Maria Zajac-Kaye, PhD
Haskel Hess Professor
Teaching Profile
Courses Taught
2016-2025
GMS6934 Cancer Biology Data Discussion
2014-2025
GMS6691 Special Topics in Cell Biology and Anatomy
2018
GMS7980 Research for Doctoral Dissertation
2018
GMS7979 Advanced Research
2015-2017
GMS6895 CTS Journal Club
2016-2017
GMS6064 Tumor Biology
2014,2016-2017
GMS6421 Cell Biology
2013-2015
GMS6692 Research Conference in Anatomy and Cell Biology
2011-2013
GMS6690 Molecular Cell Biology Journal Club
Research Profile
My long-term research interests focus on understanding mechanisms of oncogenic transformation. We have recently studied the role of thymidylate synthase (TS) in tumorigenesis since TS plays a central role in DNA synthesis/repair and high levels of TS have correlated with a poor prognostic outcome in patients with lung, pancreas, colon, and rectal carcinomas. We demonstrated that ectopic expression of catalytically active human TS (hTS) was sufficient to induce a transformed phenotype in mammalian cells both in culture and in transgenic models confirming that it serves as a bona fide cancer therapeutic target. Our current work is focused on defining patterns of cooperation between TS and other cancer genes using a series of defined mouse models. Our goal is to use these transgenic animals to study the in vivo consequences of elevated TS on DNA stability, to test how this relates to tumorigenesis, and to improve the use of TS as a biomarker and therapeutic target.
RESEARCH PROJECTS
Development of an animal model to study the effect of thymidylate synthase expression on the biology of exocrine pancreatic cancer
Cooperation of CDKN2A/p16 gene inactivation and thymidylate synthase overexpression in tumor development
Multiple endocrine neoplasia type 1 (MEN1) gene inactivation and thymidylate synthase overexpression in the development of islet cell carcinoma
Targeted drugs and siRNA delivery for pancreatic and lung cancer in an in vitro and in vivo animal models
Publications
Academic Articles
2024
PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer.
bioRxiv : the preprint server for biology.
[DOI] 10.1101/2024.02.27.582353.
[PMID] 38464204.
2023
Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.
Cell death discovery.
9(1)
[DOI] 10.1038/s41420-022-01296-8.
[PMID] 36588105.
2023
Corrigendum: Targeting thymidylate synthase enhances the chemosensitivity of triple-negative breast cancer towards 5-FU-based combinatorial therapy.
Frontiers in oncology.
13
[DOI] 10.3389/fonc.2023.1302413.
[PMID] 38162481.
2023
First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival
JCI Insight.
8(10)
[DOI] 10.1172/jci.insight.158798.
[PMID] 37097751.
2023
TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background
Oncogene.
42(23):1926-1939
[DOI] 10.1038/s41388-023-02694-7.
[PMID] 37106126.
2022
BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers.
Journal of hematology & oncology.
15(1)
[DOI] 10.1186/s13045-022-01241-3.
[PMID] 35260176.
2022
Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival
JCI Insight.
7(19)
[DOI] 10.1172/jci.insight.147417.
[PMID] 36048542.
2021
Targeting Thymidylate Synthase Enhances the Chemosensitivity of Triple-Negative Breast Cancer Towards 5-FU-Based Combinatorial Therapy.
Frontiers in oncology.
11
[DOI] 10.3389/fonc.2021.656804.
[PMID] 34336653.
2019
MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma.
Oral oncology.
98:147-155
[DOI] 10.1016/j.oraloncology.2019.09.005.
[PMID] 31606723.
2019
Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival
The Journal Of Clinical Investigation.
129(6):2279-2292
[DOI] 10.1172/JCI121323.
[PMID] 31033480.
2018
CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition.
Oncotarget.
9(100):37352-37366
[DOI] 10.18632/oncotarget.26424.
[PMID] 30647837.
2018
Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models.
Carcinogenesis.
39(8):1068-1078
[DOI] 10.1093/carcin/bgy073.
[PMID] 29846515.
2018
Microbial marauders: pancreatic microbiota and its impact on carcinogenesis.
Annals of translational medicine.
6(Suppl 1)
[DOI] 10.21037/atm.2018.10.34.
[PMID] 30613638.
2017
Efficient Gene Delivery and Expression in Pancreas and Pancreatic Tumors by Capsid-Optimized AAV8 Vectors.
Human gene therapy methods.
28(1):49-59
[DOI] 10.1089/hgtb.2016.089.
