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Promising Research Results Using Kinase Inhibitors Continue To Roll In

Home/Promising Research Results Using Kinase Inhibitors Continue To Roll In

Promising Research Results Using Kinase Inhibitors Continue To Roll In

Here is a research abstract, published in Blood, testing the viability of one of the new kinase inhibitors:

Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor

Bao Hoang1, Patrick Frost1, Yijiang Shi1, Eileen Belanger1, Angelica Benavides1, Gholam Pezeshkpour2, Susanna Cappia3, Tommasina Guglielmelli3, Joseph Gera1 and Alan Lichtenstein1,* 1 Division of Hematology Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, Los Angeles, California, United States; 2 Department of Pathology, Greater Los Angeles VA Healthcare Center and USC School of Medicine, United States; 3 University of Turin and San Luigi Hospital, Orbassano, Turin, Italy
* Corresponding author; email: alan.lichtenstein@med.va.gov
Abstract
Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mTOR kinase primarily curtailing activity of the TORC1 complex. To assess if mTOR within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates, p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on S473. Potential mechanisms of upregulated TORC2 activity in MM were stimulation with IL-6 or IGF-1, and PTEN or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM. PP242 was also more effective than rapamycin in achieving cytoreduction

Analyzing this data is way above my pay grade!   My take on these studies:  Myeloma is a sensitive, almost “wimpy” cancer.   It responds to many different types of treatment.  Trouble is, it never goes away.  Think about it:  Dex alone can have a profound, short term affect in many myeloma patients.  The trick will be finding combinations which have a lasting impact.

Feel good and keep smiling!  Pat