Dr Rachel Gibson

Research Interests

Chemotherapy-induced diarrhoea: role of the gut microbiome
The Human Microbiome Project (HMP) has been recently established and is identifying novel methods of thinking about the role of the human microbiome in determining predisposition to a range of pathologies (Turnbaugh, 2007 Nature 449:804) including chemotherapy-induced diarrhoea (CID).  Furthermore the HMP is defining parameters which are fundamental to develop strategies to manipulate the microbiome (Turnbaugh, 2007 Nature 449:804).  With this in mind, this study has been designed to firmly establish that the human gut microbiome plays a key role in the development of CID.  Our previous published studies have clearly demonstrated that bacterial changes occur prior to the onset of diarrhoea (Stringer et al, 2008, Cancer Biol Ther; Stringer et al, 2009 Int J Exp Path). The aim of this proposal is to conduct a larger time course study in the clinic to further measure the changes to the gastrointestinal microbiome and correlate these with circulating pro-inflammatory cytokine changes.  Results from this study will impact clinical practice by identifying clinically relevant biomarkers allowing for early intervention and management of patients with chemotherapy-induced diarrhoea.  This study will examine the gastrointestinal microbiome using both qualitative microbiology and quantitative real time PCR in patients receiving chemotherapy, which our group has established and validated the protocols.  Changes in faecal flora will be investigated using our established methods and correlated with circulating pro-inflammatory cytokine expression.  This shall determine how these changes relate specifically to the diarrhoea observed following chemotherapy and will allow the determination of specific clinically relevant biomarkers for the development of chemotherapy-induced diarrhoea.  Students will be exposed to a wide range of techniques including: clinical patient recruitment, routine microbiological techniques, ELISA’s, RT-PCR, immunohistochemistry, and histopathology.

Cytokines and chemotherapy-induced diarrhoea
In recent years it has been realised that various cytokines play important roles in the pathogenesis of mucositis.  Previous studies have demonstrated that cytokines that target epithelial cell proliferation such as epidermal growth factor (EGF) (Sonis et al., 1992 Oral Surg, Oral Med Oral Path, 74: 749) or transforming growth factor-beta 3 (TGF-β3) (Sonis, 1997, Oral Oncol 33:47) modified the course of mucositis in animal models.  More recently, studies in our laboratory have clearly demonstrated that the transcription factor NF-kB is upregulated in the mucosa following chemotherapy (Logan 2008 Cancer Biol Ther).  NF-kB results in the upregulation of pro-inflammatory cytokines (TNF, IL-1B and IL-6), which play an important role in the pathogenesis of mucositis (Logan 2008 Cancer Biol Ther).  Much of the information regarding chemotherapy-induced diarrhoea in the published literature is based on clinical observations with very little basic science.  Recent research conducted in our laboratory has attempted to correct this anomaly and has found a correlation between chemotherapy-induced diarrhoea and an altered gastrointestinal microbiome (Stringer et al, 2008, Cancer Biol Ther; Stringer et al, 2009 Int J Exp Path).  In addition research has shown that circulating pro-inflammatory cytokines play a key role in the development of mucositis However, the role that anti-inflammatory cytokines play has not been determined.  This project aims to determine if the levels of anti-inflammatory cytokines alter in response to chemotherapy.  Students will be exposed to a wide range of techniques including ELISAs, RT-PCR, and immunohistochemistry.

Development of an animal model to study novel targeted therapies for cancer
Cancer treatment causes significant injury to normal "mucosal" tissues and is a major cause of morbidity in patients. Recently, a new class of therapy, known as “targeted therapy”, has been introduced into the clinical setting to treat cancers, with spectacular success. However, these targeted therapies can also cause significant damage to normal tissues. This damage is referred to as “mucosal injury” rather than “mucositis” as it is not caused by chemotherapy or radiotherapy, rather it is caused by a specific targeted small molecule.  Currently there is no established animal model available to investigate the mechanisms by which these small molecules induce mucosal injury. Therefore the aim of this study is to develop an appropriate animal model.  An accurate animal model will prove invaluable for the development of preventative treatments of targeted therapy-induced mucosal injury. Testing compounds in a clinically relevant animal model will streamline translation from bench to bedside.  This project will use the Wistar rat as the study animal as this species has an appropriate metabolic profile to study small molecules and previous pre-clinical work has been conducted in this species. Furthermore a tumour, known as Walker 256, spontaneously arose in this species, making it ideal to study.  Students will be exposed to a wide range of techniques including: small animal handling (including minor procedures), histological and histopathological techniques, immunohistochemistry and microdissection.

 

Research Funding

The Gut Microbiome Group
The Gut Microbiome Group is a recently established dynamic and innovative research laboratory in the School of Medical Sciences (Level 3, Medical School North) headed by Dr Rachel Gibson. As a branch of the internationally recognised Mucositis Research Group, the focus of their research is to investigate the toxic effects of chemotherapy on the gut microbiome (bacterial population) of cancer patients and the development of clinically diagnosed diarrhoea (a manifestation of intestinal mucositis).  Specific changes in the gut microbiome may lead to the development of a biomarker to predict the onset of the toxic effects of chemotherapy and improve patient care.  This novel research may also lead to the development of intervention agents to prevent or treat chemotherapy-induced mucositis and diarrhoea. The group members have extensive experience in a variety of techniques and are widely published in fields including, pathology, molecular biology, microbiology and immunology. Their studies are supported by access to the research laboratories first-class facilities and a stimulating work environment.

