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France  Carrier
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France Carrier Ph.D.

Academic Title: Associate Professor
Primary Appointment: Radiation Oncology
fcarr001@umaryland.edu
Location: Bressler Research Building, 10-037
Phone: (410) 706-5105
Fax: (410) 706-3260
Lab: (410) 706-3263

Personal History:

Education

  • 1983 - B.Sc., Medical Biology, University of Quebec at Trois-Rivieres Quebec, Canada
  • 1988 - Ph.D., Clinical Sciences/Biochemistry, University of Montreal Quebec, Canada Post Graduate Education
  • 1988-1989 - Postdoctoral fellow, Protein Engineering group, Biotechnology Research Institute, National Research Council, Montreal Canada.
  • 1989-1991 - Guest Researcher, Developmental Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
  • 1991-1998 - Visiting Associate, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Professional Experience

  • 07/2009- present: Associate Professor, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, Department of Radiation Oncology, University of Maryland, Baltimore
  • 07/2007-06/2009: Assistant Professor, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, Department of Radiation Oncology, University of Maryland, Baltimore
  • 1998-06/2007: Assistant Professor, School of Medicine, Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore

Professional Memberships

  • 1992-present: American Association for Cancer Research
  • 1992-2003: American Association for the Advancement of Science
  • 2000-present: New York Academy of Sciences
  • 1999-present: Cosmos Club, Washington, D.C.

Research Interests:

My laboratory is interested in basic and translational cancer research. Our main focus is to understand molecular events underlying cancer progression. Our goal is to delineate intrinsic differences between normal and cancer cells in order to more specifically target cancer cells and improve current cancer therapies.

Carcinogenesis is a multiple steps process that includes initiation, promotion, transformation and finally propagation of the cancer cells. Our basic science projects focus on the first two steps of carcinogenesis, initiation and propagation and our collaborations on translational cancer research allow us to target the last step of carcinogenesis, propagation. The initiation step is usually triggered by exposure to carcinogens that can damage DNA. The cellular response that ensues, genotoxic stress response, is complex but generally plays a protective role against the cellular insults. Our studies on the genotoxic stress response have focused on the role of stress-activated RNA binding proteins. We have recently identified the stress-responsive heterogeneous ribonucleoprotein A18 (hnRNP A18) as a key regulator of protein translation in cancer cells (1). hnRNP A18 is usually not expressed in normal cells but is upregulated in about 20-30% of several human cancers including, breast, prostate, colon and melanoma. We have identified a consensus hnRNP A18 RNA binding motif in several mRNAs transcripts that can confer growth advantages to cancer cells (Fig.1). Down regulation of hnRNP A18 reduces tumor growth by 70-80% in a xenograft mouse model (Fig.2). Our long term goal is to identify and/or develop new drugs to rationally target hnRNP A18 in cancer cells in order to stop or control cancer progression. As a first step toward this goal we are collaborating with Dr. David Weber to solve hnRNP A18 three dimensional structures by Nuclear Magnetic Resonance (NMR).

Figure 1: mRNA circulation model of translational control involving hnRNP A18. hnRNP A18 may mediate this 5’UTR and 3’UTR loop formation by binding both the 3’UTR of transcripts and the initiation factor elF4G in the translation initiation complex. PABP: PolyA Binding Protein. The arrows indicate the direction of ribosome scanning and translating.
 
Figure 2: Melanoma tumors in mouse xenografts. A-B) LOX-IM VI cells stably transfected with shhnRNP A18 injected on the left flank and parent cells injected on the right flanks. B) Tumors weight formed in three animals. Black bar; parent cell lines, white bar; LOX-IM VI stably transfected with shhnRNP A18. * p<0.05

