SRC Inhibitors are SupeRCharged

The development of imatinib (Gleevec) heralded and confirmed that the era of mechanism-based, molecu- larly-targeted therapeutics had arrived. However, as pointed out this weekend in multiple different sessions, disease relapse after therapy with imatinib is now more and more commonly being encountered, often associated with mutations in the ABL tyrosine kinase that interfere with the ability of imatinib to block kinase activity.

Arriving at center stage today as the first plenary session presenter, Dr. Charles Sawyers will introduce us to BMS-354825. This is a novel, orally available, dual SRC/ABL kinase inhibitor. It has no relationship at all to imatinib, but in the end, BMS-354825 might just show up its predecessor on stage. It has 100-fold greater potency than imatinib and has activity in 14/15 imatinib-resistant BCR-ABL mutants (Shah et. al, Science 305:399, 2004). Dr. Sawyers will present data from a phase I dose escalation study conducted at UCLA and M.D. Anderson Cancer Centers. The bottom line is that BMS-354825 has significant efficacy and is safe in imatinib-resistant chronic phase CML patients. It is a potent inhibitor of SRC family kinases, BCR-ABL, c-KIT, EPHA2 receptor, and the PDGF beta receptor. As we speak, a multitude of phase II trials are about to spring to life in CML imatinib-resistant chronic phase, accelerated phase, and myeloid and lymphoid blast crisis, as well as in BCR- ABL positive ALL. So time will tell as to whether or not the “new kid on the block,” BMS-354825, can show up the “still fairly-new kid” Gleevec.

And for the myeloid enthusiasts, today’s plenary session is just an appetizer. There are many other sessions dealing with targeting of malignant myeloid cells. Take, for instance, the ASH-ASCO Joint Symposium from 9:45 – 11:30 a.m. this morning. Chaired by the respective society Presidents, Drs. Schrier and Johnson, this session will also feature Dr. Sawyers speaking about c-Kit, PDGF, and abl as targets for therapeutic agents. Other speakers include Dr. Scott Hiebert, updating us on the role of the ETO family of transcriptional co-repres- sors in acute leukemia as well as in solid tumors, and Dr. Dan Tenen will discuss the potential of C/EBP alpha as a bull's-eye to aim for. Then, when this year’s simultaneous sessions kick off at 4:30 p.m. today, there are a slew of sessions from which to choose. The CML-Clinical Trials with Tyrosine Kinase Inhibitors Session will give updates from the IRIS trial for imatinib as well as other imatinib trial updates, will give more info about BMS354825 and a report on initial studies with AMN107 (a second dual SRC/ABL kinase inhibitor), and will finally give some results about combination therapy regimens such as imatinib and cytarabine.

The session on Mechanisms of Leukemogenesis will examine molecules which are disrupted and playing pathogenetic roles in AML. Finally, the Prognosis and Treatment of AML Session will discuss the use of HSP90 inhibitors to induce apoptosis in leukemia cells as well as other promising new therapeutics. All in all, by the end of the day, attendees should be able to say that they are definitely at the cutting-edge of therapy for myeloid malignancies.