scholarly journals Targeted Therapy in Multiple Myeloma

2005 ◽  
Vol 12 (2) ◽  
pp. 91-104 ◽  
Author(s):  
Wee Joo Chng ◽  
Lee Gong Lau ◽  
Noorainun Yusof ◽  
Benjamin M. F. Mow
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Intracellular Signaling ◽  
Resistance Mechanism ◽  
Growth Factor Receptor ◽  
Therapeutic Agents ◽  
Farnesyltransferase Inhibitors ◽  
Antisense Gene ◽  
Novel Therapeutic

Background: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. Methods: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. Results: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. Conclusions: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.

Reduced Response of IRE1α/Xbp-1 Signaling Pathway to Bortezomib Contributes to Drug Resistance in Multiple Myeloma Cells

2016 ◽  
Vol 103 (3) ◽  
pp. 261-267 ◽  
Author(s):  
Xiaoxuan Xu ◽  
Junru Liu ◽  
Beihui Huang ◽  
Meilan Chen ◽  
Shiwen Yuan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Resistance Mechanism ◽  
Proteasome Inhibition ◽  
Myeloma Cells ◽  
Potential Marker ◽  
Rpmi 8226 ◽  
Basic Level

Purpose Proteasome inhibition with bortezomib eliminates multiple myeloma (MM) cells by partly disrupting unfolded protein response (UPR). However, the development of drug resistance limits its utility and resistance mechanism remains controversial. We aimed to investigate the role of IRE1α/Xbp-1 mediated branch of the UPR in bortezomib resistance. Methods The expression level of Xbp-1s was measured in 4 MM cell lines and correlated with sensitivity to bortezomib. LP1 and MY5 cells with different Xbp-1s level were treated with bortezomib; then pivotal UPR regulators were compared by immunoblotting. RPMI 8226 cells were transfected with plasmid pEX4-Xbp-1s and exposed to bortezomib; then apoptosis was determined by immunoblotting and flow cytometry. Bortezomib-resistant myeloma cells JJN3.BR were developed and the effect on UPR signaling pathway was determined. Results By analyzing 4 MM cell lines, we found little correlation between Xbp-1s basic level and bortezomib sensitivity. Bortezomib induced endoplasmic reticulum stress-initiated apoptosis via inhibiting IRE1α/Xbp-1 pathway regardless of Xbp-1s basic level. Exogenous Xbp-1s reduced cellular sensitivity to bortezomib, suggesting the change of Xbp-1s expression, not its basic level, is a potential marker of response to bortezomib in MM cells. Furthermore, sustained activation of IRE1α/Xbp-1 signaling pathway in JJN3.BR cells was identified. Conclusions Our data indicate that reduced response of IRE1α/Xbp-1 signaling pathway to bortezomib may contribute to drug resistance in myeloma cells.

Effect of complete response pre- and post- autologous stem cell transplantation in multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7604-7604
Author(s):  
F. Sayani ◽  
D. Stewart ◽  
L. Kmet ◽  
P. Faris ◽  
M. L. Savoie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Complete Response ◽  
Therapeutic Agents ◽  
Line Treatment ◽  
Front Line ◽  
Response Status ◽  
The Impact ◽  
Novel Therapeutic

7604 Background: The value of achieving a complete response (CR) pre or post high dose therapy and autologous stem cell transplant (HDT-ASCT) in multiple myeloma is still uncertain. Knowing the impact of achieving a CR prior to HDT-ASCT on survival, may lead to the incorporation of novel therapeutic agents into the front line treatment of this disease. The aim of our study was to determine whether achieving a CR before or after HDT-ASCT affects overall survival (OS) in multiple myeloma patients. Methods: We performed a retrospective analysis of 88 consecutive myeloma patients receiving HDT-ASCT at our center from 1993 to 2004. The OS of patients achieving at least 90% reduction in their M-protein, i.e. complete response and very good partial response (CR/VGPR), pre or post HDT-ASCT, was compared to that of patients achieving a partial response or less (<90% reduction in M-protein). OS, defined as the number of months from HDT-ASCT to death or last follow up, was estimated by the Kaplan-Meier method. Response status was evaluated pre and at 100 days post HDT-ASCT. Results: Prior to HDT-ASCT, twenty-two (25%) patients achieved a CR/VGPR. Median follow-up time was 39 months for patients in CR/VGPR and 18 months for non-CR/VGPR group. OS at 5 years was 58% (95% CI: 21%-82%) for patients in CR/VGPR, compared to 69% (95% CI: 51%-81%) for all patients in PR or less prior to stem cell collection. Post HDT-ASCT, 48 (55%) patients achieved a CR/VGPR. Their OS estimate at 5 years was 67% (95% CI: 44%-82%) compared to 71% (95% CI: 27%-92%) for all other patients. Overall, 30% more patients achieved CR/VGPR post HDT-ASCT. However, the survival curves did not differ by response status pre or post HDT-ASCT (log-rank test p=0.58 and 0.57 respectively). Conclusions: Our results suggest that achieving a clinical CR/VGPR pre or post HDT-ASCT does not appear to impact OS. These results might have been influenced by the small sample size and the possible need for a longer follow-up time. A more robust definition of CR at the molecular level, plus the use of novel therapeutic agents in front-line treatment, may better define the impact of achieving CR in multiple myeloma. No significant financial relationships to disclose.