Propagation is the last and most devastating step of carcinogenesis. A major goal of several chemotherapeutic regimens is therefore to prevent or inhibit this step. The inhibitors of histone deacetylases (HDACIs) are considered one of the most promising anticancer drugs in development (2). As their name suggests, their primary targets are enzymes that deacetylate histones but several non-histone targets have also been described. HDACIs are most effective as combination agent against cancer cell proliferation. They are about ten times more efficient on cancer cells as compared to normal cells. The reason for this preferred sensitivity is not fully understood but is currently being investigated by a number of laboratories including ours. Our lab published one of the first studies demonstrating (3,4)that pre-treatment of cancer cells with HDACIs sensitize cancer cells to conventional chemotherapeutic agents. This work served as a basis to develop a recently completed Phase 1 clinical trial lead by Dr. Douglas Ross at the University of Maryland Greenebaum Cancer Center, to evaluate the effect of HDACI pretreatment in combination with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia (5). We are also interested in studying the effect of HDACIs and the alkylating agent temozolomide (TMZ) on promotion of hyper-radiosensitivity (HRS) in order to develop new clinical trials with low dose fractionated radiation therapy (LDFRT). Our preclinical data on HDACIs and TMZ demonstrated that HDACIs and TMZ can promote HRS in glioblastoma cells (6). These data served as a basis to develop a currently ongoing Phase II clinical trial (1224GCC) at our institution led by Dr. Young Kwok to evaluate the effect of Low-Dose Whole Brain Radiotherapy with Concurrent Temozolomide and Adjuvant Temozolomide in Patients with Newly-Diagnosed Glioblastoma Multiforme. We are currently pursuing similar studies on LDFRT with Dr. Navesh Sharma to study the potential use of Low-Dose Fractionated Whole-Abdomen Radiation Therapy (LDFRT) as a chemosensitizer in patients with peritoneal carcinomatosis from gastric or gastroesophageal junction primary adenocarcinomas and with Dr. Michael Chuong to study LDFRT for colon cancer treatments.

References

  1. Pamboukian, R and Carrier, F. hnRNP A18: A new pathway to regulate protein translation in cancer cells. Molecular and Cellular Pharmacology, 4(1):41-48, 2012.
  2. Minucci, S. and Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer, 6: 38-51, 2006.
  3. Kim, M. S., Blake, M., Baek, J. H., Kohlhagen, G., Pommier, Y., and Carrier, F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res, 63: 7291-7300, 2003.
  4. Carrier, F. Blake, M., Khelifa, T. Chromatin structure opening by the Histone Deacetylase Inhibitor Trichostatin A (TSA) increases cellular cytotoxicity to Topoisomerase inhibitors. In: American Association for Cancer Research, New Orleans, LA, March 2001, pp. #1354.
  5. Gojo, I,Tan, M, Fang, H-B, Sadowska, M., Lapidus, R., Baer, M.R., Carrier, F., Beumer,J.H., Anyang, B.N., Srivastava, R.K., Espinoza-Delgado, I.and Ross. D.D. Translational phase I trial of vorinostat combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clinical Cancer Res. Apr 1;19(7):1838-1851. Epub 2013 Feb 12., 2013.
  6. Diss, E, Nalabothula, N, Nguyen, DM, Chang, E., Kwok, Y., Carrier, F. Vorinostatsaha promotes hyper-radiosensitivity in wild type p53 human glioblastoma cells. Journal of Clinical Oncology and Research, JSM Clin Oncol Res 2(1): 1004, 1-9, 2014.

Clinical Speciality:

Translational Research

Lab Techniques and Equipment:

Cellular and Molecular Biology


Current Grant Support:

07/01/13-06/30/18 - Lead and contact PI
NIH: NCI MPIs RO1 CA177981-01
David Weber co-PI (10% effort)
Rational targeting of protein translation for cancer treatments

11/01/11-3/31/14 - Co- Investigator
Principal Investigator: Dr. Navesh Sharma
A Phase II Study of Low-Dose Fractionated Whole abdomen radiation therapy (LDFRT) as a chemosensitizer in patients with peritoneal carcinomatosis from gastric or gastroesophageal junction primary adenomacarcinomas.
Department of Radiation Oncology
Pilot Project Program

09/11/12-03/11/14 - Co-Investigator
Principal Investigators: Drs. Curt Civin and David Weber
UMGCC pilot grant application to support the development of a multi PI grant application


Honors & Awards:

