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Francis Swaby Markland, PhD

Title(s)Professor of Biochemistry & Molecular Medicine
SchoolKeck School of Medicine of USC
Phone+1 323 442 2747
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    Collapse Biography 
    Collapse Education and Training
    Penn State University, State College, PAB.S.06/1957Ag. Bio. Chem.
    Johns Hopkins University Medical School, Baltimore, MDPh.D.02/1964Physiological Chemistry
    Collapse Awards and Honors
    UCLA1968  - 1973NIH Career Development Award

    Collapse Overview 
    Collapse Overview
    DISINTEGRINS - EFFECTIVE INHIBITORS OF CANCER INVASION AND DISSEMINATION:
    We have been studying a peptide from southern copperhead snake venom that we call contortrostatin (CN). CN is a homodimer with two identical chains held together by two inter-chain disulfide bonds. The peptide possesses potent anti-tumor and anti-invasive activity. CN is a member of a family of peptides called disintegrins that are found in snake venoms. Many members of this family are distinguished by the presence of an amino acid sequence, arginine-glycine-aspartic acid (RGD), that enables them to bind to a subset of cell surface receptors called integrins found on cancer cells and newly growing (angiogenic) blood vessels supplying the tumor. Integrins mediate interactions between cells and their surroundings, and on cancer cells they play important roles in tumor invasion and dissemination. We postulated that since contortrostatin disrupts integrin interactions, it should block both cancer cell and newly growing blood vessel cell integrins and may, therefore, have significant anti-angiogenic and anti-metastatic activity. We have shown that CN acts as an effective inhibitor of breast cancer progression. Importantly, CN displays impressive inhibitory activity on the growth of new blood vessels into the breast cancer. But, there is a problem with CN and that is it is present in snake venom in very small quantities, making its translation to the clinic very difficult. However, we recently succeeded in producing a recombinant version of CN using an E. coli expression system. The recombinant protein is a monomer, called vicrostatin (VCN), purposefully designed with a slightly different amino acid sequence at its COOH-terminus to improve binding affinity to an important member of the integrin family. Using a delivery system in which VCN is encapsulated in unilamellar lipid particles (liposomes), we have shown that intravenous delivery of the liposomal formulation (LVCN) twice weekly in animal models of human, triple-negative, metastatic breast cancer, or human prostate cancer, leads to close to 80% inhibition of tumor growth and angiogenesis. More recently we have been examining the effect of VCN introduced intraperitoneally on the growth of human ovarian cancer cells in mice and have observed potent inhibition of tumor growth and dissemination. Presently we are studying human breast, prostate and ovarian cancer and glioma (a devastating brain tumor) animal models to demonstrate the anti-invasive and anti-tumor activities of VCN. We are also examining the mechanism by which VCN dramatically disrupts the actin cytoskeleton of cancer and angiogenic blood vessel cells leading to an abrupt halt to the locomotor apparatus of these cells. Finally, we are examining the diagnostic activity of VCN as an imaging agent to detect integrin positive cancer in prostate cancer mouse model studies, and then use VCN to treat the tumor.
    In separate studies we are examining another class of related proteins derived from members of the ADAM (A Disintegrin and Metalloproteinase domain) family. We are able to recombinantly produce large quantities of the disintegrin domain (DD) of the ADAM proteins using a highly engineered bacterial expression system. One of these ADAM DDs has interesting antitumor activity based on its interaction with integrins on the tumor cell surface. Since members of the ADAM family have different structures of their DDs, we are interested in characterizing the integrin binding specificities and affinities of these ADAM DDs and characterizing their biological activities with potential application to human cancer or other diseases.

