Cardiovascular complications of novel kinase inhibitors

ESC CardioMed ◽  
2018 ◽  
pp. 1170-1176
Author(s):  
Mark Sweeney ◽  
Alexander Lyon
Keyword(s):  
High Risk ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blood Pressure Measurement ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Cancer Therapies ◽  
Serine Kinase ◽  
Include Blood Pressure ◽  
New Cancer Therapies

Tyrosine and serine kinase inhibitors are new cancer therapies which have revolutionized the field of modern oncology and have transformed previously fatal conditions such as chronic myeloid leukaemia into treatable chronic diseases. The cardiovascular complications related to kinase inhibitor treatments have emerged and the importance of effective cardiovascular management is becoming clear. Precise cardiovascular toxicity profiles vary among different classes of kinase inhibitors and between different specific agents. The most important cardiovascular complications of these kinase inhibitors include hypertension, heart failure, arterial thromboembolic disease, QT prolongation, and pulmonary hypertension. The aim of effective cardiovascular management in this setting should be to minimize the impact of toxicities to facilitate the continuation of these highly effective cancer treatments. It is key to perform a thorough baseline cardiovascular risk assessment prior to commencing treatment so that reversible risk factors are identified and addressed appropriately. Preliminary assessment should, at a minimum, include blood pressure measurement, serum creatinine, lipid profile and fasting glucose, and a resting electrocardiogram. Additionally, in selected high-risk patients or those starting high-risk kinase inhibitors, baseline assessment of left ventricular function can also be helpful. Effective risk stratification will allow appropriate, individualized surveillance to be arranged for each patient in order to identify complications early and manage them effectively. When significant cardiovascular complications occur, decisions regarding the need to suspend or discontinue potentially life-prolonging treatments are exceptionally challenging and the input of the multidisciplinary team in this setting and communication between the cardiologists and the oncologists or haemato-oncologists is invaluable.

scholarly journals ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1197
Author(s):  
Julia Pohl ◽  
Raluca-Ileana Mincu ◽  
Simone M. Mrotzek ◽  
Reza Wakili ◽  
Amir A. Mahabadi ◽  
...  
Keyword(s):  
High Risk ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Cancer Therapies ◽  
University Hospitals ◽  
Anti Cancer ◽  
Risk Patients ◽  
Qrs Duration ◽  
Ecg Score

Objective: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. Methods: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). Results: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77–0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. Conclusion: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Mario Tiribelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
Maria Cristina Miggiano ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Chronic Phase ◽  
Front Line ◽  
Line Therapy ◽  
Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged &lt;45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p&lt;0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC &gt;100,000/mm3 vs 38.2% if WBC &lt;100,000/mm3; p&lt;0.001), lower Hb (53.8% if Hb &lt;10 g/dl vs 41.9 if Hb &gt;10 g/dl; p=0.001) and bigger spleen (65.1% if spleen &gt;5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p&lt;0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for &gt;5 drugs, respectively (p&lt;0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p&lt;0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age &gt; 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

scholarly journals Correlations between Mutations in Cancer-Related Genes, Therapy Responses and Outcomes of the 3 rd Generation Tyrosine Kinase-Inhibitor (TKI) in Persons with Chronic Myeloid Leukemia Failing Prior TKI-Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 308-308
Author(s):  
Xiaoshuai Zhang ◽  
Zongru Li ◽  
Yazhen Qin ◽  
Robert Peter Gale ◽  
Xiaojun Huang ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Functional Enrichment ◽  
Molecular Response

