GIST Support Wiki29 Mar 2007
Subject: AXL Kinase, recently identified as a means to Gleevec resistant GIST
AXL Kinase was recently identified as a means to Gleevec resistant GIST at least in laboratory conditions and in two Gleevec resistant pateints--The resistant GIST cells LOST their KIT expression and switched to AXL. AXL is not blocked by Gleevec, but it is inhibited by MP470, a new drug in preclinical development.
During development, AXL is expressed in various organs, including the brain, suggesting that this RTK is involved in mesenchymal and neural development.
THe article below has some interesting background about AXL in its introduction. It has full access at the link. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1458653#B10
The Axl receptor is a RTK originally identified as a transforming gene in chronic myeloid leukemia. Axl is characterized by a unique molecular structure, in that the intracellular region has the typical structure of a RTK, and the extracellular domain contains fibronectin III and Ig motifs similar to cadherin-type adhesion molecules. During development, Axl is expressed in various organs, including the brain, suggesting that this RTK is involved in mesenchymal and neural development. In the adult, Axl expression is low but returns to high expression levels in a variety of tumors. Gas6 is, so far, the single, activating ligand for Axl. Moreover, additional ligand-independent mechanisms may exist by which Axl functions, such as signaling through homophilic interactions. Rather than conferring a mitogenic signal, Axl has been suggested to be involved in cell survival, cellular adhesion, and chemotaxis as well as blood vessel function. Because its expression correlates with the metastaticpotential of neoplasms, Axl may also play a role during invasion. Thus, Axl behaves as an oncoprotein when it is overexpressed, but its mechanisms of action have not been understood so far.
In fact, inhibition of AXL signaling to some extent negatively interfered with tumor cell proliferation, cell-cell interactions, and cell migration and invasion, suggesting multiple roles for AXL in tumorigenesis. Nevertheless, the most relevant observation that we made was that inhibition of Axl signaling almost completely suppresses the cell's ability to migrate into and invade healthy host tissue........ These observations clearly suggest that the role of AXL in gliomagenesis may, in part, depend on the host mircoenvironment.
That Gas6/Axl interactions may be involved in directed cell migration has been suggested for vascular smooth muscle cells in the context of remodeling of the vessel wall after vascular injury and for endothelial cells during tumor angiogenesis. By using an in vitro chemotaxis assay, the ectopic expression of Axl in vascular smooth muscle cells has been shown to increase the Gas6-induced migratory response, a phenomenon that depends on an intact, signaling-competent Axl tyrosine kinase. Investigations of the downstream signaling pathways have demonstrated a role for phosphatidylinositol 3-kinase and phospholipase C in Gas6-induced migration of vascular smooth muscle cells.
18 Jun 2007
Subject: MP470
MP470 will enter its first clinical trial soon. One site is rumored to be Arizona, where the research paper (scroll down below for abstract) came from...
SuperGen Receives FDA Clearance to Initiate Phase I Clinical Trial With MP470 First-in-Human Study Triggers Stock Milestone Payment DUBLIN, Calif., April 25 /PRNewswire/ -- SuperGen Inc. (Nasdaq: SUPG) today announced that the Food and Drug Administration cleared MP470, a novel oral multi-targeted tyrosine kinase inhibitor (TKI), for a first-in-human Phase I clinical trial.
The Phase I accelerated titration dose-escalation trial will assess the safety and tolerability of MP470 and determine the maximum tolerated dose (MTD). Pharmacokinetic and biomarkers data will also be collected and assessed to assist in designing follow-on clinical studies for the use of MP470 as a single agent and in combination treatment modalities. Up to 30 patients with advanced stage solid tumor cancers will be enrolled.
"Today signifies our complete transition to a discovery and development company." said Dr. James S. Manuso, SuperGen's Chairman, President and Chief Executive Officer. "Strategically, we remain focused on becoming a key player in the hematology and oncology markets. Not only will we enter the clinic with MP470 this quarter, we anticipate advancing MP529, our selective Aurora-A kinase inhibitor, into clinical trials later this year."
