{"id":2622,"date":"2023-03-03T21:45:05","date_gmt":"2023-03-04T02:45:05","guid":{"rendered":"https:\/\/www.bocsci.com\/blog\/?p=2622"},"modified":"2023-04-21T01:38:53","modified_gmt":"2023-04-21T06:38:53","slug":"small-molecule-targeted-cancer-immunotherapy-draws-the-new-roadmap-for-cancer-treatment","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/small-molecule-targeted-cancer-immunotherapy-draws-the-new-roadmap-for-cancer-treatment\/","title":{"rendered":"Small Molecule Targeted Cancer Immunotherapy Draws the New Roadmap for Cancer Treatment"},"content":{"rendered":"\n<p>As an alternative to surgery, radiotherapy, and chemotherapy, tumor therapy <em>via<\/em> the immune pathway has made significant advances in recent years. Among the targeted drugs of immuno-oncology (IO), Ab drugs have become&nbsp;the focus of research due to their excellent therapeutic&nbsp;abilities. Small molecule targeted drugs,&nbsp;another growing category,&nbsp;are also used in tumor therapy in various ways, making up for the shortcomings of Ab drugs.<\/p>\n\n\n\n<p><strong>Therapies targeting&nbsp;the <a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/cancer-immunotherapy.html\">cancer&nbsp;pathway<\/a><\/strong><\/p>\n\n\n\n<p>Cancer is primarily caused by dysregulation of cell cycle homeostasis and enhanced resistance to apoptosis. Besides, in the process of tumor development, a variety of inhibitory signals appear, leading to&nbsp;the proliferation of immune cells&nbsp;and weakened&nbsp;effect function. Current small-molecule drugs that target these molecules fall into the following categories:<\/p>\n\n\n\n<ul>\n<li><strong>BRAF inhibitor<\/strong><strong>s<\/strong><strong><\/strong><\/li>\n<\/ul>\n\n\n\n<p>BRAF is a proto-oncogene, and mutation of BARF (V600E)&nbsp;can lead to tumorigenesis.&nbsp;Two Phase I studies have shown that BRAF\/<a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/tag\/mek-237.html\">MEK<\/a> inhibition increases CD8&nbsp;T cell infiltration by inducing immunogenic cell death (ICD) to produce pro-inflammatory signaling, while damage-associated molecular patterns (DAMPs)&nbsp;activate T cell effector functions. (NCT01656642, NCT02130466)<\/p>\n\n\n\n<p>The presence of immunosuppressive signals in TME is an obstacle to BRAF\/MEK-targeted&nbsp;therapy. Combining ICI drugs may be a way to improve efficacy. In the trial, the combination with anti-PD-1 antibodies fails to reach the clinical endpoint, and there may be overlapping toxicity that increases the incidence of treatment-related adverse events.<\/p>\n\n\n\n<ul>\n<li><strong>VEGF-VEGFR pathway inhibitors<\/strong><\/li>\n<\/ul>\n\n\n\n<p>Vascular endothelial growth factor (VEGF) stimulates angiogenesis, and high levels of VEGF in TME&nbsp;recruit immunosuppressive cell subsets. Blocking <a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/vegf-signaling-pathway.html\">VEGF-VEGFR<\/a> can effectively exert antitumor effects, especially against highly vascularized tumors.<\/p>\n\n\n\n<p>Several clinical trials conducted in combination with PD-1 Ab drugs have shown good overall effects.<\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><a href=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/1.jpg\"><img decoding=\"async\" loading=\"lazy\" src=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/1.jpg\" alt=\"Nat Rev Drug Discov. 2022 Nov;21(11):821-840.\" class=\"wp-image-2625\" width=\"540\" height=\"454\"\/><\/a><figcaption class=\"wp-element-caption\">Nat Rev Drug Discov. 2022 Nov;21(11):821-840.<\/figcaption><\/figure><\/div>\n\n\n<ul>\n<li><strong><a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/tag\/cytokine-receptor-30.html\">Cytokine and chemokine receptor inhibitors<\/a><\/strong><\/li>\n<\/ul>\n\n\n\n<p>Cytokines play a key role in maintaining intercellular communication, especially in the production and regulation of immune function.<\/p>\n\n\n\n<p>Many popular cytokines, including TNF\u03b1 and IL-2, have not been shown to have antitumor properties in preclinical trials. Dose-limiting toxicity caused by the systemic administration of drugs is a critical reason.<\/p>\n\n\n\n<p><strong>Therapies targeting tumor metabolic pathways<\/strong><\/p>\n\n\n\n<p>The metabolic function of tumor cells is extremely active, and the demand for oxygen and nutrients is greatly increased. By reshaping TME, large quantities of <a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/metabolites-list-1335.html\">metabolites<\/a> can inhibit the effect function of T cells, further promoting tumor growth.<\/p>\n\n\n\n<p>At present, small molecule drugs targeting metabolic pathways are being intensively studied and multiple&nbsp;drugs are now in advanced clinical development.<\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><a href=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/2.png\"><img decoding=\"async\" loading=\"lazy\" src=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/2.png\" alt=\"Arginase, Glutaminase, Adenosine, Kynurenine Nat Rev Drug Discov. 