P1 Receptor Agonists/Antagonists in Clinical Trials - Potential Drug Candidates of the Future

2019 ◽  
Vol 25 (26) ◽  
pp. 2792-2807 ◽  
Author(s):  
Pobitra Borah ◽  
Satyendra Deka ◽  
Raghu Prasad Mailavaram ◽  
Pran Kishore Deb
Keyword(s):  
Clinical Trials ◽  
Biological Activities ◽  
Therapeutic Agents ◽  
Current Status ◽  
Preclinical Studies ◽  
P1 Receptors ◽  
Drug Candidates ◽  
Wide Range ◽  
P1 Receptor ◽  
Novel Therapeutic

Background: Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus, its modulation is implicated in various disorders like Parkinson’s disease, asthma, cardiovascular disorders, cancer etc. Hence these receptors have become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions. Objective: The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective. Methods: In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects. Results: Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by the Food and Drug Administration. Conclusion: This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.

A new staging system to predict prognosis of patients with multiple myeloma in an era of novel therapeutic agents

2014 ◽  
Vol 94 (2) ◽  
pp. 145-151 ◽  
Author(s):  
Hirono Iriuchishima ◽  
Takayuki Saitoh ◽  
Hiroshi Handa ◽  
Atsushi Isoda ◽  
Morio Matsumoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Staging System ◽  
Therapeutic Agents ◽  
Novel Therapeutic

Influence of Targeted Therapy in Redefining High-Risk Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-7-sci-7
Author(s):  
Lori Hazlehurst ◽  
William S. Dalton ◽  
Danielle Yarde ◽  
Yulia Nefedova ◽  
Dmitry Gabrilovich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Residual Disease ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Acquired Drug Resistance

Abstract Multiple myeloma is a disease that typically responds to initial treatment; however, the disease is not cured by chemotherapy, and drug resistance ultimately develops. Most studies investigating the problem of drug resistance have focused on acquired resistance or resistance that occurs after response to prior therapy as a result of residual disease. Intrinsic factors, such as reduced drug uptake, enhanced damage response (i.e., DNA repair), altered drug metabolism, or inhibition of programmed cell death pathways are known to contribute to acquired drug resistance. For example, it was recently reported that the acquired melphalan resistant phenotype in myeloma cell lines was associated with over-expression of the Fanconi anemia (FA)/BRCA pathway genes. Enhanced interstrand cross-link (ICL) repair via the FA/BRCA pathway was causally related to melphalan resistance and disruption of this pathway using knock-down techniques reversed drug resistance. Furthermore, bortezomib (Velcade) has been reported to enhance melphalan treatment, and recent pre-clinical data has shown that bortezomib reduces FA/BRCA gene expression and function. Clinical trials are necessary to determine the role of the FA/ BRCA pathway in acquired drug resistance for myeloma patients and whether targeting this pathway enables prevention of or the ability to overcome acquired melphalan resistance in myeloma patients. Conversely, factors that promote tumor cell survival and drug resistance that are external to the tumor cell itself might exist. Evidence supporting the importance of understanding the influence of the tumor microenvironment on drug sensitivity has been reported by several investigators. The tumor microenvironment for hematologic malignancies, including myeloma, is principally the bone marrow. The bone marrow contains candidate components that contribute to reduced drug activity, minimal residual disease, and emergence of drug resistant cells. Cell adhesion molecules expressed by myeloma cells, including the β integrins, bind to fibronectin and other extracellular matrix components of the bone marrow, and this interaction contributes to a reversible, de novo drug resistance phenotype called “cell adhesion mediated drug resistance” or CAMDR. Adhesion via integrins is known to activate a network of signal transduction pathways that influence cell survival, growth, and differentiation. Several targets that are influenced by integrin adhesion and may contribute to CAM-DR include the following: reduced proapoptotic Bim levels, alterations in nuclear topoisomerase II levels, increased p27 kip1 levels, and changes in FLIP1 levels. In addition, myeloma cell adhesion to bone marrow stroma (BMS) involves other adhesion molecules and signaling events that promote CAMDR. For example, Notch1 receptors expressed on multiple myeloma cells when stimulated by Jagged causes growth arrest and protection from drug-induced apoptosis. Recently, approaches to inhibit integrin and Notch signaling associated with CAM-DR have been examined pre-clinically. Clinical trials are necessary to determine if these approaches will prevent or overcome CAM-DR in patients.

Drug Resistance in Multiple Myeloma: Novel Therapeutic Targets Within the Malignant Clone

1999 ◽  
Vol 32 (3-4) ◽  
pp. 199-210 ◽  
Author(s):  
Linda M. Pilarski ◽  
Michael J. Mant ◽  
Andrew R. Belch
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Therapeutic Targets ◽  
Novel Therapeutic
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