Current cancer drug targets
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Multiple myeloma (MM) is a hematological cancer caused by a proliferation of clonal plasma cells, leading to anemia, renal failure, hypercalcemia and destructive bone lesions resulting in significant morbidity. The overall survival has significantly improved with the incorporation of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). ⋯ The clinical use of IMiDs in MM has significantly improved long-term survival and quality of life. Future studies are looking into novel biomarkers predictive of outcome in MM and new combinations of lenalidomide and pomalidomde with PI, monoclonal antibodies, immune checkpoint blockers and several other chemotherapies.
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One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal proliferation of malignant plasma cells mainly in the bone marrow (BM). ⋯ Therefore, it is vital to develop novel therapeutic agents that not only target the MM clone itself but also the MM immune microenvironment. However, the complexity of the BM microenvironment and heterogeneity of tumor cell clones make it a difficult task for developing appropriate immune therapies of MM. In this article, we review the current knowledge of the interaction between malignant plasma cells and the bone marrow immune microenvironment during disease progression.
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Curr Cancer Drug Targets · Jan 2017
ReviewTargeting the Immune Niche within the Bone Marrow Microenvironment: The Rise of Immunotherapy in Multiple Myeloma.
Multiple Myeloma (MM) cells inhibit the development of an effective anti- MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive proinflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease. ⋯ Given continuing efforts to target the immune niche within the bone marrow microenvironment we are confident that the rise of immunotherapies in MM will result in long-lasting responses in many of our patients within the next decade.
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High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients younger than 65 years of age with multiple myeloma (MM). However, this therapeutic approach has undergone substantial advances in this last decade, mainly due to the introduction of new drugs such as thalidomide, lenalidomide and bortezomib. ⋯ Preliminary data from studies investigating next generation proteasome inhibitors, such as carfilzomib and ixazomib, used upfront as well as at subsequent therapeutic lines, demonstrate the possibility of achieving molecular remission in most of the patients. The deeper responses obtained with new drugcombinations questioned the role of ASCT, and large, ongoing, phase 3 trials will shed light on the role and the timing of ASCT.
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Curr Cancer Drug Targets · Jan 2016
ReviewTherapeutic Approach to Patients with Chronic Lymphocytic Leukemia and Significant Comorbid Conditions.
Clinical trials in chronic lymphocytic leukemia (CLL) have focused mainly on younger fit patients until recently. However, CLL is a disease of elderly and many patients have significant comorbid conditions which together with advanced age preclude the use of aggressive regimens like FCR (fludarabine, cyclophosphamide, rituximab). Therefore, parameters such as performance status, renal function and number/severity of comorbidities together with clinical judgment should be used to guide the decision-making process regarding intensity of treatment. ⋯ Impressive efficacy of novel targeted small molecules interfering with B-cell receptor signaling, namely Bruton tyrosine kinase inhibitor ibrutinib and phosphatidylinositol-3 kinase delta inhibitor idelalisib, radically changed the treatment paradigms for relapsed/refractory CLL; relatively mild toxicity of these agents make them very good candidates for elderly/comorbid patients. Other options for relapsed/refractory disease include alemtuzumab, ofatumumab, high-dose glucocorticoids+rituximab and bendamustine+rituximab. This review summarizes the current knowledge on prognostication and therapy of elderly and comorbid patients with CLL.