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1.
Momelotinib: an emerging treatment for myelofibrosis patients with anemia.
Chifotides, HT, Bose, P, Verstovsek, S
Journal of hematology & oncology. 2022;(1):7
Abstract
The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib's unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib.
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2.
[Targeting the cyclin-dependent kinases 4/6 in advanced breast cancers].
Coussy, F, Deluche, E, Pistilli, B, Ladoire, S, Ferrero, JM, Cottu, P
Bulletin du cancer. 2021;(9):843-854
Abstract
The historical median survival of advanced luminal breast cancer does not exceed four years. The deciphering of the mechanisms of resistance to hormone therapy has led to the development of inhibitors of cyclin D dependent kinases (CDK4 and 6). Three drugs, palbociclib, ribociclib and abemaciclib, very similar pharmacologically, have been evaluated in the context of pivotal, randomized phase III trials. Strikingly and regardless of the endocrine therapy backbone, and in both hormone-sensitive and hormone-resistant patients, the addition of a CDK4 / 6 inhibitor doubles progression-free survival with a hazard ratio always around 0.55. The benefit in overall survival begins to be demonstrated. This review presents all published results, as well as the main safety data.
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3.
Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer-Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension.
Kaae, AC, Kreissl, MC, Krüger, M, Infanger, M, Grimm, D, Wehland, M
International journal of molecular sciences. 2021;(22)
Abstract
Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.
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4.
Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment.
Mroweh, M, Roth, G, Decaens, T, Marche, PN, Lerat, H, Macek Jílková, Z
International journal of molecular sciences. 2021;(4)
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.
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5.
ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents.
Khalifa, M, Few, LL, See Too, WC
BioMed research international. 2020;:1823485
Abstract
Novel antimicrobial agents are crucial to combat antibiotic resistance in pathogenic bacteria. Choline kinase (ChoK) in bacteria catalyzes the synthesis of phosphorylcholine, which is subsequently incorporated into the cell wall or outer membrane. In certain species of bacteria, phosphorylcholine is also used to synthesize membrane phosphatidylcholine. Numerous human ChoK inhibitors (ChoKIs) have been synthesized and tested for anticancer properties. Inhibition of S. pneumoniae ChoK by human ChoKIs showed a promising effect by distorting the cell wall and retarded the growth of this pathogen. Comparison of amino acid sequences at the catalytic sites of putative choline kinases from pathogenic bacteria and human enzymes revealed striking sequence conservation that supports the potential application of currently available ChoKIs for inhibiting bacterial enzymes. We also propose the combined use of ChoKIs and nanoparticles for targeted delivery to the pathogen while shielding the human host from any possible side effects of the inhibitors. More research should focus on the verification of putative bacterial ChoK activities and the characterization of ChoKIs with active enzymes. In conclusion, the presence of ChoK in a wide range of pathogenic bacteria and the distinct function of this enzyme has made it an attractive drug target. This review highlighted the possibility of "choking" bacterial ChoKs by using human ChoKIs.
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6.
Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges.
Rinninella, E, Cintoni, M, Raoul, P, Pozzo, C, Strippoli, A, Ponziani, FR, Pompili, M, Bria, E, Tortora, G, Gasbarrini, A, et al
Nutrients. 2020;(10)
Abstract
In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies-such as sorafenib, regorafenib, sunitinib, and lenvatinib-on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.
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7.
Myositis - A common but underreported adverse effect of osimertinib: Case series and review of the literature.
Parafianowicz, P, Krishan, R, Beutler, BD, Islam, RX, Singh, T
Cancer treatment and research communications. 2020;:100254
Abstract
BACKGROUND Lung cancer is the second most common cancer in both men and women and the leading cause of cancer death worldwide. The development of novel tyrosine kinase inhibitors (TKIs) represented a paradigm shift in the management of lung cancer and has resulted in markedly prolonged survival. Osimertinib is a TKI that was fast-tracked by the United States Food and Drug Administration in 2015 and subsequently approved for the treatment of metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. However, despite the generally favorable outcomes associated with osimertinib, rapid development and deployment of any new drug increases the risk of unforeseen adverse effects. Post-marketing surveillance studies therefore play an important role in further elucidating the risks and benefits of novel anti-neoplastic agents. MATERIAL AND METHODS We describe four patients with non-small cell lung cancer who developed myositis after beginning treatment with osimertinib. In addition, we review the literature on osimertinib-associated myositis. Using PubMed, the following terms were searched and relevant citations assessed: creatine phosphokinase, myositis, osimertinib, rhabdomyolysis, osimertinib, and Tagrisso. CASE PRESENTATION Thirty-eight patients were treated with osimertinib in our community clinic. Four with non-small cell lung cancer developed myositis after beginning treatment. The onset of symptoms and/or elevation of creatine phosphokinase occurred between two weeks and eleven months after osimertinib was initiated. Alternative causes for myositis were not identified. In two patients, myositis resolved within one month of withdrawing treatment. Two other patients continued osimertinib treatment with close monitoring. CONCLUSION Myositis is a serious and potentially underreported adverse effect of osimertinib. Previous studies suggest that osimertinib-associated myositis is rare, occurring in less than 1% of patients. However, myositis occurred in over 10% of patients treated with osimertinib in our clinic population. We suggest regular monitoring for myositis among patients being treated with osimertinib and dose-reduction or cessation of treatment if clinically indicated.
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8.
Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections.
Blázquez, AB, Saiz, JC
International journal of molecular sciences. 2020;(24)
Abstract
Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.
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9.
Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies.
Sharifi, MN, Anandan, A, Grogan, P, O'Regan, RM
Cancer. 2020;(15):3400-3416
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Abstract
Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.
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10.
FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives.
Mosquera Orgueira, A, Bao Pérez, L, Mosquera Torre, A, Peleteiro Raíndo, A, Cid López, M, Díaz Arias, JÁ, Ferreiro Ferro, R, Antelo Rodríguez, B, González Pérez, MS, Albors Ferreiro, M, et al
Minerva medica. 2020;(5):427-442
Abstract
Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.