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Faculty Detail     Name CHARLES N. LANDEN, JR.   Campus Address 176F 1025 Zip 7333 Phone 205-934-4986 E-mail clanden@uab.edu Other websites

Faculty Appointment(s) Appointment Type Department Division Rank Primary  OB/GYN   OB/GYN Chair Office Associate Professor Secondary  Cell, Developmntl, & Integrative Biology  Cell, Developmntl, & Integrative Biology Associate Professor Secondary  Pathology   Pathology Chair Office Assistant Professor Center  Comprehensive Cancer Center  Comprehensive Cancer Center Associate Professor Center  General Clinical Research Center  Ctr for Clinical & Translational Sci Associate Professor

Graduate Biomedical Sciences Affiliations Medical Scientist Training Program

Biographical Sketch  Charles obtained his Bachelor's and Doctor of Medicine degrees from the University of North Carolina at Chapel Hill. He completed a residency in Obstetrics and Gynecology at the Medical University of South Carolina in Charleston, SC, with a one-year postdoctoral fellowship in the Department of Microbiology/Immunology. He was a fellow in Gynecologic Oncology at MD Anderson Cancer Center, during which he obtained a Master in Science, focus on Cancer Biology, at the University of Texas Graduate School in Biomedical Sciences in Houston, TX. After completion of fellowship he sayed at MD Anderson as an Assstant Professor in research, as part of K12 award. he then accepted an Assistnat Professor position at the University of Alabama at Birmingham in July 2009. His time is divided at 80% research and 20% clinical/surgical duties.

Society Memberships Organization Name Position Held Org Link American Association of Cancer Research      American College of Obstetricians and Gynecologists      American Society of Clinical Oncology      Felix Rutledge SOciety      Society of Gynecologic Oncology      UAB Griffin Society

Research/Clinical Interest Title Targeting novel pathways of chemoresistance in ovarian cancer Description Our laboratory is interested in understanding the pathophysiology of ovarian cancer in an effort to improve outcomes for patients with this disease. To that end, we are examining several pathways, processes, and preclinical models of disease to allow identification and testing of potential therapeutic agents and approaches. One interest of ours is in the cancer stem cell hypothesis. This hypothesis holds that there is a small subset of tumors, on the order of less that 5%, that has enhanced tumorigenicity, differentiation potential, and resistance to therapy compared to the majority of the tumor. Subpopulations within the tumor can be separated and examined for such endpoints. Thus far populations that express CD44, c-kit, BCRP, and/or CD133 have shown properties of ovarian cancer stem cells (CSC’s) or tumor-initiating cells (TIC’s). We are examining whether another population, which expresses aldehyde dehydrogenase (ALDH), has similar properties. ALDH plays a role in differentiation, detoxification, and chemoresistance to some agents. It may prove to be a valid target for therapy, as our initial findings suggest that downregulation of ALDH sensitizes ovarian cancer cells to both platinum and taxane agents, both in vitro and in vivo. In addition to characterizing the properties of the ALDH-positive population, we are interested in identifying other markers or pathways that may be active in this highly aggressive population. We are developing models of neoadjuvant therapy, and examining patient specimens that will allow identification of the cells most capable of surviving chemotherapy. Once this population can be isolated, we will be able to characterize the pathways on which it depends for chemoresistance, and identify novel targets for therapy against this specialized population. One pathway important to both normal and cancer stem cell biology appears to be the Notch pathway. The Notch family of receptors and their ligands, Jagged and DLL, have been shown to contribute to malignant progression in ovarian and other cancers. We are studying whether members of these pathways are potential targets for therapy, the role they may play in the stem cell population, and whether this pathway exhibits crosstalk with other pathways important to malignant progression and chemoresistance. Through these efforts, we hope to identify important mediators of malignant progression and chemoresistance in ovarian cancer, characterize the potential of various agents and approaches to treatment in preclinical models, which can then be taken to the clinic for phase I and II trials in patients.

