Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In 2003 it was approved by the FDA under the accelerated approval scheme for use in patients with progressive myeloma following previous treatment and was also approved in Europe in 2004. The data review for the FDA accelerated approval took just four months and was based on two Phase II studies of 256 patients, all of whom had been pretreated with other agents. Across these two trials, objective responses were observed in 23–35% of the patients and complete responses in 7 patients, with a median duration of response of 365 days. Thus, the trials demonstrated that bortezomib was more effective at delaying disease progression than a standard treatment of high-dose dexamethasone. Although certain serious side effects were worse for patients taking bortezomib, more patients taking the drug were alive after one year than those on the standard treatment. Bortezomib is now approved for multiple myeloma in combination with other agents, and also for the treatment of mantle-cell lymphoma.
Pain in cancer survivors
Nigel Sykes, Michael I Bennett, Chun-Su Yuan in Clinical Pain Management, 2008
Bortezomib is a proteasome inhibitor used for the treatment of several malignancies and is licensed for relapsed multiple myeloma. Bortezomib causes axonopathy.34 In a randomized trial (APEX), 36 percent of patients developed bortezomib-induced CIPN and 8 percent discontinued treatment because of CIPN.35 Evidence of preexisting peripheral neuropathy was present in 69 percent at baseline and was a risk factor for severe neuropathy.34, 35, 36 Fifty-one percent with grade 2 CIPN or above improved with a median time of 107 days.35 Another controlled trial identified cumulative, dose-related sensory neuropathy as the most important adverse event.37 Here, 12 percent required dose reduction and cessation of treatment in 4 percent, although the majority experienced some improvement of CIPN symptoms.37 The timeline of clinical progression or resolution is still unclear, but 71 percent of the patients that developed CIPN improved after 1 to 529 days.36
Proteasome and Protease Inhibitors
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
The most frequently described and well-known proteasome inhibitor is bortezomib (Velcade®, PS-341), a dipeptide boronic acid analog with a broad antitumor activity in several cell lines and murine and human tumor models (19,36,42,46,47). It is the first proteasome inhibitor that has been approved by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMEA) for use in MM. Bortezomib specifically inhibits the proteasome pathway rapidly and in a reversible manner by binding directly to the β-5 subunit of the 20S complex, thereby blocking its enzymatic activity (48). Exposure to bortezomib in vitro leads to stabilization of several intracellular protein levels such as cyclin-dependent kinase inhibitors (e.g., p21) and proapoptotic Bik/NBK (49,50). Cells accumulate in the G2-M phase of the cell cycle and subsequently undergo apoptosis.
Advances in autoimmune myasthenia gravis management
Published in Expert Review of Neurotherapeutics, 2018
Shuhui Wang, Iva Breskovska, Shreya Gandhy, Anna Rostedt Punga, Jeffery T. Guptill, Henry J. Kaminski
Elimination of plasma cells responsible for synthesis of autoantibodies would be expected to be a highly effective therapy [203]. The first therapy to become available is bortezomib [204]. Bortezomib is a proteasome inhibitor used for treatment of mantle cell lymphoma and multiple myeloma, which causes accumulation of nondegraded, misfolded proteins within plasma cells leading to apoptosis. Bortezomib treatment of EAMG animals reduces disease severity and in vitro studies of MG patient thymus cultures treated with bortezomib demonstrated plasma cell depletion [205]. In EAMG studies, reduced AChR antibody production, reduced postsynaptic muscle membrane damage, and clinical improvement have been observed [206]. Clinical trials of bortezomib to treat MG are currently underway and other proteasome inhibitors are under development for multiple myeloma and could be considered as a treatment for MG. Unfortunately, upwards of 35% of bortezomib treated patients with cancer develop a painful neuropathy [207]. This level and severity of toxicity would not be suitable for patients with MG who are otherwise relatively healthy and have many other treatment options. Next-generation proteasome inhibitors are under development with the expectation that they will have fewer adverse effects [208]. Given the prime role of plasma cells in autoantibody production, a therapeutic that selectively targets autoreactive plasma cells and overcomes the current limitations of existing therapies should be a focus for therapeutic development in MG.
Caplacizumab: a change in the paradigm of thrombotic thrombocytopenic purpura treatment
Published in Expert Opinion on Biological Therapy, 2019
Maëlle le Besnerais, Agnès Veyradier, Ygal Benhamou, Paul Coppo
New drugs stemming from a better understanding of TTP pathophysiology should complete the therapeutic. N-acetylcysteine (NAC) inhibits platelet adherence to endothelial cell-anchored soluble ULvWF by reducing their size [30]. Preclinical animal models suggest a pre-emptive role of NAC since prophylactic administration prevents severe TTP signs. Nonetheless, in mice and baboons, NAC is not effective in resolving preexisting TTP signs in contrast to caplacizumab [30]. Bortezomib is a proteasome inhibitor inhibiting autoantibody generation by inducing apoptosis in both B-cells and plasma cells [31]. Evidence for the use of bortezomib is still limited to case reports and a case series of iTTP that were refractory to TPE, steroids, and rituximab. In seven published papers, 12 patients with relapsed/refractory acquired TTP received bortezomib, of which 11 survived the acute episode and maintained remission [32].
Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5
Published in OncoImmunology, 2019
Mattias Carlsten, Ali Namazi, Robert Reger, Emily Levy, Maria Berg, Cynthia St. Hilaire, Richard W. Childs
Bortezomib is a reversible proteasome inhibitor that upon binding to the 26S subunit of the proteasome causes cellular growth arrest, inhibition of migration and apoptosis.4 Proteasome inhibition also induces endoplasmatic reticulum (ER)-stress due to accumulation of misfolded and unfolded proteins in the ER.5 Cells respond to ER-stress by activating the unfolded protein response (UPR) which reduces unfolded protein burden via production of a set of pro-survival enzymes and chaperons that facilitate proper protein folding in the ER.6 In addition to promoting cell survival via proper protein folding, UPR signaling also drives cells into autophagy,7 a state where cells become quiescent while recycling damaged organelles and proteins before returning to a normal cellular state.8 Cells that cannot resolve ER-stress undergo cell death via apoptosis.6
Related Knowledge Centers
- Hypotension
- Mantle Cell Lymphoma
- Posterior Reversible Encephalopathy Syndrome
- Proteasome Inhibitor
- Tumor Lysis Syndrome
- Multiple Myeloma
- Chemotherapy
- Thrombocytopenia
- Leukopenia
- Heart Failure