[PMID] 28125909.
2017
NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations.
Oncotarget.
8(34):57246-57264
[DOI] 10.18632/oncotarget.19778.
[PMID] 28915668.
2015
Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer.
Journal of the National Cancer Institute.
107(1)
[DOI] 10.1093/jnci/dju358.
[PMID] 25465874.
2015
Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors.
Journal of the National Cancer Institute.
107(8)
[DOI] 10.1093/jnci/djv123.
[PMID] 25971297.
2014
A small molecule FAK kinase inhibitor, GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells.
Cell cycle (Georgetown, Tex.).
13(19):3143-9
[DOI] 10.4161/15384101.2014.949550.
[PMID] 25486573.
2014
A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets.
Oncotarget.
5(24):12528-42
[PMID] 25587024.
2014
Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival.
International journal of cancer.
135(1):128-37
[DOI] 10.1002/ijc.28675.
[PMID] 24347111.
2014
CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement.
Proceedings of the National Academy of Sciences of the United States of America.
111(32):E3260-8
[DOI] 10.1073/pnas.1319176111.
[PMID] 25071166.
2014
Deregulated Thymidylate Synthase Promotes Tumorigenecity in Pancreatic Neuroendocrine Tumors
Cancer Research.
74(19, S):3922-3922
[DOI] 10.1158/1538-7445.AM2014-3922.
2014
Deregulated Ts Promotes Tumor Progression in Diverse Hematopoietic and Mesenchymal Cell Lineages
Cancer Research.
74(19, S):2042-2042
[DOI] 10.1158/1538-7445.AM2014-2042.
2014
Overexpression of Histone Deacetylases in Cancer Cells Is Controlled By Interplay of Transcription Factors and Epigenetic Modulators
The FASEB's Journal.
28(10):4265-4279
[DOI] 10.1096/fj.14-250654.
[PMID] 24948597.
2013
Current understanding of the molecular biology of pancreatic neuroendocrine tumors.
Journal of the National Cancer Institute.
105(14):1005-17
[DOI] 10.1093/jnci/djt135.
[PMID] 23840053.
2013
Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo.
Anti-cancer agents in medicinal chemistry.
13(4):595-602
[PMID] 23272972.
2012
A Novel Focal Adhesion Kinase Inhibitor (Pf-04554878) Decreases Growth and Induces Apoptosis in Pancreatic Neuroendocrine Tumor Cells
European Journal of Cancer.
48
2012
Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.
Cell cycle (Georgetown, Tex.).
11(17):3250-9
[DOI] 10.4161/cc.21611.
[PMID] 22894899.
2012
DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer.
Molecular cancer therapeutics.
11(2):370-82
[DOI] 10.1158/1535-7163.MCT-11-0458.
[PMID] 22203734.
2011
Accelerated Tumor Growth and Enhanced Tumor Burden in Genetically Engineered Animal Models With Targeted Thymidylate Synthase Activation
International Journal of Molecular Medicine.
28
2011
Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent.
Cell cycle (Georgetown, Tex.).
10(23):4074-82
[DOI] 10.4161/cc.10.23.18170.
[PMID] 22101337.
2010
Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer.
Oncogene.
29(11):1672-80
[DOI] 10.1038/onc.2009.453.
[PMID] 20010869.
2010
Enhanced growth inhibition by combined DNA methylation/HDAC inhibitors in lung tumor cells with silenced CDKN2A.
International journal of oncology.
37(4):963-71
[PMID] 20811718.
2010
Lkb1 Regulates a Novel Crtc1: Creb: Nr4A2 Pathway in Lung Cancer
Journal of Thoracic Oncology.
5:S242-S243
2010
Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.
European journal of cancer (Oxford, England : 1990).
46(2):340-7
[DOI] 10.1016/j.ejca.2009.10.026.
[PMID] 19945858.
2007
Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas.
Oncogene.
26(33):4817-24
[PMID] 17297449.
2006
EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins.
Oncogene.
25(49):6497-509
[PMID] 16702950.
2004
Elevated levels of thymidylate synthase linked to neoplastic transformation of mammalian cells.
Cell cycle (Georgetown, Tex.).
3(8):1005-7
[PMID] 15280655.
2004
Evolutionary conservation of a 2-kb intronic sequence flanking a tissue-specific alternative exon in the PTBP2 gene.
Genomics.
83(1):76-84
[PMID] 14667811.
2004
Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme.
Cancer cell.
5(4):341-51
[PMID] 15093541.
