Glucose transporters in cancer metabolism Adekola, Kehinde; Rosen, Steven T; Shanmugam, Mala
Current opinion in oncology,
2012-November, 2012-Nov, 2012-11-00, 20121101, Volume:
24, Issue:
6
Journal Article
Open access
PURPOSE OF REVIEWTransformed cells exhibit a high rate of glucose consumption beyond that necessary for ATP synthesis. Glucose aids in the generation of biomass and regulates cellular signaling ...critical for oncogenic progression. A key rate-limiting step in glucose utilization is the transport of glucose across the plasma membrane. This review will highlight key glucose transporters (GLUTs) and current therapies targeting this class of proteins.
RECENT FINDINGSGLUTs, enabling the facilitative entry of glucose into a cell, are increasingly found to be deregulated in cancer. Although cancer-specific expression patterns for GLUTs are being identified, comprehensive analyses substantiating a role for individual GLUTs are still required. Studies defining GLUTs as being rate-limiting in specific tumor contexts, the identification of GLUT1 inhibitors via synthetic lethality screens, novel engagement of the insulin-responsive GLUT4 in myeloma and identification of GLUT9 being a urate transporter, are key advances underscoring the need for continued investigation of this large and enigmatic class of proteins.
SUMMARYTumor cells exhibit elevated levels of glucose uptake, a phenomenon that has been capitalized upon for the prognostic and diagnostic imaging of a wide range of cancers using radio-labeled glucose analogs. We have, however, not yet been able to target glucose entry in a tumor cell-specific manner for therapy. GLUTs have been identified as rate-limiting in specific tumor contexts. The identification and targeting of tumor-specific GLUTs provide a promising approach to block glucose-regulated metabolism and signaling more comprehensively.
IMPORTANCE: The most common leukemia is chronic lymphocytic leukemia (CLL). Every year, there are 15 000 new diagnoses and 5000 CLL deaths in the United States. Although therapeutic choices were once ...limited, treatment of this disease has vastly improved in the last decade. OBJECTIVE: Evidence-based review of the diagnosis, staging, and treatment of CLL. EVIDENCE REVIEW: PubMed, Cochrane Library, Scopus, and Google Scholar databases were searched through August 28, 2014. English-language peer-reviewed articles published between 2000-2014 were found using the keywords chronic lymphocytic leukemia, upfront therapy, upfront therapies, upfront therapeutic, upfront therapeutics, upfront treatment, front-line treatment, first-line treatment, front-line treatments, first-line treatments, front-line therapy, front-line therapies, randomized, randomized studies, randomized study, clinical trial, clinical trials, phase 3, and phase 3 clinical trial. Abstracts and presentations at scientific meetings were excluded. A total of 277 articles were retrieved, of which 24 met our predefined selection criteria; treatment recommendations were based on subsequent analysis of these 24 articles. FINDINGS: The Rai and Binet systems for staging CLL were established in 1975 and 1977, respectively. However, they do not account for new disease categories such as monoclonal B-cell lymphocytosis (peripheral blood clonal lymphocytosis that does not meet other criteria for CLL). Two subsets of CLL are now recognized based on risk stratification involving molecular and cytogenetic analyses. Outcomes are improved by the addition of immunotherapy to combination chemotherapy for initial treatment in all subsets of treated patients. Overall response rates between 75% and 90% and complete responses between 22% and 45% are expected in the current era, with more than 80% of treated patients alive at 3 years. Overall, 5-year survival has increased to 66% from 60% (P < .001) in the past 10 years. CONCLUSIONS AND RELEVANCE: Chemoimmunotherapy is the standard first-line option approach for CLL, the most common leukemia observed in adults. Treatment is initiated when the disease becomes symptomatic, and survival is high following treatment.
Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated ...through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Targeting SUMOylation in cancer Du, Li; Liu, Wei; Rosen, Steven T
Current opinion in oncology,
09/2021, Volume:
33, Issue:
5
Journal Article
In the article, we focus on the role of SUMOylation in tumorigenesis and cancer-related processes, including Epithelial-mesenchymal transition (EMT), metastasis, resistance to cancer therapies, and ...antitumor immunity. Clinical perspective on small ubiquitin-like modifier (SUMO) inhibitors will be discussed.
SUMOylation regulates multiple important biologic functions including gene transcription, DNA damage repair, cell cycle, and innate immunity. The SUMO pathway enzymes are usually elevated in various cancers and linked with cancer progression and poor clinical outcomes for patients. Recent studies have revealed the role of SUMOylation in EMT and metastasis through regulating E-Cadherin and Snail expression. Multiple studies demonstrate SUMOylation is involved with chemoresistance and hormone treatment resistance. Oncogene Myc and SUMOylation machinery regulation has been revealed in pancreatic cancer. SUMOylation is involved in regulating antitumor immune response through dendritic cells and T cells. A breakthrough has been made in targeting SUMOylation in cancer as first-in-class SUMO E1 inhibitor TAK-981 enters clinical trials.
