1. Neurofibromatosis type 1

2. Biallelic NF1 inactivation leads to multiple symptoms

3. NF1 mutant mice have severe edema, fail to achieve neural tube closure and are inviable past 13.5 days

4. Treatment Surgical/laser removal Doxirubicin-Dna Intercalation Carboplatin chemotherapy

5. NF1 is a tumor suppressor gene that functions as a Ras Gap

6. Excessive Ras signaling leads to de-differentiation and proliferation

7. Bi-allelic inactivation of NF1 plus heterozygosity in neighboring tissues are required to initiate/accelerate tumor formation

8. The RTK Ras pathway is NOT the whole story! The first clue came from the correlation between expression of trans-membrane glycoprotein CD44 with metastasis as well as poor patient prognosis

9. Elevated CD44 expression and invasion are Ras-independent but dependent on Src

10. EGFR induces CD44 expression by a SRC-dependent mechanism

11. CD44 Promoter was found to have an EGF Responsive element CD44 Gene

12. Egfr  Src  CD44  metastasis Rtk Ras pathway  metastasis and proliferation

13. In vitro studies of these pathways will likely lead to preclinical and then clinical trials for patients 1.EGFR-SRC-CD44 Pathway Erlotinib-EGFR inhibitor 2. RTK-RAS Pathway Farnesyl transferase inhibitors combined with Lovastatin

14. Sources Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA. Tumor predisposition in mice heterozygous for a targeted mutation in NF1. Nat Genet. 1994;7,:353–361. [PubMed]PubMed Zhu Y, Ghosh P, Charnay P, et al. Neurofibromas in NF1: Schwann cell.. origin and role of tumor environment. Science 2002; 296:920–922. Su W, Sin M, Darrow A, et al. Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberrant CD44 expression. Glia 2003; 42:350–358. Li H, Velasco-Migual S, Vass WC, et al. Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. Cancer Res 2002; 62:4507–4513. McLaughlin ME, Jacks T: Thinking beyond the tumor cell: Nf1 haploinsufficiency in the tumor environment. Cancer Cell 1:408–410 (2002). Arun D, Gutmann DH. Recent advances in neurofibromatosis type Current Opinion in Neurology. 2004;17(2):101–105. [PubMed]PubMed Harrisingh MC, et al. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J. 2004;23(15):3061–3071. [PMC free article] [PubMed]PMC free articlePubMed Scheffzek K, Ahmadian MR, Wiesmuller L, Kabsch W, Stege P, Schmitz F, Wittinghofer A (1998) Structural analysis of the GAP ‐ related domain from neurofibromin and its implications. EMBO J 17: 4313–4327 [PMC free article] [PubMed]PMC free articlePubMed Hsieh, David T., MD. Medscape. N.p., n.d. Web. http://emedicine.medscape.com/article/1177266-treatment

15. Additional Image Sources http://learn.genetics.utah.edu/content/disorders/singlegene/nf1/ http://www.atdbio.com/content/16/Nucleic-acid-drug-interactions https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1 087933&p_IsPs=N https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1 087933&p_IsPs=N http://www.nature.com/onc/journal/v26/n32/images/1210261f3.jpg http://atlasgeneticsoncology.org/Genes/CD44ID980CH11p13.html http://www.discoverymedicine.com/Toni-M-Brand/2011/11/22/the-nuclear-epidermal-growth-factor- receptor-signaling-network-and-its-role-in-cancer/ http://www.biomed-search.com/search?q=cortactin&s=342&r=9 http://en.wikipedia.org/wiki/Erlotinib http://ar.iiarjournals.org/content/32/3/831/F1.expansion.html http://www.drugsdb.com/rx/lovastatin/lovastatin-side-effects/