Advances in the molecular understanding of multiple myeloma (MM) onset and disease development have enabled the production of effective drugs, such as bortezomib,thalidomide, and lenalidomide, that increase the length of progression-free survival and prolong overall survival.
While the drugs have dramatically improved the day-to-day quality of life of patients with MM, a cure for the malignancy remains elusive and research continues to get to advance the effectiveness of treatments.
A recent review article, “The Role of Intracellular Signaling Pathways in the Pathogenesis of Multiple Myeloma and Novel Therapeutic Approaches” published in the Journal of Clinical and Experimental Hematopathology, pooled the most promising new “next generation” drug candidate that are being considered for MM treatment.
From the beginning
Extremely complex communication between bone marrow cells and diseased plasma cells, called myeloma cells, causes the progression of MM. The complex communication is called cell signaling, which is coordinated by collections of proteins and signaling molecules that make up cell signaling pathways. In the pathways, proteins generate, transmit, and receive the signaling molecules, while the signals specify the physiological output that occurs.
To date, researchers have determined that irregular signaling of seven or more cell signaling pathways contributes to the progression of MM. Overlap and crosstalk between the signaling pathways is also common, further complicating drug targeting strategies.
IL-6 is one such signaling molecule that is important for inflammation and the immune response and is thought to be the most important contributor to MM disease progression. One mechanism by which IL-6 contributes to disease development is through activation of a signaling pathways that increase the proliferation of myeloma cells. Siltuximab, an inhibitor of IL-6, has been demonstrated to be effective in mouse models of MM; clinical trials are ongoing.
Another signaling pathway of critical importance to MM disease progression is the PI3K/AKT/mTOR pathway which is permanently activated in myeloma cells. Both myeloma cell proliferation and drug resistance are associated with activation of this particular pathway, making it an important target.
Drugs on trial
Currently, drugs that target each component (P13K, AKT, and mTOR) of this pathway are being studied in clinical trials.
Perifosine, which targets AKT, stimulates the death of myeloma cells and in Phase I/II clinical trials resulted in an overall efficacy rate of 41%. Phase III trials are currently ongoing. Several P13K inhibitors are being developed, with two candidates, GDC-0941 and BYL719, showing anti-tumor properties. Temsirolimus, which inhibits mTOR, resulted in a 38% response rate in Phase II trials.
Bortezomib is a current drug thought to inhibit the activation of yet another signaling component, NF-κB. In some patients, bortezomib is susceptible to resistance that develops over time. Marizomib is a drug with a similar function that overcomes this resistance, potentially making it a more lasting and efficient therapy for MM treatment.
Histone deacetylase (HDAC) is a protein that modulates DNA to affect the production and ability of many important cell signaling proteins. With this ability, HDAC activation is capable of stimulating myeloma cell proliferation. Panobinostat is a drug that inhibits HDAC and has been shown to significantly extend progression-free survival and reduce bone lesions that result from MM. Due to that, it has recently been approved for use in the U.S. and E.U. Vorinostate, which inhibits HDAC, has been shown to stimulate the destruction of myeloma cells and has exhibited incredible promising results in Phase I studies, boasting an efficacy of 52 percent.
Numerous other drugs that target several other pathways are being tested, including those that target the p38 MAPK, HSP90, WNT, Notch, and Hedgehog signaling pathways – although less is known about the overall impact of these pathways on MM disease progression at the molecular level.
Future for ‘next generation’ candidates
Overall, the future for many ‘next-generation drug candidates’ seems bright. In addition,given the complexity and overlap of signaling, combination therapies of more effective drugs will likely lead to increase effectiveness and promote MM treatment beyond what is currently seen today.
The study, co-authored by Masahiro Kizaki and Takayuki Tabayashi, concluded: “More novel agents will target affected signaling pathways to provide new treatment options for patients with MM, and are expected to further improve treatment outcomes.”
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