  • 1990: International fellowship. Among the first awardees of a Long-term postdoctoral fellowship from the Human Frontier Science Program Organization.
  • 1991: International fellowship. Visiting associate Fellowship from the National Institutes of Health
  • 1994: Co-author on the second most-cited paper in biology in 1994. Science Watch, September 1994, p.5; Kastan, M., B., Zan, Q., El-Deiry, W., S., Carrier, F., Jacks, T., Walsh, W., V., Plunkett, B., S.,Vogelstein, B., Fornace, A.J.,Jr. A Mammalian cell cycle checkpoint pathway utilizing p53 and GADD 45 is defective in Ataxia Telangiectasia. Cell 71: 587-597
  • 1992 1998, 1999: Intramural award entitled: "Induction of Mammalian RNA-Binding Proteins" from the office of the Dean, University of Maryland, School of Medicine
  • 2001: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
  • 2002: Sponsor: Brigid Leventhal Award from the American Association for Cancer Research (Myoung Sook Kim).
  • 2002: Sponsor: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
  • 2003: Sponsor: Graduate Student Research Day Award, 1st Place in Molecular Biology (Jing Lin)
  • 2003: Sponsor: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
  • 2004-present: Biography selected for publication in Who's Who in America
  • 2004-present: Biography selected for publication in Who's Who in the World
  • 2004-2007: National Kidney Foundation. Post-doctoral fellowship (Devulapalli Chakravarty) Editorial board: Cancer Research, J.Clinical Oncology and Research

Patents:

  • 1994 - Patent: U.S. No. 5,858,679
    European patent # WO 9411533
    Title: Methods for determining the presence of functional p53 in mammalian cells.Addendum: Development and use of Gadd45 antibody. Licensed by Santa Cruz Biotech., Santa Cruz, California.
  • 2006 - European Patent: 03723795.5-2123-US0308678
    Title: Inhibitors of the S100-p53 protein-protein interaction and method of inhibiting cancer employing the same.
  • 2008 - Australian patent Number 2003230705 issued September 11, 2008 for the above mentioned patent.
  • 2011 - Patent: U.S. No. 8,053,477 issued on November 8, 2011.
    Authors: David J. Weber, Alex MacKerell, Joseph Markowitz, France Carrier
    Title: Inhibitors of the S100-p53 Protein-Protein Interaction and Method of Inhibiting Cancer Employing the Same.
  • 2013 - Patent: U.S. No. 8,367,340 issued on February 5, 2013.
    Authors: France Carrier, Narasimharao Nalabothula
    Title: Diagnostic tools to predict the efficiency of anticancer drug treatment targeting chromatin DNA or enzymes acting on the DNA

Publications:

Kastan, M., B., Zhan, Q., El-Deiry, W., S., Carrier, F., Jacks, T., Walsh, W., V., Plunkett, B., S., Vogelstein, B., Fornace, A.J.,Jr. A Mammalian cell cycle checkpoint pathway utilizing p53 and GADD 45 is defective in Ataxia Telangiectasia. Cell, 71: 587-597, 1992. Times Cited: 2682

Zhan, Q., Carrier, F., and Fornace, Jr., A. J. Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol. Cell. Biol., 13, 4242-4250, 1993. Times Cited: 416

Carrier, F., Georgel, P.T., Pourquier, P., Blake, M., Kontny,H.U., Antinore, M.J., Gariboldi, M., Myers, T. G, Weinstein, J.N., Pommier,Y,and Fornace, A.J., Jr. Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol. Cell. Biol. 19: 1673-1685, 1999. Times Cited: 94

Yang, C. and Carrier, F. The UV-inducible RNA binding protein A18 (A18 hnRNP) plays a protective role in the genotoxic stress-response. J.Biol.Chem., Dec 14: 276(50):47277-47284, 2001. Times Cited: 17

Yang, C., Maiguel, D.A., and Carrier, F. Identification of Nucleolin and Nucleophosmin as genotoxic stress-responsive RNA binding proteins. Nucl. Acids Res., 30 (10):2251-2260, 2002. Times Cited: 35

Kim, M.S., Blake, M., Baek, J.H., Kohlhagen, G., Pommier, Y., and Carrier, F#. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Research, 63, 7291-7300, 2003. Times Cited: 107

Cha, H., Hancock, C., Dangi, S., Maiguel, D., Carrier, F., and Shapiro, P. Phosphorylation regulates nucleophosmin targeting to the centrosome during mitosis as detected by cross reactive phosphorylation specific MKK1/2 antibodies. Biochem.J, 378, 857-865, 2004.

Maiguel, D.A., Jones, L., Chakravarty, D., Yang, C., and Carrier, F. Nucleophosmin sets a threshold for p53 response to UV radiation. Molecular and Cellular Biology, 24, 9, 3703-3711, 2004.

Lin, J., Yang, Q., Yan, Z., Markowitz, J.M., Wilder, P., Carrier, F and Weber, D.J. Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J.Biol.Chem. August 6: 279 (32), 34071-34077, 2004.