SUMOylation plays an important role in tumor EMT, metastasis, therapy resistance, and antitumor immune response. Pharmaceutical inhibition of SUMOylation has become promising clinical therapy to improve the outcome of the existing chemo and immune therapies.
Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab ...enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov , number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities included upper respiratory tract infections (in 28 57% of 49 patients), diarrhoea (27 55%), and nausea (25 51%). Grade 3–4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 53%), thrombocytopenia (eight 16%), anaemia (seven 14%), febrile neutropenia (six 12%), and leucopenia (six 12%). The most common serious adverse events were pyrexia (six 12%), febrile neutropenia (five 10%), lower respiratory tract infection, and pneumonia (each three 6%). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66–91) and 89% (95% CI 72–96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. Interpretation A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. Funding AbbVie Inc and Genentech Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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•SUMOylation inhibition does not activate IFNB1 gene promoter.•Cytosolic DNA increase due to SUMOylation inhibition does not activate IFNB1 expression.•SETDB1 mediates ...SUMOylation-dependent regulation of IFNB1 expression.•Our study identified a novel mechanism of regulation of type I IFN expression.
Type I interferons (IFN) are cytokines that bridge the innate and adaptive immune response, and thus play central roles in human health, including vaccine efficacy, immune response to cancer and pathogen infection, and autoimmune disorders. Post-translational protein modifications by the small ubiquitin-like modifiers (SUMO) have recently emerged as an important regulator of type I IFN expression as shown by studies using murine and cellular models and recent human clinical trials. However, the mechanism regarding how SUMOylation regulates type I IFN expression remains poorly understood. In this study, we show that SUMOylation inhibition does not activate IFNB1 gene promoter that is regulated by known canonical pathways including cytosolic DNA. Instead, we identified a binding site for the chromatin modification enzyme, the SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1), located between the IFNB1 promoter and a previously identified enhancer. We found that SETDB1 regulates IFNB1 expression and SUMOylation of SETDB1 is required for its binding and enhancing the H3K9me3 heterochromatin signal in this region. Heterochromatin, a tightly packed form of DNA, has been documented to suppress gene expression through suppressing enhancer function. Taken together, our study identified a novel mechanism of regulation of type I IFN expression, at least in part, through SUMOylation of a chromatin modification enzyme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens ...using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Merkel cell polyomavirus (MCV) is a virus discovered in our laboratory at the University of Pittsburgh that is monoclonally integrated into the genome of almost equal to80% of human Merkel cell ...carcinomas (MCCs). Transcript mapping was performed to show that MCV expresses transcripts in MCCs similar to large T (LT), small T (ST), and 17kT transcripts of SV40. Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation. Using coimmunoprecipitation and origin replication assays, we show that tumor-derived virus mutations do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity. Identification of an MCC cell line (MKL-1) having monoclonal MCV integration and the signature LT mutation allowed us to functionally test both tumor-derived and wild type (WT) T antigens. Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Individualizing patient treatment is a core objective of the medical field. Reaching this objective has been elusive owing to the complex set of factors contributing to both disease and health; many ...factors, from genes to proteins, remain unknown in their role in human physiology. Accurately diagnosing, monitoring, and treating disorders requires advances in biomarker discovery, the subsequent development of accurate signatures that correspond with dynamic disease states, as well as therapeutic interventions that can be continuously optimized and modulated for dose and drug selection. This work highlights key breakthroughs in the development of enabling technologies that further the goal of personalized and precision medicine, and remaining challenges that, when addressed, may forge unprecedented capabilities in realizing truly individualized patient care.
Engineering approaches to precision medicine will harness population-wide data to identify individualized treatment strategies.Personalized medicine harnesses a subject’s own data to individualize their own care, from diagnosis through treatment selection and monitoring.Novel clinical trial designs will play a vital role in assessing the efficacy and safety of emerging therapies and diagnostics.Artificial intelligent platforms will globally optimize combination therapy from the preclinical through clinical stages of validation.The widespread deployment of precision and personalized medicine technologies will involve the convergence of several factors ranging from evolving education at the interface of engineering and medicine and policies that support new clinical trial designs, to scaling the use of electronic medical records (EMR) to drive clinical decision support.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Targeting microRNA in hematologic malignancies Han, Zhen; Rosen, Steven T; Querfeld, Christiane
Current opinion in oncology,
2020-September, 2020-09-00, 20200901, Volume:
32, Issue:
5
Journal Article
Open access
PURPOSE OF REVIEWMiRNAs are critical regulators for gene expression. Numerous studies have revealed how miRNAs contribute to the pathogenesis of hematologic malignancies.
RECENT FINDINGSThe ...identification of novel miRNA regulatory factors and pathways crucial for miRNA dysregulation has been linked to hematologic malignancies. miRNA expression profiling has shown their potential to predict outcomes and treatment responses. Recently, targeting miRNA biogenesis or pathways has become a promising therapeutic strategy with recent miRNA-therapeutics being developed.
SUMMARYWe provide a comprehensive overview of the role of miRNAs for diagnosis, prognosis, and therapeutic potential in hematologic malignancies.
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