    Collapse Research 
    Collapse Research Activities and Funding
    Development of a combination therapy for the treatment of prostate cancer
    NIH/NCI R41CA126001Aug 13, 2007 - Jul 31, 2009
    Role: Principal Investigator
    Liposomal Disintegrin: Novel and Effective Antitumor Agent Phase I
    NIH/NCI R41CA121452May 4, 2007 - Apr 30, 2009
    Role: Principal Investigator
    Antiidiotype mAb:an Antiangiogenic /Antimetastatic Agent
    NIH/NCI R41CA096368Mar 1, 2002 - Feb 28, 2004
    Role: Principal Investigator
    TREATMENT OF OVARIAN CANCER WITH CONTORTROSTATIN
    NIH/NCI R41CA089848Sep 11, 2001 - Aug 31, 2004
    Role: Principal Investigator
    THROMBOLYSIS BY RAPID DIRECT-ACTING FIBRINOLYTIC AGENTS
    NIH/NHLBI R01HL031389Jan 1, 1984 - Dec 31, 1987
    Role: Principal Investigator
    CHARACTERIZATION OF THE MAMMARY GLUCOCORTICOID RECEPTOR
    NIH/NCI R01CA022910Jan 1, 1979 - Dec 31, 1986
    Role: Principal Investigator