Selected Publications  Publication PUBMEDID Landen CN, Klingelhutz A, Coffin JE, Sorosky JI, Sood AK. Genomic instability is associated with lack of telomerase activation in ovarian cancer. Cancer Biol Ther. 3(12): 1250-53, 2004. Landen CN Jr, Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G, Sood AK. Therapeutic EphA2 gene targeting in vivo using neutral liposomal siRNA delivery. Cancer Research 65(15): 6910-18, 2005. Landen CN, Kinch MS, Sood AK. EphA2 as a target for ovarian cancer therapy. Expert Opin Ther Targets 9(6): 1179-1187, 2005. Landen CN, Lu C, Han LY, Coffman KT, Bruckheimer E, Halder J, Mangala LS, Merritt WM, Lin YG, Gao C, Schmandt R, Kamat AA, Li Y, Thaker P, Gershenson DM, Parikh NU, Gallick GE, Kinch MS, Sood AK. Efficacy and antivascular mechanisms of EphA2 downregulation with an agonistic antibody in ovarian cancer. JNCI 98(21): 1558-70, 2006. Landen CN, Merritt WM, Mangala LS, Sanguino AM, Bucana C, Lu C, Lin YG, Han LY, Kamat AA, Schmandt R, Coleman RL, Gershenson DM, Lopez-Berestein G, Sood AK. Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer. Cancer Biol Ther 5(12): 1708-13, 2006. Landen CN Jr, Lin YG, Immaneni A, Deavers MT, Merritt WM, Spannuth WA, Bodurka DC, Gershenson DM, Brinkley WR, Sood AK. Overexpression of the centrosomal protein Aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients. Clin Cancer Res 13(14):4098-104, 2007. Landen CN Jr, Lin YG, Armaiz Pena GN, Das PD, Arevalo JM, Kamat AA, Han LY, Jennings NB, Spannuth WA, Thaker PH, Lutgendorf SK, Savary CA, Sanguino AM, Lopez-Berestein G; Cole SW, Sood AK. Neuroendocrine modulation of STAT3 in ovarian cancer. Cancer Res, 67(21):10389-96, 2007. Landen CN Jr, Birrer MJ, Sood AK. Early genetic events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol 26(6): 995-1005, 2008. Landen CN, Kim TJ, Lin YG, Merritt WM, Kamat AA, Han LY, Spannuth WA, Nick AM, Jennnings NB, Kinch MS, Tice M, Sood AK. Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer. Neoplasia 10(11): 1259-67, 2008. Landen CN, Goodman B, Katre AA, Steg AD, Nick AM, Stone RL, Miller LD, Mejia PV, Jennings NB, Gershenson DM, Bast RC, Jr., Coleman RL, Berestein G, and Sood AK. Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer. Molecular Cancer Therapeutics 9(12): 3186-99, 2010. Steg AD, Katre AA, Goodman B, Han HD, Nick AM, Stone RL, Coleman RL, Alvarez RD, Lopez-Berestein G, Sood AK, Landen CN. Targeting the Notch Ligand Jagged1 in Both Tumor Cells and Stroma in Ovarian Cancer. Clin Can Res, 17(17): 5674-85, 2011. Steg AS, Bevis KS, Katre AA, Ziebarth A, Alvarez RD, Zhang K, Conner M, Landen CN. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Can Res, 18(3):869-81, 2012. Ziebarth AJ, Landen CN Jr, Alvarez RD. Molecular/genetic therapies in ovarian cancer: future opportunities and challenges. Clin Obstet Gynecol, 55(1):156-72, 2012. Steg AS, Katre AA, Bevis KS, Ziebarth A, Dobbin ZC, Shah MS, Alvarez RD, Landen CN. Smoothened Antagonists Reverse Taxane Resistance in Ovarian Cancer. Mol Cancer Ther, in press.

Keywords ovarian cancer, small interfering RNA, cancer stem cells, chemoresistance, ALDH1, Notch, Jagged

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