Markowitz, J., Chen, I., Gitti, R., Baldisseri, D.M., Pan, Y., Udan, R., Carrier, F., MacKerell, A.D., Jr., Weber, D.J. Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction. J. Med. Chem., 47, 5085-5093, 2004.

Kim, M.S., Baek, J.H., Chakravarty, D., Sidransky, D. and Carrier, F.. Sensitization to UV-induced apoptosis by the histone deacetylase inhibitor Tricostatine A. Experimental Cell Research, 306, 94-102, 2005.

Markowitz, J., MacKerell, A.D., Jr., Carrier, F., Charpentier, T.H., Weber, D.J. Design of Inhibitors for S100B. Current Topics in Medicinal Chemistry, 5, 1093-1108, 2005.

Yang, R., Weber, D.J. and Carrier, F#. Post-transcriptional regulation of thioredoxin by the stress-inducible hnRNP A18. Nucleic Acid Research, 34 (4), 1224-1236, 2006.

Wilder, P.T., Lin, J., Bair, C.L., Charpentier, T.H., Yang, D., Liriano, M., Varney, K.M., Lee, A., Oppenheim, A.B., Adhya, S., Carrier, F., Weber, D.J. Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B. Biochim Biophys Acta-Molecular Cell Research, 1763 (11):1284-1297 Sp. Nov 2006.

Yang, R., Zhan, M., Nalabothula, N., Yang, Q., Indig, F.E., Carrier, F. Functional significance for an heterogenous ribonucleoprotein A18 (hnRNP A18) signature RNA motif in the 3'UTR of Ataxia Telangiectasia Mutated and Rad3 related (ATR) transcript. J.Biol.Chem. March 19: 285 (12), 8887-8893, 2010.

Lin, J., Yang, Q., Wilder, P.T., Carrier, F (corresponding author), and Weber, D.J. The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J.Biol.Chem, 2010. Aug 27;285(35):27487-98.

Nalabothula, N. Chakravarty, D.,Pierce, A. Carrier, F. Over expression of Nucleophosmin and Nucleolin contributes to the suboptimal activation of a G2/M checkpoint in Ataxia Telangiectasia fibroblasts. Mol.Cell.Pharmacol.,2(5), 179-189, 2010.

Abdelmohsen, K., Tominaga, K., Lee, E-K., Srikantan, S., Kang, M.J., Kim, M., Selimyan, R., Martindale, J.,Yang, X., Carrier, F., Zhan, M., Becker, K., Gorospe, M. Enhanced translation by Nucleolin via G-rich elements in coding and non-codingregions of target mRNAs. Nucleic Acids Res. 2011, Vol. 39, No. 19 8513â?"8530.

Indig, F.E., Rybanska, I., Karmakar, P., Devulapalli, C., Haiqing, F., Carrier, F. and Bohr, V.A. Nucleolin inhibits G4 oligonucleotide unwinding by Werner Helicase. PLoS One. 2012;7(6):e35229. Epub 2012 Jun 4.

Gojo, I,Tan, M, Fang, H-B, Sadowska, M., Lapidus, R., Baer, M.R., Carrier, F., Beumer,J.H., Anyang, B.N., Srivastava, R.K., Espinoza-Delgado, I.and Ross. D.D. Translational phase I trial of vorinostat combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clinical Cancer Res. Apr 1;19(7):1838-1851. Epub 2013 Feb 12., 2013.

Diss, E, Nalabothula, N, Nguyen, DM, Chang, E., Kwok, Y., Carrier, F. Vorinostatsaha promotes hyper-radiosensitivity in wild type p53 human glioblastoma cells. Journal of Clinical Oncology and Research, JSM Clin Oncol Res 2(1): 1004, 1-9, 2014.

Recent Reviews:

Nalabothula, N. and Carrier, F. Cancer cells' epigenetic composition and predisposition to HDACi sensitization. Epigenomics, April, Vol. 3, No. 2, Pages 145-155, 2011.

Pamboukian, R and Carrier, F. hnRNP A18: A new pathway to regulate protein translation in cancer cells. Molecular and Cellular Pharmacology, 4(1):41-48, 2012.

Invited guest editor: Carrier, F. New insights in the cellular and molecular response to Radiation Therapy. Molecular and Cellular Pharmacology, 5(1):3-4, 2013.

Carrier, F. Chromatin modulation by Histone Deacetylase Inhibitors; impact on cellular sensitivity to ionizing radiation. Molecular and Cellular Pharmacology, 5(1):51-59, 2013.