    Collapse ORNG Applications 
    Collapse Required Scholarly Project Mentor

    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
    List All   |   Timeline
    1. Swenson S, Minea RO, Tuan CD, Thein TZ, Chen TC, Markland FS. A Novel Venom-Derived Peptide for Brachytherapy of Glioblastoma: Preclinical Studies in Mice. Molecules. 2018 Nov 08; 23(11). PMID: 30413113.
      View in: PubMed
    2. Janib SM, Gustafson JA, Minea RO, Swenson SD, Liu S, Pastuszka MK, Lock LL, Cui H, Markland FS, Conti PS, Li Z, MacKay JA. Multimeric disintegrin protein polymer fusions that target tumor vasculature. Biomacromolecules. 2014 Jul 14; 15(7):2347-58. PMID: 24871936; PMCID: PMC4098058.
    3. Levine M, Swenson S, McCormick T, Henderson SO, Thomas SH, Markland FS. Reversal of thienopyridine-induced platelet dysfunction following desmopressin administration. J Med Toxicol. 2013 Jun; 9(2):139-43. PMID: 23161280; PMCID: PMC3657025.
    4. Lee JY, Markland FS, Lucchesi BR. Hirudin and s18886 maintain luminal patency after thrombolysis with alfimeprase. J Cardiovasc Pharmacol. 2013 Feb; 61(2):152-9. PMID: 23188127.
      View in: PubMed
    5. Markland FS, Swenson S. Snake venom metalloproteinases. Toxicon. 2013 Feb; 62:3-18. PMID: 23000249.
      View in: PubMed
    6. Hubbard S, Choudhary S, Maus E, Shukla D, Swenson S, Markland FS, Tiwari V. Contortrostatin, a homodimeric disintegrin isolated from snake venom inhibits herpes simplex virus entry and cell fusion. Antivir Ther. 2012; 17(7):1319-26. PMID: 22875654.
      View in: PubMed
    7. Minea R, Helchowski C, Rubino B, Brodmann K, Swenson S, Markland F. Development of a chimeric recombinant disintegrin as a cost-effective anti-cancer agent with promising translational potential. Toxicon. 2012 Mar 15; 59(4):472-86. PMID: 21354198; PMCID: PMC3130806.
    8. Lin E, Wang Q, Swenson S, Jadvar H, Groshen S, Ye W, Markland FS, Pinski J. The disintegrin contortrostatin in combination with docetaxel is a potent inhibitor of prostate cancer in vitro and in vivo. Prostate. 2010 Sep 01; 70(12):1359-70. PMID: 20623636.
      View in: PubMed
    9. Minea RO, Helchowski CM, Zidovetzki SJ, Costa FK, Swenson SD, Markland FS. Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities. PLoS One. 2010 Jun 03; 5(6):e10929. PMID: 20532165; PMCID: PMC2880590.
    10. Markland FS, Swenson S. Fibrolase: trials and tribulations. Toxins (Basel). 2010 04; 2(4):793-808. PMID: 22069611; PMCID: PMC3153196.
    11. Helchowski CM, Minea RO, Swenson SD, Markland FS. The use of pepsin in receptor internalization assays. Biochem Biophys Res Commun. 2009 Oct 16; 388(2):240-6. PMID: 19665997.
      View in: PubMed
    12. Moiseeva N, Bau R, Swenson SD, Markland FS, Choe JY, Liu ZJ, Allaire M. Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1.7 A resolution. Acta Crystallogr D Biol Crystallogr. 2008 Apr; 64(Pt 4):466-70. PMID: 18391413.
      View in: PubMed
    13. Swenson S, Ramu S, Markland FS. Anti-angiogenesis and RGD-containing snake venom disintegrins. Curr Pharm Des. 2007; 13(28):2860-71. PMID: 17979731.
      View in: PubMed
    14. Pyrko P, Wang W, Markland FS, Swenson SD, Schmitmeier S, Schönthal AH, Chen TC. The role of contortrostatin, a snake venom disintegrin, in the inhibition of tumor progression and prolongation of survival in a rodent glioma model. J Neurosurg. 2005 Sep; 103(3):526-37. PMID: 16235686.
      View in: PubMed
    15. Schmitmeier S, Markland FS, Schönthal AH, Chen TC. Potent mimicry of fibronectin-induced intracellular signaling in glioma cells by the homodimeric snake venom disintegrin contortrostatin. Neurosurgery. 2005 Jul; 57(1):141-53; discussion 141-53. PMID: 15987550.
      View in: PubMed
    16. Swenson S, Markland FS. Snake venom fibrin(ogen)olytic enzymes. Toxicon. 2005 Jun 15; 45(8):1021-39. PMID: 15882884.
      View in: PubMed
    17. Golubkov V, Garcia A, Markland FS. Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005 Jan-Feb; 25(1A):249-53. PMID: 15816545.
      View in: PubMed
    18. Minea R, Swenson S, Costa F, Chen TC, Markland FS. Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent. Pathophysiol Haemost Thromb. 2005; 34(4-5):177-83. PMID: 16707923.
      View in: PubMed
    19. Swenson S, Costa F, Ernst W, Fujii G, Markland FS. Contortrostatin, a snake venom disintegrin with anti-angiogenic and anti-tumor activity. Pathophysiol Haemost Thromb. 2005; 34(4-5):169-76. PMID: 16707922.
      View in: PubMed
    20. Swenson S, Costa F, Minea R, Sherwin RP, Ernst W, Fujii G, Yang D, Markland FS. Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Mol Cancer Ther. 2004 Apr; 3(4):499-511. PMID: 15078994.
      View in: PubMed
    21. Schmitmeier S, Markland FS, Ritter MR, Sawcer DE, Chen TC. Functional effect of contortrostatin, a snake venom disintegrin, on human glioma cell invasion in vitro. Cell Commun Adhes. 2003 Jan-Feb; 10(1):1-16. PMID: 12881036.
      View in: PubMed
    22. Golubkov V, Hawes D, Markland FS. Anti-angiogenic activity of contortrostatin, a disintegrin from Agkistrodon contortrix contortrix snake venom. Angiogenesis. 2003; 6(3):213-24. PMID: 15041797.
      View in: PubMed
    23. Moiseeva N, Swenson SD, Markland FS, Bau R. Purification, crystallization and preliminary X-ray analysis of the disintegrin contortrostatin from Agkistrodon contortrix contortrix snake venom. Acta Crystallogr D Biol Crystallogr. 2002 Dec; 58(Pt 12):2122-4. PMID: 12454474.
      View in: PubMed
    24. Markland FS, Shieh K, Zhou Q, Golubkov V, Sherwin RP, Richters V, Sposto R. A novel snake venom disintegrin that inhibits human ovarian cancer dissemination and angiogenesis in an orthotopic nude mouse model. Haemostasis. 2001 May-Dec; 31(3-6):183-91. PMID: 11910184.
      View in: PubMed