Amirfarzan M, Dipiro P J, Jagannathan J P, Shinagare A B. Korean J Radiol(Korean journal of radiology), 2017, 18(1):28-41. [5] Puri T. Indian J Cancer(Indian journal of cancer), 2017, 54(1):83-88. Related Articles: [1] CDK4/6 Inhibitors: How Do They Work against Breast Cancer? [2] GLUT1 Inhibitor, A New Therapy For Triple-negative Breast Cancer [3] The Rise of Antibody-Drug Conjugates (ADCs) - 'Guided-Missile' Cancer Drugs