Group Members:
Laboratory Head: Dr Rachel Gibson
Visiting Research Fellow: Dr Andrea Stringer
Research Assistant: Ms Bronwen Mayo
Honours candidate: Mr Daniel Thorpe

Publications

Gibson, R.J., Leigh, C.M., and Breed, W.G., (2000). Unusual macromorphology of the ductuli efferentes and epididymis of the koala (Phascolarctos cinereus), Australian Journal of Zoology, 48: 681-689.
Gibson, R.J., Keefe, D.M.K., Thompson, F.M., Clarke, J.M., Goland, G.J. and Cummins, A.G., (2002). Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats, Digestive Diseases and Sciences, 47(12): 2751-2757
Gibson, R.J., Keefe, D.M.K., Clarke, J.M., Regester G.O., Thompson, F.M., Goland, G.J., Edwards, B.G., and Cummins, A.G., (2002). The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer, Cancer Chemotherapy and Pharmacology, 50: 53-58.
Gibson, R.J., Bowen, J.M., Inglis, M.R.B., Cummins, A.G., and Keefe, D.M.K., (2003). Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer, Journal of Gastroenterology and Hepatology, 18(9): 1095-1100.
Keefe, D.M.K., Gibson, R.J., and Hauer-Jensen M., (2004). Gastrointestinal mucositis, Seminars in Oncology Nursing, 20: 38-47.
Yeoh, A.S.J., Bowen, J.M., Gibson, R.J., and Keefe, D.M.K., (2005). Nuclear factor ?B (NF B) and cyclooxygenase-2 (Cox-2) expression in the irradiated colorectum is associated with subsequent histopathological changes, International Journal of Radiation, Oncology, Biology and Physics, 63(5):1295-1303.
Bowen, J.M., Gibson, R.J., Keefe, D.M. and Cummins, A.G., (2005). Cytotoxic chemotherapy increases proapoptotic Bax and Bak expression in crypts of the rat and human small intestine, Pathology, 37(1):56-62.
Gibson, R.J., Bowen, J.M., and Keefe, D.M.K., (2005). Palifermin reduces diarrhoea and increases survival following irinotecan treatment in tumour-bearing DA rats, International Journal of Cancer, 116(3):464-470.
Gibson, R.J., Bowen, J.M., Cummins, A.G., and Keefe, D.M.K., (2005). Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat, Clinical and Experimental Medicine, 4:188-195.
Yeoh, A.S.J., Gibson, R.J., Bowen, J.M., Stringer, A.M., Logan, R.M., Yeoh E, and Keefe, D.M.K., (2006) Radiation therapy-induced mucositis: Relationships between fractionated radiation, NF-kB, Cox-1 and Cox-2, Cancer Treatment Reviews 32: 645-651
Bowen, J.M., Gibson, R.J., Cummins, A.G., and Keefe, D.M.K., (2006). Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage, Journal of Supportive Care in Cancer, 14(7): 713-731.
Gibson, R.J., and Keefe, D.M.K., (2006). Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies, Journal of Supportive Care in Cancer, 14(9): 890-900.
Gibson, R.J., Cummins, A.G., Bowen, J.M., Logan, R.M., Healey, T and Keefe, D.M.K., (2006). Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy, Asia-Pacific Journal of Clinical Oncology, 2(1): 39-49.
Logan, R.M., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2006). Oral mucositis - clinical presentation, histological features and proinflammatory cytokine expression following cancer chemotherapy, Australian Dental Journal (special research supplement) 51(4): 518.
Gibson, R.J., Bowen, J.M., Alvarez, E., Finnie, J.W., and Keefe, D.M.K., (2007). Establishment of a single dose irinotecan model of gastrointestinal mucositis, Chemotherapy 53(5): 360-369.
Bowen, J.M., Gibson, R.J., Stringer, A.M., Chan, T.W., Prabowo, A.S., Cummins, A.G., and Keefe, D.M.K., (2006). The role of p53 in irinotecan-induced intestinal cell death and mucosal damage, Anti-Cancer Drugs (in press).
Stringer, A.M., Gibson, R.J., Logan, R.M., Bowen, J.M., Yeoh, A.S.J., and Keefe, D.M.K., (2006) Chemotherapy-induced mucositis: the role or gastrointestinal microflora and mucins in the luminal environment, Journal of Supportive Oncology 5(6): 259-26
Keefe, D.M.K., and Gibson, R.J., (2006). The combination of oral and small intestinal mucositis, paediatrics and biomarkers: a particularly tricky problem! - commentary, Cancer Biology and Therapy 5(10) 1282-1284.
Keefe, D.M.K., and Gibson, R.J., (2006). Sucrose Breath Testing and Intestinal Mucositis - Commentary, Cancer Biology and Therapy 5(9) 1196-1198.
Logan, R.M., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2007). Nuclear Factor B (NF B) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy, Oral Oncology 43(4) 395-401.
