Written by Paula Vettel
In vitro activity of novel KIT/ PDGFRA switch pocket kinase inhibitors against mutations associated with drug-resistant GI stromal tumors.
A new type of kinase inhibitor from Deciphera Pharmaceuticals has been developed. Dr. Heinrich reported on preclinical testing of inhibitors that bind more fully and tightly to the KIT/PDGFRA ATP binding pocket and block enzymatic activity. He explained that the binding site resembles a swinging gate. If the gate is open, imatinib can come in and bind to KIT and control GIST. If the gate is closed, the kinase inhibitors cannot bind properly to KIT resulting in tumor growth. Certain secondary mutations can lock the gate making the KIT resistant to kinase inhibitors. Inhibitors were sought that would keep the gate from swinging around and make the binding pocket always available.
Deciphera Pharmaceuticals are developing Switch Pocket Kinase Inhibitors (SPKI) that have long residency times on the kinase, are resilient to ATP interference, show thermal stabilization of the target kinase, and bind to both the active and inactive forms of the kinase, resulting in conformational control (of the gate). Dr. Mike Heinrich, of Oregon Health & Science University, reported testing of three compounds that showed very potent activity as SPKI in the lab, particularly against GIST drug-resistant mutations. Toxicity screening and pharmacological profiles are very encouraging. Research is continuing to optimize the candidate structure. Phase I clinical trials have not yet begun, but Heinrich hopes to have the optimal candidate identified by the end of 2010.
Nilotinib for patients with advanced GIST who failed imatinib and sunitinib: Negative effect of prior major gastrectomy on exposure to nilotinib.
Nilotinib is being tested in patients who have progressed on imatinib and sunitinib. Drug-food interaction studies on the bioavailability of nilotinib show the importance of the stomach in nilotinib absorption. The authors conclude that nilotinib was active and safe in patients with advanced GIST resistant to both imatinib and sunitinib. Prior gastrectomy seemed to decrease the bioavailability of nilotinib significantly, at least in some patients. Monitoring of plasma drug concentration may be particularly important for proper nilotinib therapy in GIST patients with major gastrectomy. This may also be very important for patients taking sunitinib. A scientist from Novartis commented to us that imatinib is much more easily dissolved and absorbed in the stomach than other kinase inhibitors. This information is important for all GIST patients who have had large amounts of stomach removed.
Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib (IM)
Dr. Sebastian Bauer, of the West German Cancer Center, University of Essen in Germany, conducted a study to follow the overall survival of GIST patients who had metastasectomy to reduce tumor loads. He found a possible longterm benefit from R0/R1 metastasectomy (clear margins) in patients with metastatic GIST. In contrast, incomplete resection, including debulking surgery, appears not to be beneficial to overall survival. Debulking surgery can be beneficial for symptom relief. The location of the metastases is an important factor.
Activity of GDC-0941, an inhibitor of phosphoinositol 3 kinase (PI3K), in gastro intestinal stromal tumor (GIST) xenograft and duration of response after discontinuation of treatment in combination with imatinib.
Dr. Maria Debiec-Rychter, of the Catholic University of Leuven in Belgium, has studied the combination of imatinib and GDC-0941, a P13K inhibitor in mice bearing KIT exon 11 mutation. She found that the combination of GDC-0941 and imatinib has extensive antitumor efficacy in GIST mice, inducing more substantial cell death and durable effects than imatinib alone. This effect was sustained even after treatment withdrawal. These results highlight the success that various research teams are finding with combinations of KIT and mTOR inhibitors such as GDC-0941 and everolimus (RAD001).
Pharmacoepidemiology of clinically relevant hypothyroidism and hypertension from sunitinib and sorafenib
The authors studied hypothyroidism and hypertension in patients receiving at least 45 days of sunitinib or sorafenib by analyzing the Medco database of about 60 million individuals. They found significant side effects between months two and months seven of sunitinib treatment requiring blood pressure monitoring and thyroid replacement medication. Hypertension, but not hypothyroidism was found with patients on sorafenib. It would be worthwhile for patients on sunitinib to talk to their doctors about monitoring heart and thyroid condition. Hypothyroidism could be a contributing factor to fatigue on sunitinib.