Abstract Background Most, but not everyone with chronic myeloid leukaemia (CML) responds to imatinib or 2 nd-generation tyrosine kinase-inhibitors (TKIs). Mutations in cancer-related genes and in other than ABL1 may explain variable responses and outcomes to the 3 rd-generation TKIs including ponatinib and olverembatinib. Aim Interrogate correlations between mutations in cancer-related genes and therapy responses and outcomes to 3 rd-generation TKIs. Methods We used deep targeted sequencing for cancer-related mutations and Sanger sequencing for BCR::ABL1 on DNA samples from 167 subjects with CML failing to the prior imatinib and/or 2 nd-generation TKI-therapy and just before receiving a 3 rd-generation TKI. Gene ontology (GO) analysis was used to evaluate functional enrichment in GO terms among mutated genes. Optimal cut-offs for variant allele frequencies (VAFs) of the common mutations were determined by analyzing receiver-operator characteristic (ROC) curves. A Cox multi-variable regression model was used to identify correlations between mutations in cancer-related genes and therapy responses and outcomes of 3 rd-generation TKI-therapy. Results 167 subjects in chronic phase (n = 125) and accelerated phase (n = 42) received ponatinib (n = 28) or olverembatinib (n = 139) therapy. 27 subjects were exposed to imatinib; 79, a 2 nd-generation TKI; 61, imatinib and a 2 nd generation TKI. 142 (85%) subjects had ABL1 mutations including ABL1T315I (n = 116) or others (n = 26). 163 subjects had other cancer-related mutations which were evaluated in epigenetic regulators (n = 150), transcription factors (n = 84), cell signaling (n = 42), tumor suppressors (n = 39), protein kinases (n = 27), chromatin modification (n = 9) and DNA damage repair (n = 3) related-genes according to functional enrichment. The top 10 mutations were ASXL1 (n = 115), RUNX1 (n = 12), KMT2D (n = 12), PHF6 (n = 8), KMT2C (n = 8), IKZF1 (n = 8), STAT5A (n = 8), DNMT3A (n = 7), TET2 (n = 6) and BCOR (n = 6). 20 subjects had high-risk additional chromosomal abnormalities (ACAs). Frequency of BCR::ABL1 mutations was inversely- (p &lt; 0.001) and of cancer-related mutations directly-related (p = 0.009) to increasing exposure to prior TKI therapies. These relationships were especially so for mutations in KMT2C (p = 0.06), DNMT3A (p = 0.09), KDM6A (p = 0.06) and TNFAIP3 (p = 0.08). BCR::ABL1 (82% vs. 95%, p = 0.03), RUNX1 (5% vs. 14%, p = 0.04), KMT2C (3% vs. 10%, p = 0.08) and IKZF1 (3% vs. 10%, p = 0.10) were more common in accelerated phase. With a median follow-up of 34 months (interquartile range [IQR], 12-40 months), 95 and 71 subjects achieved a complete cytogenetic response (CCyR) and major molecular response (MMR). 18 subjects transformed to accelerated (n = 8) or blast (n = 10) phases, 16 died of disease progression (n = 12) or other causes (n = 4). 3-year cumulative incidences of CCyR and MMRwere 65% (95% Confidence Interval [CI], 58, 71%) and 52% (43, 61%). 3-year probabilities of progression-free survival (PFS) and survival were 88% (81, 92%) and 91% (85, 95%). Mutations in tumor suppressor genes were more common in subjects not achieving a CCyR (27% vs. 19%, p = 0.01). In multi-variable analyses ASXL1 mutation with a VAF ≥ 17% and a PHF6 mutation were significantly associated with lower cumulative incidences of CCyR (p &lt; 0.001 and p = 0.032) and MMR (p &lt; 0.001 and p = 0.04). Moreover, subjects with BCR-ABL1T315I mutation had significantly higher cumulative incidences of CCyR (p = 0.07) and MMR (p = 0.04) than those with no BCR-ABL1 mutation and other BCR-ABL1 non-T315I mutation. Increasing age, more Ph 1-chromosome-positive cells, the best prior therapy-response &lt; partial cytogenetic response (PCyR) and more TKI-therapies were associated with poor responses. STAT5A mutation was significantly associated with worse PFS (p = 0.002) and survival (p &lt; 0.001), RUNX1 mutation (p = 0.006), high-risk ACAs (p = 0.07) and accelerated phase (p = 0.002) with worse PFS and increasing age (p = 0.05) and comorbidity(ies) (p = 0.05) with wosre survival. Conclusions ASXL1 mutations with a VAF ≥ 17% and PHF6 mutations were associated with poor responses of the 3 rd-generation TKI-therapy. STAT5A and RUNX1 mutations and high-risk ACAs were also associated with worse outcomes in persons receiving a 3 rd-generation TKI. These data should help physicians select people to receive 3 rd-generation TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Janus kinase inhibitors: jackpot or potluck?

