Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19.

ABSTRACT: Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton's tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.

SUBMITTER: Jacobs CF

PROVIDER: S-EPMC7871903 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies.

Project description:Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not.SignificancePatients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549.

| S-EPMC8580617 | biostudies-literature

Screening Strategies for COVID-19 in Patients With Hematologic Malignancies.

Project description:COVID-19 has been declared a pandemic by the world health organization. Patients with cancer, and particularly hematologic malignancies may be at higher risk for severe complications due to their malignancy, immune dysregulation, therapy, and associated comorbidities. The oncology community has been proactive in issuing practice guidelines to help optimize management, and limit infection risk and complications from SARS-COV-2. Although hematologic malignancies account for only 10% of all cancers, their management is particularly complex, especially in the time of COVID-19. Screening or early detection of COVID-19 are central for preventative/mitigation strategy, which is the best current strategy in our battle against COVID-19. Herein, we provide an overview of COVID-19 screening strategies and highlight the unique aspects of treating patients with hematologic malignancies.

| S-EPMC7348065 | biostudies-literature

Outcomes of patients with hematologic malignancies and COVID-19 from the Hematologic Cancer Registry of India.

Project description: Not available

| S-EPMC8728704 | biostudies-literature

Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation.

Project description:Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1β production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.

| S-EPMC6856986 | biostudies-literature

COVID-19 in Patients with Hematologic Malignancies: Outcomes and Options for Treatments.

Project description:Patients with hematologic malignancies are particularly vulnerable to infections due to underlying humoral and cellular immune dysfunction, cytotoxic chemotherapy regimens, advanced age, and the presence of comorbid conditions. Infection from severe acute respiratory syndrome coronavirus 2, the causative agent of the COVID-19 pandemic, has become a leading cause of death globally and has disproportionally affected this high-risk population. Here, we review the cumulative evidence demonstrating worse outcomes for patients with hematologic malignancies when compared to patients with solid tumors and the general population. We examine risk factors shared with the general population (age, sex, comorbid conditions, and race) and those that are cancer-specific (cytotoxic chemotherapy, progressive disease, and cancer type), all of which confer an increased risk of severe COVID-19. Despite the historical exclusion of cancer patients from COVID-19 therapy trials, we review the emerging evidence that patients with hematologic malignancies benefit from specific treatments such as convalescent plasma. Although COVID-19 vaccines are significantly less effective in this patient population, encouraging results are observed in a subset of these patients after receiving a booster dose.

| S-EPMC9059013 | biostudies-literature

COVID-19 in Patients With Hematologic Malignancies: A Single Center Retrospective Study.

Project description:Initial studies that described the novel coronavirus (COVID-19) reported increased morbidity and mortality in patients with cancer. Of this group, patients with hematologic malignancies (HM) had the highest disease severity and death rates. Subsequent studies have attempted to better describe how COVID-19 affects patients with HM. However, these studies have yielded variable and often contradictory results. We present our single-institution experience with patients with HM who were diagnosed with COVID-19 from March 2020 to March 2021. We report 62 total cases with 10 patients who died during this time. The overall mortality was 16.1%. Mortality during the first two waves of COVID was 27.8% and 25%. Mortality during the third wave of COVID was 10%. The median age of patients was 67 years (range 20-89 years). 55% of patients had lymphoid malignancies and the majority had active disease at the time of diagnosis with COVID-19. 87% of patients had more than one co-morbidity. Important co-morbidities included cardiovascular disease and smoking history. 38.7% of patients had asymptomatic or mild disease, 54.8% required hospitalization, and 17.5% required ICU level care. In patients who required ICU level care, the mortality was 60%.

| S-EPMC8581235 | biostudies-literature

COVID-19 in patients with hematological malignancies: Considering the role of tyrosine kinase inhibitors.

Project description: Not available

| S-EPMC8250378 | biostudies-literature

Cyclin-dependent kinase inhibitor therapy for hematologic malignancies.

Project description:IntroductionCyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anticancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction.Areas coveredA number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising.Expert opinionIn general, the antitumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad-spectrum CDK inhibition will likely be required for most cancers.

| S-EPMC4039040 | biostudies-literature

Immune checkpoint blockade for hematologic malignancies: a review.

Project description:Immune checkpoint blockade has revolutionized the treatment of cancer, with impressive responses seen in a broad variety of tumor types. Blockade of immune checkpoints and immune signaling antibodies has shown promise in multiple types of hematologic malignancies (HMs), with dramatic single agent responses for pembrolizumab and nivolumab in Hodgkin lymphoma (HL). In this review, we outline the current state of immune checkpoint blockade drug development in HMs, and discuss mechanisms of activity and resistance, and highlight potential targets in the immune tumor microenvironment (TME). Blockade of T-cell checkpoint molecules PD-1/PD-L1 and CTLA-4 are the most clinically mature of the immune checkpoint strategies. Novel and upcoming strategies for immune checkpoint blockade drug development in HMs using innovative combinations to modulate immunologic targets shows significant promise as a way to expand the number of patients with blood cancers who could benefit from immunotherapy.

| S-EPMC5420526 | biostudies-literature

Dasatinib for Immune Modulation After Donor Stem Cell Transplant for Hematologic Malignancies

Project description:This study uses a drug called dasatinib to produce an anti-cancer effect called large granular lymphocyte cellular expansion. Large granular lymphocytes are blood cells known as natural killer cells that remove cancer cells. Researchers think that dasatinib may cause large granular lymphocyte expansion to happen in patients who have received a blood stem cell transplant (SCT) between 3 to 15 months after the SCT. In this research study, researchers want to find how well dasatinib can be tolerated, the best dose to take of dasatinib and how to estimate how often large granular lymphocytic cellular expansion happens at the best dose of dasatinib.

| 2128801 | ecrin-mdr-crc

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data