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Scaffold-kinase interaction blockade for treatment of RAS/MAPK-Pathway driven cancers


Stanford Reference:

10-397


Abstract


Researchers in Prof. Paul Khavari’s laboratory have discovered a novel compound and method to block invasive neoplasia without effects on normal cells. This technology targets a small domain (WW domain) of a scaffolding protein (IQGAP1) that binds proteins in the Ras/MAP kinase-signaling pathway. The Ras-Raf-Mek-Erk MAPK pathway is implicated in >40% of all human cancers, but targeting components of the pathway have not yielded valid therapeutics due to the risk of side effects on normal cells and mechanisms of acquired resistance. Targeting scaffold proteins rather than the canonical kinases provides a unique approach to develop therapies to treat a range of solid tumors without affecting homeostasis of normal tissues as well as to circumvent acquired tumor resistance to kinase inhibitors.

Applications


  • Cancer therapeutic — to prevent and/or diminish tumor formation, proliferation, and/or metastasis in >40% of all human cancers characterized as Ras-Raf-Mek-Erk MAPK pathway overexpressing.

Advantages


  • Tumor-selective — this domain is NOT required for normal human tissue homeostasis, therefore it could affect tumorigenesis without side effects on normal cells.
  • Non-toxic — we have not observe any morbidity in WW-treated mice nor did we find anysignificant hematological or chemical abnormalities.

Publications



Stage of Research


General A 30 amino acid peptide (WW) corresponding to a conserved scaffold domain disrupted neoplastic action of the Ras/MAPK pathway and significantly impairs proliferation of cancer cells in both in vitro and in vivo models as well as inhibits neoplastic invasion in a human tissue model of skin cancer.

Pancreatic Cancer Genetically engineered mouse models expressing p48CRE, KRasG12D, p53fl/fl mutant mice rapidly develop advanced pancreatic lesions at 35 days of age characterized by both significant tumor burden and palpable tumor mass. Animals treated with gemcitabine, a chemotherapeutic agent commonly used in pancreatic ductal adenocarcinoma patients, had an average lifespan of 58 days. Data for systemic WW peptide treatment in mouse models of pancreatic cancer are available under confidentiality.

PLX-4032 Resistant Melanoma Skin Cancer The newly available kinase inhibitor Vemurafenib (PLX-4032) targets mutant BRAFV600EMAP3K in melanoma, however, its long-term effectiveness has been hindered by acquired resistance via bypass mechanisms that restore Erk1/2 activation. Three PLX-4032sensitive BRAFV600E–expressing parental human melanoma cancer cell lines (COLO-829, SK-Mel-28, and A375) were rendered resistant to PLX-4032. PLX-4032 resistance of these resulting subclones was confirmed by assays of PLX-4032-mediated growth inhibition as compared to vehicle control (DMSO) and was accompaniedby genetic alterations previously associated with the emergence of PLX-4032 resistance including inIGF1-R, PDGFR-β, NRAS, and COT. Data for WW peptide treatment in models of PLX-4032 resistant melanoma skin cancer are available under confidentiality.

Related Web Links



Innovators & Portfolio


  • Katherine Jameson   
  • Paul Khavari   

Patent Status



Date Released

 6/27/2014
 

Licensing Contact


Chu Chang, Licensing Associate
650-723-0652 (Direct)
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Related Keywords


therapeutic: anticancer   anti-tumor   cancer drug therapy   KRAS   melanoma   metastasis   p38 MAP kinase   peptides   ras signalling   solid tumors   squamous cell carcinoma   therapeutic peptide   therapeutic: peptides   tumor targeting   top pharma companies   kinase inhibitors   pancreatic cancer   peptide therapeutics   protein kinase inhibitors   
 

   

  

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S10-397 Scaffold-kinase interaction blockade for treatment of RAS/MAPK-Pathway driven cancers