2002
Alternative splicing of brain-specific PTB defines a tissue-specific isoform pattern that predicts distinct functional roles.
Genomics.
80(3):245-9
[PMID] 12213192.
2002
The identification of thymidylate synthase peptide domains located in the interface region that bind thymidylate synthase mRNA.
Biochemical and biophysical research communications.
297(1):24-31
[PMID] 12220503.
2001
Downregulation of p21/WAF1 expression by thymidylate synthase.
Biochemical and biophysical research communications.
285(2):195-200
[PMID] 11444825.
2001
Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer.
Lung cancer (Amsterdam, Netherlands).
34 Suppl 2:S43-6
[PMID] 11720740.
2000
Disruption of Myc-tubulin interaction by hyperphosphorylation of c-Myc during mitosis or by constitutive hyperphosphorylation of mutant c-Myc in Burkitt’s lymphoma.
Molecular and cellular biology.
20(14):5276-84
[PMID] 10866684.
2000
Induction of Myc-intron-binding polypeptides MIBP1 and RFX1 during retinoic acid-mediated differentiation of haemopoietic cells.
The Biochemical journal.
345 Pt 3(Pt 3):535-41
[PMID] 10642512.
2000
Multiprotein complexes present at the MIF motifs flanking the promoter of the human c-myc gene.
FEBS letters.
474(1):23-8
[PMID] 10828444.
1999
The 100-kDa proteolytic fragment of RB is retained predominantly within the nuclear compartment of apoptotic cells.
Molecular cell biology research communications : MCBRC.
1(3):216-20
[PMID] 10425229.
1998
RET cooperates with RB/p53 inactivation in a somatic multi-step model for murine thyroid cancer.
Oncogene.
17(12):1625-8
[PMID] 9794240.
1997
c-Raf kinase binds to N-terminal domain of c-Myc.
FEBS letters.
414(2):465-70
[PMID] 9315742.
1996
Gene-specific repair in human CD4+ lymphocytes reflects transcription and proliferation.
Mutation research.
363(3):191-9
[PMID] 8765160.
1996
Interactions of the transcription factors MIBP1 and RFX1 with the EP element of the hepatitis B virus enhancer.
Journal of virology.
70(9):6060-6
[PMID] 8709229.
1995
HIV-1 expression induced by anti-cancer agents in latently HIV-1-infected ACH2 cells.
Biochemical and biophysical research communications.
207(3):903-9
[PMID] 7532407.
1995
The myc intron-binding polypeptide associates with RFX1 in vivo and binds to the major histocompatibility complex class II promoter region, to the hepatitis B virus enhancer, and to regulatory regions of several distinct viral genes.
Molecular and cellular biology.
15(6):3041-8
[PMID] 7760800.
1995
The N-terminal domain of c-Myc associates with alpha-tubulin and microtubules in vivo and in vitro.
Molecular and cellular biology.
15(9):5188-95
[PMID] 7651436.
1994
c-myc Down-regulation in suramin-treated HL60 cells precedes growth inhibition but does not trigger differentiation.
Molecular pharmacology.
46(1):73-8
[PMID] 8058059.
1993
Somatic mutations in c-myc intron I cluster in discrete domains that define protein binding sequences.
The Journal of biological chemistry.
268(26):19586-92
[PMID] 8366102.
1992
Functional analysis at the Cys706 residue of the retinoblastoma protein.
The Journal of biological chemistry.
267(36):25998-6003
[PMID] 1334491.
1990
Downstream regulatory elements in the c-myc gene.
Current topics in microbiology and immunology.
166:279-84
[PMID] 2073807.
1990
Phosphorylation-dependent binding of a 138-kDa myc intron factor to a regulatory element in the first intron of the c-myc gene.
The Journal of biological chemistry.
265(8):4547-51
[PMID] 2407738.
1988
A point mutation in the c-myc locus of a Burkitt lymphoma abolishes binding of a nuclear protein.
Science (New York, N.Y.).
240(4860):1776-80
[PMID] 2454510.
1988
Multifactorial regulation of the human c-myc oncogene.
Current topics in microbiology and immunology.
141:247-52
[PMID] 3215053.
1987
Depletion of sodium butyrate from the culture medium of Friend erythroleukemia cells undergoing differentiation.
Cancer research.
47(2):378-82
[PMID] 3466690.
1987
Recent studies on the mechanism of induction of differentiation in murine erythroleukemia cells.
Haematologica.
72(6 Suppl)
[PMID] 3127303.
