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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
A variety of targeted agents against RET pathways has been studied in other malignancies. These include vandetanib, cabozantinib, sunitinib, sorafenib, fostamatinib and ponatinib with good response, especially in RET mutated tumors [73]. However, studies with RET inhibitors in NSCLC are lacking. Vandetanib has been shown to have some in vitro activity against cancer cells with RET rearrangements [74]. Gautschi et al. described a case of lung adenocarcinoma, positive for RET-KIF5B, where vandetanib was used at disease progression following chemotherapy, surgery and radiation, with the development of disease remission after four weeks of vandetanib treatment [78]. A prospective phase II trial studying the role of cabozantinib, a multi-tyrosine kinase inhibitor and a potent inhibitor of RET, in NSCLC patients with RET rearrangements also showed partial responses in two out of three cases and prolonged stable disease after eight months in the third case, with no progression of the disease reported in any of the three [77]. There are ongoing phase II trials to evaluate the efficacy of lenvatinib, vandetanib, and sunitinib in NSCLC with RET rearrangements [79].
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Following the success of ibrutinib and venetoclax inhibitors in high- and ultra-high-risk patients, particularly those with mutated TP53 clones, research is assessing not only the earlier use of these agents in an effort to prevent the emergence of chemorefractory disease but also their use in combination regimens; venetoclax is being tested in patients receiving bendamustine initially, followed by a combination of obinutuzumab and venetoclax. The interim results of this study are impressive, with an overall response rate of 97%, and 89% MRD negative. Studies are also assessing venetoclax-based combinations with other anti-CD20 antibodies and with/without ibrutinib. There is also renewed interest in navitoclax, another BCL2 inhibitor, which is more active against BCL-xL, as opposed to venetoclax, which is more potent against BCL2. Other candidate investigational approaches include acalabrutinib, a second-generation BTK inhibitor, alisertib (MLN8237), an aurora A kinase inhibitor, and several forms of immunotherapy. Acalabrutinib appears to have a better BTK occupancy compared with ibrutinib, and it will be of interest to determine whether this reduces the emergence of resistance. SYK inhibitors, such as fostamatinib and entospletinib, remain in clinical trials at present, with impressive results so far. The immunotherapy efforts include several monoclonal antibodies, such as lumiliximab (anti-CD23), epratuzumab (anti-CD22), and apolizumab (anti-HLA-DR), IDEC-114 (anti-CD80), immune-modulatory drugs, such as lenalidomide, and adoptive immunotherapy using CD19-specific CAR T-cells in patients who progress on ibrutinib. There has also been much interest in the use of immune checkpoint inhibitors, but the results of these Phase I/II studies have not been encouraging so far.
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Bendamustine, a synthetic chemotherapeutic drug with structural similarities to alkylating agents and purine analogues, was tested against chlorambucil and found to improve response rates but not overall survival. Bendamustine was also associated with greater toxicity. Alemtuzumab, a recombinant, fully humanized monoclonal antibody against the CD52 antigen, has also been in the clinic for over 15 years and accords about 43% response rates when used as a monotherapy in previously treated patients, including those with established poor-risk features, such as del(11q) and del(17p) and TP53 mutations. It was also tested against chlorambucil in treatment-naïve patients, and found to be superior, in terms of higher response rates and CRs. Patients with ‘ultra-high-risk features’ should be considered for treatment with inhibitors of BCR signalling, of which three main classes of drugs, which comprise of BTK inhibitors, PI3K inhibitors and SYK inhibitors. Amongst the BTK inhibitors, ibrutinib is licensed in the United States for both first-line and subsequent therapy, and in Europe for relapsed disease; PI3K inhibitors include idelalisib, which is licensed in the United States and Europe for the treatment of relapsed disease; SYK inhibitors, such as fostamatinib and entospletinib, remain in clinical trials at present. Experience with ibrutinib and idelalisib confirm the drugs’ short- and long-term efficacy and safety. Side effects associated with ibrutinib tend to be mild, and include diarrhoea, arthralgia, cough and rash; idelalisib is associated with diarrhoea, colitis, nausea, fatigue, hypertension, pneumonitis and abnormal liver transaminases. Other observations, however, suggest that both drugs can induce genomic instability and in murine models can result in potential tumour-promoting mutations. Such serious potential longer term side effects have led to efforts to consider discontinuation, or at least de-escalation of therapy once agreeable remissions have been achieved.
Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases
Published in Expert Opinion on Investigational Drugs, 2022
Su’an Tang, Qinghong Yu, Changhai Ding
Fostamatinib was approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the treatment of ITP in April 2018 [36,37]. This approval was based on two identical, multicenter clinical trials (ClinicalTrials.gov Identifier: NCT02076399 and NCT02076412) that enrolled 150 patients with persistent or chronic ITP. Stable platelet response (the primary endpoint, platelets at least 5000/µL at least 4 of 6 visits between weeks 14 to 24) occurred in 18% of participants on fostamatinib compared with 2% on placebo [38]. Fostamatinib offers new option for ITP patients who failed in the treatment of corticosteroids, splenectomy, immunoglobulins or thrombopoietic agents. A recent study evaluating the risk of thromboembolism during long-term fostamatinib treatment reported thromboembolic events in only 1 of 146 patients treated with fostamatinib for up to 5 years. In addition, no new toxicity was observed during the 5-year follow-up [39]. Moreover, fostamatinib could efficaciously inhibit BCR signaling in vivo, thereby reducing the proliferation and survival rate of malignant B cells, and significantly prolonging the survival of Eμ-TCL1 mice with the chronic lymphocytic leukemia (CLL) model of leukemia [40]. These results indicate that fostamatinib may be a drug for the treatment of CLL and is worthy of further research in clinical trials.
Immune thrombocytopenia
Published in Expert Review of Hematology, 2021
James Bussel, Nichola Cooper, Ralph Boccia, Francesco Zaja, Adrian Newland
Fostamatinib is an inhibitor of spleen tyrosine kinase (Syk), which is involved in the Fc receptor (FcR) and B-cell antigen receptor (BCR) signaling pathways. In macrophages, Syk inhibition impairs the phagocytosis of autoantibody-coated platelets which bind to cell surface FcRs. Among ITP therapeutic agents, fostamatinib has a novel mechanism of action: inhibiting platelet phagocytosis by macrophages, and possibly reducing B cell activation [68–70] (Figure 3). Fostamatinib is an oral medication that can be taken with or without food. The FIT program included two phase 3, randomized trials (FIT-1, FIT-2) and a long-term extension study that included patients with persistent and chronic ITP. Responses (platelet count ≥50 × 109/L) were achieved by 54% of patients treated with fostamatinib (n = 146), with 43% of patients responding within 12 weeks and a median time to response of 15 days [70–72]. Responses were maintained for up to 52 months, and the median duration of response was >28 months with a median platelet count of 89 ×109/L.
Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs
Published in Expert Review of Anti-infective Therapy, 2020
Liliana Rodrigues, Pedro Cravo, Miguel Viveiros
Fostamatinib is indicated for the treatment of rheumatoid arthritis, chronic thrombocytopenia and autoimmune diseases and acts as an inhibitor of the tyrosine kinase. Fostamatinib is a pro-drug, requiring hydrolysis by the intestine’s alkaline phosphatase that generates R406, which is the active metabolite [122]. Neither fostamatinib nor R406 were found to be carcinogenic or mutagenic. Serious adverse effects include hypertension, neutropenia, diarrhea, and hepatotoxicity in the recommended human dose [123–125]. In 2018, Kanehiro et al. described R406 as an inhibitor of the mycobacterial serine/threonine-protein kinase PknG. The same study demonstrated that R406 showed bactericidal activity against M. bovis BCG in infected human macrophages without cytotoxicity [126]. Fostamatinib was revealed by our in silico method to have several potential targets in M. tuberculosis: transmembrane serine/threonine-protein kinase B (Rv0014c); transmembrane serine/threonine-protein kinase A PknA (Rv0015c); probable transmembrane serine/threonine-protein kinase E PknE (Rv1743) and anchored-membrane serine/threonine-protein kinase PknF (Rv1746). Interestingly, Rv0014c and Rv0015c are essential genes.