The Phase I study protocol is undergoing final approval by Institutional Review Boards at two study centers in the U.S. The first patient is expected to be treated later this quarter. The receipt of FDA clearance for the MP470 first-in-human use triggers a milestone payment to the previous Montigen shareholders of $10 million dollars to be paid in SuperGen common stock.
About MP470 MP470 is an oral selective multi-targeted TKI that inhibits MET, RET and the mutant forms of KIT, PDGFR and FLT3 as well as suppresses the Rad51 protein, a critical component of double-stranded DNA repair in cancer cells. The compound was developed using a fragment-based approach with the aid of company's CLIMB(TM) technology.
About SuperGen Based in Dublin, Calif., SuperGen is a pharmaceutical company dedicated to the discovery, rapid development and commercialization of therapies for solid tumors and hematological malignancies. SuperGen is developing a number of therapeutic anticancer products focused on kinase inhibitors and DNA methyltransferase inhibitors. For more information about SuperGen, please visit http://www.supergen.com.
Oncogene. 2007 Jun 7;26(27):3909-19. Epub 2007 Feb 26
A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.
Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, Nagle R, Bearss D. 1Arizona Cancer Center, Tucson, AZ, USA.
KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.Oncogene (2007) 26, 3909-3919. doi:10.1038/sj.onc.1210173; published online 8 January 2007
PMID: 17325667
5 Jul 2007
Subject: Trial sites for MP470 are announced, San Antonio and Arizona
The Translational Genomics Research Institute (TGen) and TGen Clinical Research Services (TCRS) at Scottsdale Healthcare in Scottsdale, Arizona, have dosed the first patient in a Phase I clinical trial of MP470, a novel, oral, multi-targeted tyrosine kinase inhibitor (TKI). The study is also open to accrual at South Texas Accelerated Research Therapeutics (START) in San Antonio, Texas. The trial is expected to enroll up to 30 patients at the two study centers.
http://ir.supergen.com/phoenix.zhtml?c=105560&p=irol-newsArticle&ID=1022920&highlight
SuperGen Reports Dosing of First Patient in Phase I Trial of NovelTyrosine Kinase Inhibitor
DUBLIN, Calif., July 5 /PRNewswire-FirstCall/ -- SuperGen, Inc. (Nasdaq:SUPG) today announced that collaborators at The Translational GenomicsResearch Institute (TGen) and TGen Clinical Research Services (TCRS) at Scottsdale Healthcare in Scottsdale, Arizona, have dosed the first patient in a Phase I clinical trial of MP470, a novel, oral, multi-targeted tyrosine kinase inhibitor (TKI). The study is also open to accrual at South Texas Accelerated Research Therapeutics (START) in San Antonio, Texas. The trial is expected to enroll up to 30 patients at the two study centers.
The Phase I trial is an accelerated titration dose-escalation study designed to assess the safety and tolerability of MP470, and to determine the maximum tolerated dose of the compound in patients with advanced-stage solid tumors. Additionally, the Company will assess pharmacokinetic and biomarker data from the study to assist in designing follow-on clinical studies for the use of MP470 as a single agent and in combination treatment modalities.
About MP470
MP470 is an oral, selective multi-targeted tyrosine kinase inhibitor that suppresses c-MET, c-RET and the mutant forms of c-KIT, PDGFR and FLT3. MP470 also suppresses Rad51 protein, a critical component of double-stranded DNA repair in cancer cells. Preclinical testing of MP470 has identified anti-tumor activity against a wide spectrum of cancers.
Frances's family member
11 Jul 2007
Hi all, I do not post, although occasionally I do ask questions. My family member is starting the MP470 this month in Scottsdale. All I ask for is your prayers and insight as things go along. He was on Gleevic, Student and also in another clinical study that Herb (CNF 2024) was on here in Scottsdale, Herb and his wife wrote a blog on that experience. My heart goes out to their family.
I pray this will work new treatment will work. The GIST in our family started in the throat, which is unusual, now it has completely taken over the left lung area. I continue to pray for all.