Browsing by Author "Batra, Sandeep"
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Item Asparagine bioavailability regulates the translation of MYC oncogene(Springer Nature, 2022) Srivastava, Sankalp; Jiang, Jie; Misra, Jagannath; Seim, Gretchen; Staschke, Kirk A.; Zhong, Minghua; Zhou, Leonardo; Liu, Yu; Chen, Chong; Davé, Utpal; Kapur, Reuben; Batra, Sandeep; Zhang, Chi; Zhou, Jiehao; Fan, Jing; Wek, Ronald C.; Zhang, Ji; Pediatrics, School of MedicineAmino acid restriction has recently emerged as a compelling strategy to inhibit tumor growth. Recent work suggests that amino acids can regulate cellular signaling in addition to their role as biosynthetic substrates. Using lymphoid cancer cells as a model, we found that asparagine depletion acutely reduces the expression of c-MYC protein without changing its mRNA expression. Furthermore, asparagine depletion inhibits the translation of MYC mRNA without altering the rate of MYC protein degradation. Of interest, the inhibitory effect on MYC mRNA translation during asparagine depletion is not due to the activation of the general controlled nonderepressible 2 (GCN2) pathway and is not a consequence of the inhibition of global protein synthesis. In addition, both the 5' and 3' untranslated regions (UTRs) of MYC mRNA are not required for this inhibitory effect. Finally, using a MYC-driven mouse B cell lymphoma model, we found that shRNA inhibition of asparagine synthetase (ASNS) or pharmacological inhibition of asparagine production can significantly reduce the MYC protein expression and tumor growth when environmental asparagine becomes limiting. Since MYC is a critical oncogene, our results uncover a molecular connection between MYC mRNA translation and asparagine bioavailability and shed light on a potential to target MYC oncogene post-transcriptionally through asparagine restriction.Item Asparagine: A Metabolite to Be Targeted in Cancers(MDPI, 2021-06-19) Jiang, Jie; Batra, Sandeep; Zhang, Ji; Pediatrics, School of MedicineAmino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.Item Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells(Springer Nature, 2022) Halbrook, Christopher J.; Thurston, Galloway; Boyer, Seth; Anaraki, Cecily; Jiménez, Jennifer A.; McCarthy, Amy; Steele, Nina G.; Kerk, Samuel A.; Hong, Hanna S.; Lin, Lin; Law, Fiona V.; Felton, Catherine; Scipioni, Lorenzo; Sajjakulnukit, Peter; Andren, Anthony; Beutel, Alica K.; Singh, Rima; Nelson, Barbara S.; Van Den Bergh, Fran; Krall, Abigail S.; Mullen, Peter J.; Zhang, Li; Batra, Sandeep; Morton, Jennifer P.; Stanger, Ben Z.; Christofk, Heather R.; Digman, Michelle A.; Beard, Daniel A.; Viale, Andrea; Zhang, Ji; Crawford, Howard C.; di Magliano, Marina Pasca; Jorgensen, Claus; Lyssiotis, Costas A.; Pediatrics, School of MedicineThe pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin.Item Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia(Elsevier, 2018-08) Warrick, Kasper; Althouse, Sandra K.; Rahrig, April; Rupenthal, Joy; Batra, Sandeep; Pediatrics, School of MedicineBackground High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. Procedure Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan–Meier method and log-rank test. Results Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 ± 27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/μL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. Conclusions A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients.Item Histiocytic Sarcoma Associated with Coombs Negative Acute Hemolytic Anemia: A Rare Presentation(Hindawi Publishing Corporation, 2016) Batra, Sandeep; Martin, Stephen C.; Nassiri, Mehdi; Qureshi, Amna; Markel, Troy A.; Department of Pediatrics, IU School of MedicineHistiocytic sarcoma (HS) rarely involves extranodal sites, such as the spleen. We report a unique pediatric case of massive splenomegaly and refractory Coombs negative hemolytic anemia (CNHA) secondary to HS. The CNHA resolved completely after an emergent splenectomy. Next generation sequencing (NGS) revealed novel ASXL1, PTPN11, KIT, and TP53 mutations, unmasking a clonal heterogeneity within the same neoplasm.Item Hypogammaglobulinemia in Adolescents and Young Adults with Acute Lymphoblastic Leukemia(Mary Ann Liebert, Inc., 2020-12) Lange, Cassandra S.; Rahrig, April; Althouse, Sandra K.; Nelson, Robert P.; Batra, Sandeep; Medicine, School of MedicineHypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15–39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin–Frankfurt–Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.Item Pediatric Mixed-Phenotype Acute Leukemia: What’s New?(MDPI, 2021-09-16) Batra, Sandeep; Ross, Anthony John; Pediatrics, School of MedicineMixed-phenotype acute leukemias (MPAL) are rare in children and often lack consensus on optimal management. This review examines the current controversies and emerging paradigms in the management of pediatric MPAL. We examine risk stratification, outcomes of recent retrospective and prospective collaborative trials, and the role of transplantation and precision genomics, and outline emerging targets and concepts in this rare entity.Item Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults(MDPI, 2024-02-29) Brown, Amber; Batra, Sandeep; Pediatrics, School of MedicineThere are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associated with these rare entities.Item Spitzoid melanoma of childhood: a case series and review(Future Science Group, 2015-05) Batra, Sandeep; Pediatrics, School of MedicineSpitzoid melanomas (SM) and atypical Spitz tumors (AST) are rare pediatric neoplasms. We performed a retrospective, single-institution review and report our institutional experience. We identified 10 patients (median age: 12.5 years). A sentinel node biopsy (SNB) was performed in 8/10 (80%) patients, and interestingly 7/8 (87.5%) were found to be positive for malignant cells. A complete regional lymphadenectomy was performed in all SNB-positive patients, but only 2/8 (25%) were found to have additional lymph node spread. Adjuvant therapy was administered in 5/8 SLNB-positive and 2/2 (100%) regional LN-positive cases. All patients had excellent long-term outcomes (100% survival). This report highlights the excellent outcomes associated with SNB + pediatric SM and AST.Item Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma(MDPI, 2020-08-26) Pandya, Pankita H.; Cheng, Lijun; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Tang, Shan; Sinn, Anthony L.; Trowbridge, Melissa A.; Coy, Kathryn L.; Bailey, Barbara J.; Young, Courtney N.; Ding, Jixin; Dobrota, Erika A.; Dyer, Savannah; Elmi, Adily; Thompson, Quinton; Barghi, Farinaz; Shultz, Jeremiah; Albright, Eric A.; Shannon, Harlan E.; Murray, Mary E.; Marshall, Mark S.; Ferguson, Michael J.; Bertrand, Todd E.; Wurtz, L. Daniel; Batra, Sandeep; Li, Lang; Renbarger, Jamie L.; Pollok, Karen E.; Pediatrics, School of MedicineOsteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.