Harrison College of Pharmacy

Laboratory Personnel

Staff

• Khalda Fadlalla, M.S., DVM, Ph.D.

External Links

• ORCID Profile
• NCBI MyBibliography
• LinkedIn Profile

Research Interests

Overview - The study of signal transduction and regulation of gene expression in pathophysiology has been the theme of my scientific career. During my graduate studies, I investigated the transcriptional and translational regulation of a novel tumor suppressor gene, Mig-6 (ERRFI1), which binds and downregulates ErbB family receptor signaling. Following my training as a postdoctoral fellow in the Cancer Therapeutics Cell Biology laboratory at Southern Research Institute, I have focused primarily on adapting cell growth, signal transduction, fluorescence microscopy, and gene regulation methods for high throughput screening automation. First in the Southern Research Molecular Libraries Screening Center and later at the USA Mitchell Cancer Institute I managed the laboratory for automation and high content screening. This research path has brought me to the Drug Discovery and Development Department in the Auburn University Harrison College of Pharmacy, where we continue the exciting work of developing and carrying out biochemical and cell-based preclinical studies in several drug discovery projects. This has enabled my collaborators and me to develop targeted approaches for cancer treatment. I am currently a co-Investigator on NCI-funded lung cancer prevention grant (7R01CA254197), in which we are evaluating novel indene compounds for prevention of KRAS-mediated lung carcinogenesis.

Elucidation of novel cancer targets and mechanisms of action - As a member of Dr. Piazza’s team, I contributed to this work designing and conducting medium throughput growth, apoptosis, and signal transduction experiments. Our research extended previous work showing cGMP PDE as a target for the tumor cell growth inhibitory activity of sulindac and derivatives which eliminate undesirable toxicity associated with cyclooxygenase inhibition. These studies demonstrated that cGMP PDE inhibition leads to the elevation of intracellular cGMP levels, activation of protein kinase G, and the suppression of Wnt/β-catenin transcriptional activity to induce cell cycle arrest and apoptosis.

Assay development and high throughput screening - As a member of the NIH designated Molecular Libraries Screening Center at Southern Research team, I adapted “bench scale” assays to the high throughput screening environment. In this capacity, I also worked to develop secondary assays to aid synthetic chemists, and computational chemists to develop structure activity relationships (SAR) of small molecules. Below are examples of publications that have resulted directly and indirectly from this work. In addition, as part of this team, I contributed 26 BioAssay reports to the PubChem database.

Selected Publications

• Keeton AB, Salter EA, Piazza GA. 2017 The RAS-Effector Interaction as a Drug Target. Cancer Res. 77(2):221-226. PMID:28062402.
• Piazza GA, Ward A, Chen X, Maxuitenko Y, Coley A, Aboelella NS, Buchsbaum DJ, Boyd MR, Keeton AB, Zhou G. PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity. Drug Discov Today. 2020 Jun 17:S1359-6446(20)30232-4. PMID: 32562844.
• Kwan AK, Piazza GA, Keeton AB, Leite CA. The path to the clinic: a comprehensive review on direct KRASG12C inhibitors. J Exp Clin Cancer Res. 2022 Jan 19;41(1):27. PMID: 35045886.
• Lee KJ, Chang WL, Chen X, Valiyaveettil J, Ramirez-Alcantara V, Gavin E, Musiyenko A, Madeira da Silva L, Annamdevula NS, Leavesley SJ, Ward A, Mattox T, Lindsey AS, Andrews J, Zhu B, Wood C, Neese A, Nguyen A, Berry K, Maxuitenko Y, Moyer MP, Nurmemmedov E, Gorman G, Coward L, Zhou G, Keeton AB, Cooper HS, Clapper ML, Piazza GA. Suppression of Colon Tumorigenesis in Mutant Apc Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin. Cancer Prev Res 2021 Nov;14(11):995-1008. PMID: 34584001
• Abdel-Halim M, Sigler S, Racheed NAS, Hefnawy A, Fathalla RK, Hammam MA, Maher A, Maxuitenko Y, Keeton AB, Hartmann RW, Engel M, Piazza GA, Abadi AH. From Celecoxib to a Novel Class of Phosphodiesterase 5 Inhibitors: Trisubstituted Pyrazolines as Novel Phosphodiesterase 5 Inhibitors with Extremely High Potency and Phosphodiesterase Isozyme Selectivity. J Med Chem. 2021 Apr 22;64(8):4462-4477. doi: 10.1021/acs.jmedchem.0c01120. Epub 2021 Apr 1. PubMed PMID: 33793216.
• Ward AB, Keeton AB, Chen X, Mattox TE, Coley AB, Maxuitenko YY, Buchsbaum DJ, Randall TD, Zhou G, Piazza GA. Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS. MedComm (2020). 2020 Sep;1(2):121-128. doi: 10.1002/mco2.10. Epub 2020 Jun 25. PubMed PMID: 33073260; PubMed Central PMCID: PMC7567124.
• Emmanouilidi A, Casari I, Gokcen Akkaya B, Maffucci T, Furic L, Guffanti F, Broggini M, Chen X, Maxuitenko YY, Keeton AB, Piazza GA, Linton KJ, Falasca M. Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy. Cancers (Basel). 2020 Jul 23;12(8). doi: 10.3390/cancers12082022. PubMed PMID: 32718079; PubMed Central PMCID: PMC7465469.
• Chung WJ, Goeckeler-Fried JL, Havasi V, Chiang A, Rowe SM, Plyler ZE, Hong JS, Mazur M, Piazza GA, Keeton AB, White EL, Rasmussen L, Weissman AM, Denny RA, Brodsky JL, Sorscher EJ. Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics. PLoS One. 2016;11(10):e0163615. doi: 10.1371/journal.pone.0163615. eCollection 2016. PubMed PMID: 27732613; PubMed Central PMCID: PMC5061379.
• Rezk MS, Abdel-Halim M, Keeton A, Franklin D, Bauer M, Boeckler FM, Engel M, Hartmann RW, Zhang Y, Piazza GA, Abadi AH. Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex. Chem Pharm Bull (Tokyo). 2016;64(1):34-41. doi: 10.1248/cpb.c15-00608. PubMed PMID: 26726742.
• Li N, Lee K, Xi Y, Zhu B, Gary BD, Ramírez-Alcántara V, Gurpinar E, Canzoneri JC, Fajardo A, Sigler S, Piazza JT, Chen X, Andrews J, Thomas M, Lu W, Li Y, Laan DJ, Moyer MP, Russo S, Eberhardt BT, Yet L, Keeton AB, Grizzle WE, Piazza GA. Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity. Oncogene. 2015 Mar 19;34(12):1499-509. doi: 10.1038/onc.2014.94. Epub 2014 Apr 7. PubMed PMID: 24704829; PubMed Central PMCID: PMC4212019.