The Amengual laboratory is located in the William Black Building and are members of the Herbert Irving Comprehensive Cancer Center Cancer Genomics and Epigenomics Program. We focus on developing personalized epigenetic treatment platforms by targeting specific pathogenetic mechanisms driving disease. Bridging ideas generated at the bench, these highly collaborative research projects, should allow for a strategic and rapid translation to clinical practice.
The Amengual laboratory’s research goals are focused on developing targeted therapies for the treatment of lymphoma. We aim to directly translate observations and concepts developed in the laboratory to patient care and back again to the laboratory. Specifically, we have concentrated on targeting epigenetic and transcriptional pathways in germinal-center derived diffuse large B-cell lymphoma (GC-DLBCL) and T-cell lymphomas with histone deacetylase (HDAC) inhibitors, alone and in combination with other drugs. Drug combinations partnered with HDAC inhibitors have included: sirtuin inhibitors in an effort to modulate the Bcl6 : p53 pathway; bortezomib aimed at modulating the unfolded protein response; pralatrexate as a synergistic interaction in T-cell lymphoma, and EZH2 inhibitors to target epigenetic derangements in GC-DLCBL. These projects all began at the bench for proof-of-principle investigation, and once established, have all translated into investigator-initiated early phase clinical trials where patient samples are being collected to confirm pharmacodynamics endpoints (NCT00691210, NCT02091063, NCT01947140).
Recently, our team has discovered a novel group of small molecules that can reverse the negative effects of histone acetyl transferase (HAT) mutations. Monoalleleic inactivating mutations in HAT enzymes promote lymphomagenesis in GC derived B-cell lymphomas, occurring in about 40% of patients. The intact wild-type allele offers an opportunity to leverage the normal enzyme to overcome the pathogenic impact of the mutated allele. We hypothesize that if inactivating mutations in HATs are critical to lymphomagenesis, then drugs capable of inducing enhanced function of the wild-type HAT allele product should be cytotoxic in cells harboring HAT mutations. Our lead compound was chosen because it was the most selective of the analogues in inducing cytotoxicity in cell lines harboring CREBBP/EP300 mutations compared to wild-type. Additionally, it has demonstrated CBP/p300 mediated histone and p53 acetylation in both cell free, cellular assays and animal models. Our lead compound has been found to synergize with the HDAC inhibitor romidepsin, leading to enhanced acetylation of histone and synergistic cytotoxicity. At this time, this project, funded by a NIH/NCI Developmental Therapeutics Program R01, is now being fully evaluated to enable IND filing in the first quarter of 2021. The goal of these studies is to bring this Columbia-discovered first-in-class compound to patients harboring HAT mutations in a first-in-man clinical trial.
In line with discovering a precision medicine treatment platform for lymphoma, I have been studying dual epigenetic targeting in lymphomas harboring EZH2 mutations. EZH2, a key factor of the PRC2 complex, is a histone methyltransferase that is mutated in approximately 22% of GC-lymphomas. These same malignancies also harbor HAT mutations, which in the clinic may be indirectly targeted with HDAC inhibitors. We therefore have hypothesized that dual inhibition of EZH2 and HDAC would be synergistic and have found this to be true. Basal gene expression of lymphoma cell lines was determined by RNA Seq and correlated to synergy co-efficients of the HDAC plus EZH2 inhibitor combination. Synergistic cell lines demonstrated a distinct gene expression signature predicting response as compared to the cell lines that did not achieve synergy. In addition, network analysis performed by gene set enrichment analysis (GSEA) revealed that cell lines sensitive to the combination correlated with a “chromatin silencing” gene expression signature. To build on this published work, we aim to study the impact of dual EZH2 plus HDAC inhibition on histone-chromatin interactions and subsequent changes in gene expression. Our goal is to evaluate dual epigenetic targeting with EZH2 and HDAC inhibition in an investigator-initiated clinical trial for patients harboring a chromatin remodeled state.
Taken together, our research focus is to develop personalized epigenetic treatment platforms for targeting a specific pathogenetic mechanism driving disease. The goal of these projects is to identify biomarkers for response to allow for treatment aimed precisely at the biological drivers of disease regardless of cell of origin. Bridging ideas generated at the bench, these highly collaborative research projects, should allow for a strategic and rapid translation to clinical practice.
Current Lab Members
Brian Estrella, PhD
Post-Doctoral Research FellowPost-Doctoral Research Fellow
Brian received his B.S. in Biochemistry from Rugters University in 2011. He then went on to receive a Ph. D. from Rutgers University in Toxicology in 2018 from the laboratory of Dr. Helmut Zarble. Brain join the Amengual Lab in 2019 as a post-doctoral researcher. His current research is focused on elucidation and characterization of a novel p300/CREBBP activator, YF2 in diffuse large B-cell lymphoma and T-cell lymphoma.