2022 Nov;21(11):821-840.\" class=\"wp-image-2626\" width=\"540\" height=\"414\"\/><\/a><figcaption class=\"wp-element-caption\">Arginase, Glutaminase, Adenosine, Kynurenine Nat Rev Drug Discov. 2022 Nov;21(11):821-840.<\/figcaption><\/figure><\/div>\n\n\n<ul>\n<li><strong>Glutamine, arginine metabolic pathways<\/strong><\/li>\n<\/ul>\n\n\n\n<p>Tumor cells meet their energy needs by enhancing glycolysis and by the breakdown of glutamine to compete with T cells for nutrients. Targeting this pathway with <a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/inhibitor-list-84.html\">small molecule inhibitors<\/a> can effectively suppress&nbsp;tumor growth and promote immune cell infiltration in preclinical models.<\/p>\n\n\n\n<p>Arginine is also competed for by tumor and T cells, and high levels of arginine-degrading enzymes expressed by myeloid-derived suppressor cells (MDSCs) in TMEs boost&nbsp;the need for arginine. Fortunately, a&nbsp;variety of small molecule arginine inhibitors have been developed.<\/p>\n\n\n\n<ul>\n<li><strong>Adenosine metabolic pathways<\/strong><\/li>\n<\/ul>\n\n\n\n<p>Adenosine is a potent immunosuppressant produced in large quantities by a variety of tumors. It mediates immunosuppression by binding to GPCR, A2aR, and A2bR on immune cells.<\/p>\n\n\n\n<p>A2aR has a high affinity for adenosine.&nbsp;<a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/tag\/adenosine-a2a-33.html\">Small molecule inhibitors targeting A2aR<\/a> alone were previously the major direction for research. However, the current focus shifts to dual inhibition of A2aR\/A2bR, which may be more effective in inhibiting adenosine signal transduction. But the resulting toxic effects need to be considered.&nbsp;If the concentration of adenosine in TME is too high, targeting A2bR with low affinity alone may be a safer&nbsp;strategy.<\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><a href=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/3.png\"><img decoding=\"async\" loading=\"lazy\" src=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/3.png\" alt=\"Nat Rev Drug Discov. 2022 Nov;21(11):821-840.\" class=\"wp-image-2627\" width=\"540\" height=\"496\"\/><\/a><figcaption class=\"wp-element-caption\">Nat Rev Drug Discov. 2022 Nov;21(11):821-840.<\/figcaption><\/figure><\/div>\n\n\n<ul>\n<li><strong>Kynurenine metabolic pathways<\/strong><\/li>\n<\/ul>\n\n\n\n<p>Tumor cells catalyze tryptophan decomposition to produce <a class=\"highlight\" href=\"https:\/\/www.bocsci.com\/im-kynurenine-and-impurities-list-1274.html\">kynurenine<\/a> through IDO1 and TDO. They are combined&nbsp;with AHR to inhibit T cell effect&nbsp;function&nbsp;while&nbsp;promoting&nbsp;the development of Treg and MDSC cells.<\/p>\n\n\n\n<p>An IDO1 inhibitor, echo-301, showed&nbsp;acceptable early clinical data but no significant benefit in phase III trials (NCT02862457). TDO and IDO2 can also degrade tryptophan, which is the compensatory mechanism of this pathway and&nbsp;may also be the cause of tumor insensitivity to IDO1.<\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><a href=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/4.png\"><img decoding=\"async\" loading=\"lazy\" src=\"https:\/\/www.bocsci.com\/blog\/wp-content\/uploads\/2023\/03\/4.png\" alt=\"Nat Rev Drug Discov. 2022 Nov;21(11):821-840.\" class=\"wp-image-2628\" width=\"540\" height=\"349\"\/><\/a><figcaption class=\"wp-element-caption\">Nat Rev Drug Discov. 2022 Nov;21(11):821-840.<\/figcaption><\/figure><\/div>\n\n\n<p>References<\/p>\n\n\n\n<p>1. Offringa R <em>et al<\/em>. The expanding role for small molecules in immuno-oncology. <em>Nat Rev Drug Discov<\/em>. 2022 Nov;21(11):821-840.<\/p>\n\n\n\n<p>2. Hanahan D. Hallmarks of Cancer: New Dimensions. <em>Cancer Discov<\/em>. 2022 Jan;12(1):31-46.<\/p>\n\n\n\n<p>3. Low V <em>et al<\/em>. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment. <em>Sci Signal<\/em>. 2022 Nov 8;15(759):eabj4220.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>As an alternative to surgery, radiotherapy, and chemotherapy, tumor therapy via the immune pathway has made significant advances in recent years. Among the targeted drugs of immuno-oncology (IO), Ab drugs [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":2726,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[21,181],"tags":[778,285,92,780,779],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/2622"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=2622"}],"version-history":[{"count":4,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/2622\/revisions"}],"predecessor-version":[{"id":2787,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/2622\/revisions\/2787"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media\/2726"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=2622"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=2622"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=2622"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}