The Lankenau Institute for Medical Research
Association: Resident Faculty
About her work
Dr. Gilmour is defining mechanisms by which tumor modifiers, such as polyamines and thrombin, support and accelerate the development of cancer to a malignant, metastatic state. Her overriding goal is to translate her findings about the role of polyamines in cancer to polyamine-targeted therapies that can contribute to increased survival in cancer patients.
Awards and honors
Polyamines and thrombin modify cancer cells to drive the development of malignant and metastatic tumors.
Polyamines are ubiquitous, small molecules that are essential for all cell growth and proliferation. Their cellular content is highly regulated in normal cells, and their dysregulation contributes to many disease states. The polyamines that are synthesized in mammalian cells are putrescine, spermidine and spermine.
Thrombin is an enzyme in blood plasma that causes the clotting of blood by converting fibrinogen to fibrin. Thrombin is generated as the result of a cascade of coagulation factors. Many of these coagulation factors are increased in tumor cells, resulting in the generation of thrombin and increased thrombotic complications (pulmonary embolism and blood clots) in cancer patients.
Polyamines are small molecules found in all cells. However, when compared to normal cells, the levels of polyamines are dramatically increased in tumor cells due to the tumor’s robust dependence on polyamines for growth and survival. Dr. Gilmour is elucidating mechanisms by which polyamines promote cancer by acting on the immune response, new blood vessel development (i.e., angiogenesis), and tissue-regenerating cells (i.e., stem cells).
Her work has demonstrated that increased polyamine levels activate a kind of tissue remodeling that is normally seen during wound healing and that promotes cancer development. That is, she has demonstrated that polyamines have a causal role in tumor development. Dr. Gilmour’s lab is testing a novel therapy to starve tumors of polyamines; the therapy involves blocking the synthesis of polyamines and the polyamine uptake system that brings polyamines from outside of the tumor cell into the cell. They recently demonstrated that this novel approach to polyamine depletion suppresses tumor growth in a T cell-dependent manner, highlighting a poorly appreciated role of polyamines as strong modulators of antitumor immune responses.
In addition, ongoing preclinical studies in collaboration with Dr. Otto Phanstiel at the University of Central Florida are investigating new polyamine-containing drugs that selectively enter and kill tumor cells in a “Trojan horse” approach.
Arsenic-induced skin cancer: A second project Dr. Gilmour is working on involves investigating how arsenic causes cancer. Exposure to arsenic via the drinking water is a widespread and a major public health problem; indeed, exposure to even low levels of arsenic can lead to various cancers, including skin cancer. Although epidemiological association between chronic arsenic exposure and skin cancer is strong, the mechanisms contributing to arsenic-induced cancer remain elusive.
To identify targets for new therapeutic interventions to prevent and/or treat arsenic-induced inflammation and skin cancer, Dr. Gilmour is investigating a novel mechanism for the development of skin cancer in adults following fetal arsenic exposure via the pregnant mother. Her studies using mice have shown that if a pregnant female drinks water laced with trace amounts of arsenic, her progeny have a higher incidence of cancer, primarily skin tumors. This work is important because areas of the United States have relatively high levels of arsenic in their drinking water as the result of arsenic leaching out of bedrock into water reservoirs.
Thrombin research: Dr. Gilmour also is investigating whether inhibition of thrombin can block tumor progression. This latest project is based on the observation that, in breast cancer, intravascular coagulation increases with cancer progression and is associated with poor prognosis. It is thought that thrombin may directly contribute to cancer spread.
Anticoagulants that block thrombin generation may be able to help patients by inhibiting the spread of cancer. In collaboration with Boerhinger Ingelheim Pharma, the Gilmour lab is conducting preclinical studies to examine the anti-tumor effect of a new oral thrombin inhibitor, dabigatran etexilate. Using two mouse models of tumor metastasis (breast cancer and ovarian carcinoma models), the Gilmour lab has found that co-treatment with dabigatran significantly increases the anti-tumor and anti-metastatic activity of low doses of standard chemotherapeutic agents (cisplatin or cyclophosphamide).
Dr. Gilmour is investigating possible mechanisms for this synergistic tumor inhibition with dabigatran and a cytotoxic chemotherapeutic agent. Results from their studies suggest that dabigatran may be useful in not only managing thrombotic complications frequently associated with malignancy, but also in preventing tumor growth and metastasis.
Dr. Gilmour is looking ahead to test 1) if her polyamine-blocking therapy can enhance new cancer immunotherapies, and 2) therapeutic strategies using new anticoagulants (“blood thinners”) to block the spread of cancer. Her ground-breaking research has been almost continuously supported by NIH funds throughout her career, and she has received grants from industry and foundations.
Polyamine antagonist therapies inhibit neuroblastoma initiation and progression. Evageliou NF, Haber M, Vu A, Laetsch TW, Murray J, Gamble LD, Cheng NC, Liu K, Reese M, Corrigan KA, Ziegler DS, Webber HT, Hayes CS, Pawel BR, Marshall GM, Zhao H, Gilmour SK, Norris MD, Hogarty MD. Clin Cancer Res. 2016 Mar 24.
Thrombin Inhibition and Cyclophosphamide Synergistically Block Tumor Progression and Metastasis. Alexander ET, Minton AR, Hayes CS, Goss A, Van Ryn J, Gilmour SK. Cancer Biol Ther. 2015 Sep 18:0.
1-Methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis. Pigott E, DuHadaway JB, Muller AJ, Gilmour S, Prendergast GC, Mandik-Nayak L. Autoimmunity. 2014 Sep;47(6):409-18. Epub 2014 May 6.
Polyamine blockade promotes antitumor immunity. Hayes CS, Burns MR, Gilmour SK. OncoImmunology. 2014 Jan 1;3(1):e27360.
Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Hayes CS, Shicora A, Keough M, Snook A, Burns M, Gilmour S. Cancer Immunology Research. 2014 2(3):274-285.
Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites. Hayes CS, DeFeo-Mattox K, Woster PM, Gilmour SK. Amino Acids. 2014 Mar;46(3):543-52. Epub 2013 Jul 25.