His graduate studies focused on characterization and biomarker development of a candidate mammary carcinoma susceptibility gene, called FRY and FRY Antisense-1, a long non-coding RNA which shares a bi-directional promoter with the FRY gene. Additionally, he has contributed to studies examining the toxic effects of zeranol, a potent endocrine disruptor, which contributes to mammary carcinogenesis, precocious puberty, and obesity.
Brian’s current interests include biochemistry, molecular and cellular biology, cancer biology, molecular toxicology, carcinogenesis, and epigenomics.
Manuel "Tony" Pazos, II
Tony has been interested in cancer research and pharmacology for as long as he can remember. He obtained his masters in Biomedical Sciences at the University at Albany. His thesis focused the roles that RNA modifications N4-acetylcytosine (ac4C) and 5-methylcytosine (m5C) play in aspects of epithelial to mesenchymal transition (EMT) in human breast cancer. Tony joined the Amengual lab in 2021 to pursue his interests and has the goal of obtaining his PhD.
Former Lab Members
Yuxuan Lui, PhD
Post-Doctoral Research Fellow
*Oral abstract and Abstract Award ASH
*Recipient LRF Post-Doc Fellowship
Current position: Senior Research Associate, Stanford University
Jennifer Lue, MD
*Oral abstract and Abstract Award ASH
Current position: Assistant Professor, Columbia University Irving Medical Center
Satheyn Prabhu, MS
Graduate Student/Research Technician
Current position: PhD Student, McGill University
Maximilian Lombardo, MS
Graduate Student/Research Technician
Current position: Computer Science Graduate Program, University of Amsterdam
*ASH HONORS Program
Current position: Internal Medicine Resident, New York University Medical Center
Gaston Jean-Louis, MD
*3rd Prize VP&S Student Research Day
Internal Medicine Resident, Columbia University Irving Medical Center
Lue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A, Mundi PS, Abshiru N, Camarillo JM, Mehta S, Chen EI, Qiao C, Nandakumar R, Cremers S, Kelleher NL, Elemento O, Amengual JE. Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas. Clin Cancer Res. 2019 Sep 1;25(17):5271-5283. doi: 10.1158/1078-0432.CCR-18-3989. Epub 2019 Apr 12. PubMed PMID: 30979734; PubMed Central PMCID: PMC6726529.
Amengual JE, Lichtenstein R, Lue J, Sawas A, Deng C, Lichtenstein E, Khan K, Atkins L, Rada A, Kim HA, Chiuzan C, Kalac M, Marchi E, Falchi L, Francescone MA, Schwartz L, Cremers S, O'Connor OA. A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood. 2018 Jan 25;131(4):397-407. doi: 10.1182/blood-2017-09-806737. Epub 2017 Nov 15. PubMed PMID: 29141948; PubMed Central PMCID: PMC5790128.
Amengual JE, Prabhu SA, Lombardo M, Zullo K, Johannet PM, Gonzalez Y, Scotto L, Serrano XJ, Wei Y, Duong J, Nandakumar R, Cremers S, Verma A, Elemento O, O'Connor OA. Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib. Clin Cancer Res. 2017 Jun 15;23(12):3084-3096. doi: 10.1158/1078-0432.CCR-16-2022. Epub 2016 Dec 19. PubMed PMID: 27993968; PubMed Central PMCID: PMC5474138.
Amengual JE, Johannet P, Lombardo M, Zullo K, Hoehn D, Bhagat G, Scotto L, Jirau-Serrano X, Radeski D, Heinen J, Jiang H, Cremers S, Zhang Y, Jones S, O'Connor OA. Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma. Clin Cancer Res. 2015 Oct 15;21(20):4663-75. doi: 10.1158/1078-0432.CCR-14-3068. Epub 2015 Jun 26. PubMed PMID: 26116270; PubMed Central PMCID: PMC4609274.
Amengual JE, Clark-Garvey S, Kalac M, Scotto L, Marchi E, Neylon E, Johannet P, Wei Y, Zain J, O'Connor OA. Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma. Blood. 2013 Sep 19;122(12):2104-13. doi: 10.1182/blood-2013-02-485441. Epub 2013 Aug 2. PubMed PMID: 23913470.
Amengual JE. ASH Education Book: Can we use epigenetics to prime chemoresistant lymphomas. Hematology (2020).