1986
Induction of differentiation in Friend erythroleukemia cells with dimethyl sulfoxide, hexamethylene bisacetamide and sodium butyrate is not accompanied by changes in proviral DNA or its expression.
Virus research.
6(1):45-55
[PMID] 3467519.
1985
Rat cells infected with anemia-inducing Friend leukemia virus contain integrated replication-competent but not defective proviral genomes.
Proceedings of the National Academy of Sciences of the United States of America.
82(17):5925-9
[PMID] 3862107.
1984
DNAase I encapsulated in liposomes can induce neoplastic transformation of Syrian hamster embryo cells in culture.
Cell.
39(3 Pt 2):427-37
[PMID] 6509550.
Grants
Jul 2022
ACTIVE
Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC
Role: Principal Investigator
Funding: UNIV OF TEXAS HLTH SCI CTR SAN ANTONIO
via NATL INST OF HLTH NCI
Feb 2022
ACTIVE
The Role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
Role: Principal Investigator
Funding: UNIV OF TEXAS HLTH SCI CTR SAN ANTONIO
via NATL INST OF HLTH NCI
Jul 2020
– Dec 2021
Protein kinase signaling in cisplatin-resistant ASCL1-high SCLC
Role: Other
Funding: US ARMY MED RES ACQUISITION
Feb 2020
– Dec 2021
The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
Role: Co-Investigator
Funding: NATL INST OF HLTH NCI
Dec 2019
– Dec 2021
Targeting MAST1-BCL2 signaling in small cell lung cancer
Role: Co-Project Director/Principal Investigator
Funding: LUNG CANCER RESEARCH FOUNDATION
Sep 2019
– Mar 2023
Testing novel drug combination for pancreatic cancer
Role: Principal Investigator
Funding: FL DEPT OF HLTH BIOMED RES PGM/J&E KING
Jul 2019
– Jun 2022
UF Health Cancer Center Pilot Projects funded by UF Foundation Allocated Funds
Role: Project Manager
Funding: UF FOUNDATION
Jul 2019
– Jun 2020
Targeting NFIB-MAST1 signaling in cisplatin-resistant small cell lung cancer
Role: Co-Investigator
Funding: PARDEE FOU, ELSA U
Jun 2018
– Mar 2023
Good manufacturing Practice (GMP) production to allow Phase 1 clinical trial testing intralesional delivery of myxomavirus to patients with advanced small cell lung cancer
Role: Co-Investigator
Funding: FL DEPT OF HLTH BIOMED RES PGM/J&E KING
May 2018
ACTIVE
High throughput 3D printing
Role: Principal Investigator
Funding: MERCK SHARP & DOHME
Jan 2016
– Dec 2021
Studies on thymidylate synthase as a tumor-promoting oncogene for development of new allosteric inhibitors for cancer treatment
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
May 2015
– May 2019
First-of-its-kind study of oncolytic virotherapy for Small Cell Lung Cancer (SCLC) using mouse models and human ex-vivo intralesional analyses
Role: Co-Investigator
Funding: FL DEPT OF HLTH BIOMED RES PGM/J&E KING
Feb 2015
– Oct 2023
UF Health Cancer Center Pilot Project Grants funded through the Florida Consortium of National Cancer Institute Centers Program
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL
Jan 2015
– May 2024
UF Health Cancer Center Bridge Seed Grant funded through the Florida Consortium of National Cancer Institute Centers Program
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL
Aug 2011
– Mar 2018
Small Cell Cancer Equipment and Research Competition
Role: Project Manager
Funding: UF FOUNDATION
Education
Research Fellow
1988-1989
·
Medicine Branch, National Cancer Institute, NIH, Bethesda, MD
Biotechnology Fellow
1985-1988
·
Medicine Branch, National Cancer Institute, NIH, Bethesda, MD
Post Doctoral Fellow
1985
·
Department of Experimental Cell Biology, Mt. Sinai School of Medicine, New York, NY
PhD
1982
·
Department of Biochemical and Biophysical Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD
MS, Organic Chemistry
1975
·
The Johns Hopkins University, Baltimore, MD
BS (Honors), Chemistry
1973
·
The City University of New York, New York, NY
Contact Details
Phones:
- Business:
- (352) 273-9153
Emails:
- Business:
- mzajackaye@ufl.edu
Administrative Assistant:
Addresses:
- Business Mailing:
-
PO BOX 103633
GAINESVILLE FL 326100001 - Business Street:
-
PO Box 103633
2033 MOWRY RD RM 360
GAINESVILLE FL 32610