2012 ◽  
pp. e13
Author(s):  
Pavithran Keechilat ◽  
Shripad Brahmanand Pande
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Current Evidence ◽  
Federal Drug Administration ◽  
Janus Kinase Inhibitors

The reports of a unique mutation in the Janus kinase-2 gene (JAK2) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

scholarly journals Endocrine complications of new anticancer therapies

2021 ◽  
Vol 75 ◽  
pp. 191-198
Author(s):  
Michał Miner ◽  
Michał Elbaum ◽  
Aleksandra Jawiarczyk-Przybyłowska ◽  
Eliza Kubicka
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Myelogenous Leukemia ◽  
Cytotoxic T Cell ◽  
Cancer Therapies ◽  
Programmed Death ◽  
New Cancer Therapies ◽  
Endocrine Complications

Studying and analyzing of complex molecular mechanisms and immunological processes of cancer enables oncology to introduce new cancer therapies. In the treatment of cancer, we successively increase the use of targeted therapies with tyrosine kinase inhibitors and mTOR inhibitors and immunotherapy using checkpoint inhibitors CTLA-4 (cytotoxic T-cell antigen-4) and PD-1/PD-L1 (programmed death receptor 1/programmed death ligand 1). New anticancer drugs gradually replace conventional chemotherapy and have already found application in the treatment of many cancers, including thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, kidney cancer, bladder cancer, melanoma, breast cancer, acute and chronic myelogenous leukemia. The use of these drugs is less toxic than classical chemotherapy, but it can cause gastrointestinal, cardiovascular, respiratory, skin and endocrine complications. Most of the side effects of new cancer therapies are mild and moderate disorders, however some might be severe and life-threatening. Endocrinopathies are one of the more common side effects of these treatments. They can affect many endocrine glands (pituitary, thyroid, parathyroid, adrenal, pancreas) and cause both transient and permanent disorders.

scholarly journals CARDIOVASCULAR COMPLICATIONS OF ANTICANCER THERAPY: CLINICAL FEATURES, DIAGNOSIS, TREATMENT, PREVENTION (PART II)

2018 ◽  
Vol 23 (1) ◽  
pp. 43-49
Author(s):  
N. T Vatutin ◽  
E. V Sklyannaya ◽  
Mariam A. El-Khatib ◽  
G. G Taradin
Keyword(s):  
Clinical Features ◽  
Kinase Inhibitors ◽  
Alkylating Agents ◽  
Cardiovascular Complications ◽  
Chemotherapeutic Agents ◽  
Left Ventricular ◽  
Protein Kinase Inhibitors ◽  
Anthracycline Antibiotics ◽  
Treatment And Prevention ◽  
The Given

The given review is devoted to the problem of the cardiotoxicity of chemotherapeutic agents. Many of chemotherapeutic agents can cause cardiovascular complications such as left ventricular dysfunction and heart failure development, myocardial ischemia, arterial hypertension, thromboembolism, QT prolongation and arrhythmias. The toxic influence of the most often used chemotherapeutic agents on heart (such as antimetabolites, alkylating agents, platinum compounds, taxanes, vinca alkaloids, monoclonal antibodies, anthracycline antibiotics, topoisomerase and protein kinase inhibitors, immunomodulatory agents and cytokines) has been described. The results of recent studies on etiology, pathogenesis and clinical features of chemotherapy-induced cardiotoxicity were present in the first part of review. The clinical features, diagnosis, treatment and prevention of the cardiotoxicity of chemotherapeutic agents, are described in the second part of the review

scholarly journals Janus kinase inhibitors: jackpot or potluck?

2012 ◽  
Vol 6 (1) ◽  
pp. 13
Author(s):  
Pavithran Keechilat ◽  
Shripad Brahmanand Pande
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Current Evidence ◽  
Federal Drug Administration ◽  
Janus Kinase Inhibitors

The reports of a unique mutation in the Janus kinase-2 gene (<em>JAK2</em>) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

scholarly journals Time course of changes in maternal left ventricular function during subsequent pregnancy in women with a history of gestational hypertensive disorders

2018 ◽  
Vol 315 (4) ◽  
pp. R587-R594 ◽  
Author(s):  
Michinari Hieda ◽  
Jeung-Ki Yoo ◽  
Dan-dan Sun ◽  
Yoshiyuki Okada ◽  
Rosemary S. Parker ◽  
...  
Keyword(s):  
High Risk ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Time Course ◽  
Risk Group ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Subsequent Pregnancy ◽  
High Risk Group ◽  
History Of

