Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside

Bruno, Benedetto; Giaccone, Luisa; Rotta, Marcello; Anderson, Kenneth C.; Boccadoro, Mario

doi:10.1038/sj.leu.2403905

Cited by 50 publications

(34 citation statements)

References 52 publications

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“…The proliferation and survival of MM cells have been shown to be related to the activation of several signaling pathways such as PI3K/AKT, JAK/STAT3, MAPK/ERK and NFκB (32)(33)(34), which can be stimulated by several cytokines including IL-6 and IGF-1 (35). In MM, IGFs and IGF-1R signaling was correlated with stimulation of proliferation, survival and drug-resistance (36,37).…”

Section: Discussionmentioning

confidence: 99%

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

et al. 2014

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Abstract.Recently, much progress has been achieved in the treatment of multiple myeloma (MM). However, the major challenge of chemotherapeutic drugs is acquired resistance. Oncolytic virotherapies offer promising alternatives; with the possibility of their integration with current therapeutic strategies. In the present study, we assessed the potential of ZD55-TRAIL (an oncolytic adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand) as an oncolytic agent for MM. Our results clearly indicated that ZD55 armed with TRAIL was more cytotoxic to drug-sensitive as well as drug-resistant MM cell lines, than the virus alone. Furthermore, it was also observed that ZD55-TRAIL induced apoptosis through the activation of the caspase pathway. In particular, ZD55-TRAIL significantly inhibited insulin-like growth factor-1 receptor (IGF-1R) and NFκB. However, IGF did not abrogate ZD55-TRAIL-induced cell death. Combination of ZD55-TRAIL with the PI3K inhibitor LY294002 in RPMI-8226 cells inhibited the virus-mediated activation of mTOR and AKT, thus, promoting cell death. Combined treatment of ZD55-TRAIL and MG132 (a proteasome inhibitor) robustly increased the expression of death receptor 5 (DR5), which enhanced the apoptosis response without significant toxicity to normal liver cells. Collectively, our results suggest that combined treatment of TRAIL-armed oncolytic adenovirus and a PI3K inhibitor or a proteosome inhibitor may serve as a promising therapy for MM.

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Section: Discussionmentioning

confidence: 99%

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

et al. 2014

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“…Recent advances in myeloma therapy have shown the benefit of targeting both the myeloma cell and its microenvironment (25,26). Bone marrow angiogenesis is a major microenvironmental factor that is felt to be important for myeloma cell growth and survival (27).…”

Section: Discussionmentioning

confidence: 99%

Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma

Rajkumar

Richardson

Lacy

et al. 2007

Clinical Cancer Research

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Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties.We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.

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“…Hence, it acts directly on MM plasma cells and inhibits the autocrine VEGF/ VEGFR-1-induced plasma cell growth and migration and the paracrine (IL-6 mediated) growth . PTK/ZK (1.25 mg/day) is currently being evaluated in clinical phase I trials (Bruno et al, 2005). Indazolypyrimidine GW654652 inhibits all three VEGF receptors with similar potency and the VEGF-triggered migration activity and proliferation of MM cell lines, including those sensitive and resistant to conventional therapy .…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

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Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside

Cited by 50 publications

References 52 publications

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

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