{"id":1867,"date":"2015-05-13T11:05:13","date_gmt":"2015-05-13T15:05:13","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=1867"},"modified":"2021-07-02T08:51:54","modified_gmt":"2021-07-02T12:51:54","slug":"csf-1-inhibitor-plx3397-keytruda-anti-pd1-for-multiple-cancers","status":"publish","type":"post","link":"http:\/\/blogs.shu.edu\/cancer\/2015\/05\/13\/csf-1-inhibitor-plx3397-keytruda-anti-pd1-for-multiple-cancers\/","title":{"rendered":"CSF-1 Inhibitor PLX3397 + Keytruda (Anti-PD1) for Multiple Cancers"},"content":{"rendered":"

Colony Stimulating Factor (CSF-1) is an essential growth factor for cells of the monocyte-macrophage lineage, including osteoclasts<\/a>.
\n\"CSF-1R-mac2\"<\/a>\u00a0CSF-1R is a receptor tyrosine kinase that activates<\/a> many signaling pathways responsible for growth<\/a>.<\/p>\n

\"CSF1Rsignaling\"<\/a><\/p>\n

Colony stimulating factor 1 (CSF-1) also recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity<\/a>, including M2 macrophages and myeloid-derived suppressor cells (MDSC). Tumor-associated macrophages (TAMs) interact with myeloid-derived suppressor cells (MDSCs) and T cells in the tumor microenvironment, the end result of which is to promote a Th2-type polarized environment with high levels of CD4+ T cells, and low levels of CD8+ cytotoxic T cells<\/a>, which promotes tumor growth.<\/p>\n

\"MDSC<\/a>

Certain breast cancers produce CSF-1, CCL2, STAT3 and STAT6, which promote macrophage infiltration and M2 differentiation. High Th2 CD4+ T cells with low CD8+ T cells results in a protumoral environment with increased metastatic risk. Interactions between M2 macrophages and MDSCs lead to high levels of IL-10 and low levels of IL-12, further reinforcing the M2 phenotype and increasing levels of Th2-type CD4+ T cells. These CD4+ T cells produce IL-4, which also polarizes macrophages toward M2, creating a feedback loop. Meanwhile, CD8+ T cells are suppressed, resulting in an overall immune-permissive environment for tumor growth and spread. CSF: Colony-stimulating factor; MDSC: Myeloid-derived suppressor cell.<\/p><\/div>\n

In cancer, aberrant expression of CSF-1 and CSF-1R has been found in cancers of the breast, ovaries and endometrium, correlating with disease progression and malignancy. CSF-1 is a biomarker for postmenopausal breast cancer risk. A role for CSF-1-dependent macrophages in breast cancer is well supported: 1) strong correlation between poor prognosis and TAMs (tumor associated macrophages); 2) CSF-1 is important for the angiogenic switch and progression to malignancy through recruitment and activation of tumor-associated macrophages, which secrete matrix metalloproteinases and VEGF, and induce cancer cells to produce IL-8.<\/p>\n

\"Dialog\"<\/a><\/p>\n

Plexxikon is developing PLX3397 for the treatment of breast cancer<\/a>, pigmented villonodular synovitis or giant cell tumor of the tendon sheath<\/a>, prostate cancer<\/a>, acral (palms and soles) and mucosal melanoma<\/a>, neurofibroma<\/a>, glioblastoma<\/a>, and acute myeloid leukemia<\/a>.<\/p>\n

Merck entered into a collaboration with Plexxikon<\/a> to combine PLX3397 with its PD-1 (immune checkpoint injibitor) antibody, Keytruda (pembrolizumab). The rationale for combining CSF-1 and Keytruda include:<\/p>\n

    \n
  1. Multiple mechanisms of action: CSF-1 inhibition blocks invasion and metastases of cancer cells, while Keytruda prevents the abrogation of the immune attack on cancer cells;<\/li>\n
  2. Complementary actions in heterotypic cellular interactions in the cancer micro-environment: CSF-1 inhibits the function of MDSCs, a subset of heterogeneous bone marrow-derived hematopoietic cells that are found in the peripheral blood of cancer patients and positively correlate to malignancy. Solid tumors contain MDSCs that maintain an immune-suppressive network<\/a> in the tumor microenvironment. So, Keytruda and CSF-1 may act in a complementary fashion in restoring cancer immunity.<\/li>\n<\/ol>\n

     <\/p>\n

     <\/p>\n

     <\/p>\n

     <\/p>\n

     <\/p>\n

     <\/p>\n","protected":false},"excerpt":{"rendered":"

    Colony Stimulating Factor (CSF-1) is an essential growth factor for cells of the monocyte-macrophage lineage, including osteoclasts.<\/p>\n","protected":false},"author":2252,"featured_media":394,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[28,18,22,1],"tags":[892,893,457,664,894],"class_list":["post-1867","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-checkpoint-inhibitors","category-heterotypic-cellular-interactions","category-oncogenes","category-uncategorized","tag-csf-1","tag-keytruda","tag-mdsc","tag-myeloid-derived-suppressor-cells","tag-plx3397"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/1867","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=1867"}],"version-history":[{"count":4,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/1867\/revisions"}],"predecessor-version":[{"id":4966,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/1867\/revisions\/4966"}],"wp:featuredmedia":[{"embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media\/394"}],"wp:attachment":[{"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=1867"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=1867"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=1867"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}