Highlights from the American Association for Cancer Research meeting

Editor’s note: Jerry Call, LRG Science Coordinator, attended the 97th annual meeting of the American Association for Cancer Research (AACR) held March 31 – April 5th in Washington, D.C. This is his report on the sessions that he attended.

By Jerry Call

Abstract # 3008-From the lab of Dr. Jonathan Fletcher (Brigham and Women’s Hospital and Harvard Medical School), Meijun Zhu presented a poster on “KIT oncoprotein interactions in GISTs: Therapeutic relevance.” Zhu et al. used frozen GIST tumors and GIST cell lines to evaluate KIT signaling mechanisms. They found that PDGFRA existed in a complex with KIT and that the activated KIT protein also activated (through crossphosphorylation) the PDGFRA protein. They concluded that the response of GIST patients to Gleevec likely involves inhibition of both KIT and PDGFRA (Gleevec inhibits both of these proteins). The poster also noted the major contributions of PI3-K and PKCθ (protein kinase C theta), both downstream targets of KIT in GISTs. Inhibition of PI3-K (with LY294002) or PKCθ (by lentiviral shRNA infection) resulted in either inhibition of growth or cell death in four GIST cell lines. The poster concluded that PI3-K and PKCθ are compelling therapeutic targets that might further improve the GIST therapeutic response to KIT/PDGFRA inhibition.

Note: PI3-K has long been avoided as a drug target because it is commonly expressed in normal cells; thus toxicities are expected to be high. It is one the major proteins involved in tyrosine kinase receptor signaling. One method for targeting PI3-K inhibition to tumor cells (while avoiding inhibiting it in normal cells) is to make a “prodrug” PI3-K inhibitor. This is a drug that is somehow “activated” by the tumor environment (such as be a different pH level in the tumor).

PKCθ represents an attractive target because it is only rarely expressed in normal cells. A type of immune cell known as “T cells” signals through PKCθ.

Abstract #1328-Prenen et al reported on the cellular uptake of both imatinib (Glivec) and AMN107 in GIST tumor cells. Several studies have reported that P-glycoprotein (PGP) is a transporter of imatinib and that high expression of the MDR1 gene (the gene that makes Pglycoprotein) could confer resistance to imatinib.

The Belgium scientists reported that imatinib uptake into two GIST cell lines, GIST882 and GIST GDG1, was significantly reduced compared to AMN107. Levels of AMN107 were 3 times higher than imatinib in GIST882 cells and 10 times higher in GIST GDG1 cells. Their findings suggest that AMN107 might be less susceptible to resistance caused by multi-drug resistance proteins.

Editor’s note: In a separate paper, White et al. found that AMN107 was also less affected by the influx pump, OCT1. They concluded that OCT-1 influx may be a key determinant of response to imatinib (low expression of OCT-1 may confer resistance), but it is unlikely to affect patient responses to AMN107. The unanswered question is whether it would be more effective to give AMN107 as front-line therapy before resistance developed, or to give it to patients once they become resistant to imatinib.

Abstract #1158-Salto-Tellez et al. from the National University of Singapore, reported that VEGF-A protein is a main biomarker that is able to differentiate low-risk GISTs from high-risk GISTs (p=0.0003). The authors concluded that their study showed VEGF-A status is important in the biological understanding (of GISTs), as well as clinical characterization of GISTs, and may point to an alternative and/or complementary treatment strategy to GIST.

Editor’s note: VEGF-A is one of at least five different growth factors that are able to activate one or more of the three different VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3). VEGF-A is known to activate both VEGFR-1 and VEGFR-2. Many of the newer multi-targeted tyrosine kinase inhibitors, such as Sutent, AMG706, and BAY 43-9006, inhibit two or three of the known VEGF receptors. Thus, drugs that inhibit VEGFR-1 and VEGFR-2 would be expected to inhibit signaling caused by the VEGF-A growth factor. Avastin (Bevacizumab) is another drug that blocks the signaling of VEGFR1 and VEGFR2. Avastin is a monoclonal antibody that is given intravenously and has been shown to improve survival in colon cancer when given together with chemotherapy. A new trial is being planned for GIST patients that will test whether the combination of Gleevec and Avastin will be more effective than Gleevec alone. This trial is expected to start this summer.

Abstract #4038-Yamamoto et al. reported on a multi-targeted kinase inhibitor, E7080. E7080 is made by EISAI CO. LTD, Japan. It was tested in a mouse model that had human GIST tumor cells (GIST882). E7080 inhibits VEGFR-1, VEGFR-2, FGFR1, and PDGFRbeta. All of these targets have been implicated in angiogenesis (the growth of new blood vessels that feed tumors). In addition, it also inhibits KIT at slightly higher concentrations. E7080 was able to stabilize the GIST tumors in the mice at doses of 30 mg/kg. Doses of 100 mg/kg caused tumor shrinkage of about 40 percent in this mouse model.

Soluble KIT (s-KIT) was also evaluated as a potential biomarker in the mouse model. Normal mice (no GIST) did not have detectable levels of s-KIT. Mice with implanted GIST tumors did have detectable levels of s-KIT which was correlated with tumor weight. Treatment with E7080 clearly reduced levels of s-KIT. The author’s conclusions were that E7080 has therapeutic potential via inhibition of KIT in GISTs and s-KIT might be useful as a biomarker in GIST patients.

Editor’s note: Three phase I clinical trials for E7080 were listed in the clinicaltrials. gov database. These trials included solid tumors and were located in Amsterdam, Netherlands; Glasgow, United Kingdom; Dallas, Texas (USA) and Tokyo, Japan.

Abstract #1634-Jahn et al. reported that the KIT protein is recruited to lipid rafts at the cell membrane. Inhibition of lipid raft formation prevented KITmediated activation of AKT and blocked KIT mediated cellular proliferation, including KIT mutants that were resistant to Gleevec. They hypothesize that inhibition of receptor tyrosine kinase (RTK) recruitment to lipid rafts may be a useful strategy for control of tumors dependent on RTK activity.