Women with a history of gestational hypertensive disorders (GHD) are at increased risk for developing perinatal cardiovascular complications (e.g., gestational hypertension, preeclampsia, etc.) in subsequent pregnancies. The underlying mechanisms remain uncertain, but impaired maternal left ventricular function may be one contributing factor for these complications. We evaluated the time course of changes in left ventricular function before, during, and after pregnancy in women with prior GHD. Sixteen women with a history of GHD (the high-risk group) and 25 women without such a history (controls) were enrolled. Resting hemodynamic and echocardiographic measurements were longitudinally performed before pregnancy, during early pregnancy (4–8 wk of gestation), during late pregnancy (32–36 wk of gestation), and postpartum (6–10 wk after delivery). Pregnancy outcomes were obtained after delivery. At prepregnancy, there was no difference in blood pressure and heart rate between the groups. Corrected isovolumic relaxation time was longer, E/ eʹ was larger, and Tei index was greater in the high-risk group than controls. Moreover, the rate of GHD during the study was significantly greater in the high-risk group than controls [odds ratio = 8.94 (95% confidence interval: 1.55–51.5), P = 0.007]. Multiple logistic regression analysis adjusted for age demonstrated that prepregnancy E/ eʹ was an independent predictor for GHD ( P = 0.017). Thus, women with a history of GHD have modestly impaired cardiac function prepregnancy compared with controls, which identifies an increased susceptibility to developing cardiovascular complications during a subsequent pregnancy.

scholarly journals Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jean M Mulcahy Levy ◽  
Shadi Zahedi ◽  
Andrea M Griesinger ◽  
Andrew Morin ◽  
Kurtis D Davies ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Braf Inhibitor ◽  
Pediatric Brain Tumors ◽  
Resistance Mechanisms ◽  
Cancer Therapies ◽  
Clinical Responses ◽  
Inhibitor Resistance ◽  
Autophagy Inhibition

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.

scholarly journals Multi-aspect approach to the optimization of pharmacotherapy of patients with arterial hypertension of high and very high risk

2018 ◽  
Vol 4 (4) ◽  
pp. 53-64
Author(s):  
Svetlana Gridina
Keyword(s):  
High Risk ◽  
Arterial Hypertension ◽  
Fixed Combination ◽  
Antihypertensive Drugs ◽  
Treatment Options ◽  
Hypotensive Effect ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Hypotensive Action ◽  
Very High

Introduction: Personalization of pharmacotherapy of cardiovascular diseases is one of the urgent problems of cardiology. Material and methods: The study includes 120 patients with grades 2-3 arterial hypertension with the criteria of high and very high risk of developing cardiovascular complications. The patients were randomized into three groups with differentstarting regimens of pharmacotherapy – fixed and free combinations of ACE inhibitors and dihydropyridine CCB. Evaluation of the efficacy, safety and individualization of a therapy was carried out by using pharmacokinetic, pharmacoeconomic, sonographic, and laboratory methods. Results and discussion: Antihypertensive treatment with the inclusion of Amlodipine and Lisinopril or Ramipril in patients with arterial hypertension, having a slow and very slow oxidative metabolism phenotype, is characterized by the development of a more pronounced hypotensive effect in this group of patients (p&lt;0.05-0.001) (Δ% SBP from 12.7 to 24.6 and from 19.6 to 27.9, respectively; Δ% DBP from 10.6 to 19.1 and from 15.9 to 23.6, respectively) in comparison to the group of patients with a fast phenotype (Δ% SBP from 6.42 to 9.34; Δ% DBP from 1.04 to 5.66), which allows administering a personalized pharmacotherapy. For patients with arterial hypertension of high and very high risk, the use of a fixed combination of Amlodipine and Lisinopril as a basic variant of the two-four-component therapy compared with treatment options based on free combinations of the studied drugs provided a significantly more pronounced decrease in systolic blood pressure (24.9%, 17.8 %, 19.0%, respectively, p&lt;0.01), a greater degree of regression of left ventricular myocardial hypertrophy (8.70%, 5.67%, 5.84%, respectively, p&lt;0.05), significant (p&lt;0.05-0.001) improvement in a number of parameters of the patients’ quality of life, and was characterized by the greatest economic efficiency according to various criteria of hypotensive action. Conclusion: The results obtained in the study demonstrate the advantages of a fixed combination over free combinations of antihypertensive drugs and demonstrate the possibility of a pharmacokinetic approach to individualization of pharmacotherapy.

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