Bowen, J.M., Gibson, R.J., Tsykin, A., Cummins, A.G., and Keefe, D.M., (2007). Irinotecan changes gene expression profiles in the small intestine of the rat with breast cancer, Cancer Chemotherapy and Pharmacology 59(3): 337-348.
Stringer, A.M., Gibson, R.J., Logan, R.M., Bowen, J.M., Yeoh, A.S.J., Burns, J., Finnie, J.W., and Keefe, D.M., (2007). Chemotherapy-induced diarrhoea is associated with changes in the luminal environment in the DA rat, Experimental Biology and Medicine, 232(1): 96-107.
Logan, R.M., Stringer, A.M., Bowen, J.M., Yeoh, A.S.J., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2007). Pro-inflammatory cytokines in the pathobiology of chemotherapy-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs, Cancer Treatment Reviews 33(5): 448-460.
Stringer, A.M., Gibson, R.J., Logan, R.M., Bowen, J.M., Yeoh, A.S.J., Burns, J., Finnie, J.W., and Keefe, D.M., (2007). Chemotherapy-induced diarrhoea is associated with changes in the luminal environment in the DA rat, Experimental Biology and Medicine, 232(1): 96-107.
Logan, R.M., Stringer, A.M., Bowen, J.M., Yeoh, A.S.J., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2007). Pro-inflammatory cytokines in the pathobiology of chemotherapy-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs, Cancer Treatment Reviews 33(5): 448-460.
Yeoh, A.S.J., Gibson, R.J., Yeoh, E.E.K., Bowen, J.M., Stringer, A.M., Giam, K.A., and Keefe, D.M.K., (2007). A novel animal model to investigate fractionated radiotherapy-induced gastrointestinal mucositis: The role of apoptosis, p53, NF-kB, Cox-1 and Cox-2, Molecular Cancer Therapies 6(8): 2319-2327.
Bowen J.M., Gibson, R.J., Stringer, A.M., Logan, R.M., Tsykin, A., and Keefe, D.M.K., (2007). Gene expression analysis of multiple gastrointestinal regions following cytotoxic chemotherapy by oligonucleotide microarrays, International Journal of Cancer 121(8): 1847-1856.
Bowen J.M., Stringer, A.M., Gibson, R.J., Yeoh, A.S.J., Hannum, S., and Keefe, D.M.K., (2007). VSL#3 probiotic treatment reduces chemotherapy-induced diarrhoea and weight loss, Cancer Biology and Therapy 6(9):
Logan RM, Gibson RJ, Bowen JM, Stringer AM, Sonis ST, Keefe DM. Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol. 2007 Aug 17 (in press)
Keefe, D.M.K., and Gibson, R.J., (2007). Mucosal injury from targeted anticancer therapy, Supportive Care in Cancer 15(5): 483-490.
Keefe, D.M., Rassias G., O'Neill L., and Gibson, R.J., (2007). Severe mucositis: how can nutrition help?, Current Opinion in Clinical Nutrition and Metabolic Care 10(5): 627-631.
Keefe, D.M.K., Bowen, J.M., and Gibson, R.J., (2007). Use of project teams in preclinical development, Handbook of Preclinical Development Wiley.
Gibson, R.J., Bowen, J.M., and Keefe, D.M.K., (2007). Relationship between animal models and clinical research - using mucositis as a practical example, Handbook of Preclinical Development Wiley.
Gibson, R.J., Stinger, A.M., Bowen, J.M., Logan, R.M., Yeoh, A.S-J., Burns, J., Alvarez, E., and Keefe, D.M.K., (2007). Velafermin improves gastrointestinal mucositis following irinotecan treatment in tumour-bearing DA rats, Cancer Biology and Therapy 6(4): 541-547.
Logan, R.M., Bowen, J.M., Stringer, A.M., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2008). Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemotherapy and Pharmacology (in press)
Logan, R.M., Bowen, J.M., Stringer, A.M., Gibson, R.J., Sonis, S.T., and Keefe, D.M.K., (2008). Serum levels of NF- B and pro-inflammatory cytokines following administration of mucotoxic drugs, Cancer Biology and Therapy (in press).
Gibson, R.J., Bowen, J.M., and Keefe, D.M.K., (2008). Advances in mucositis research using microarray and other novel technologies: how far have we come?, Cancer Treatment Reviews (in press).

Professional Interests

Dr Rachel Gibson studies the effects of cytotoxic agents on the gastrointestinal tract with the focus of her recent research being chemotherapy-induced mucositis. Her research into oral mucositis detailed for the first time the time course of cellular events that occur in humans following chemotherapy. As a consequence of this research she was awarded a Cancer Council South Australia Post-Doctoral Research Fellowship. More recently, Rachel has been investigating mechanisms of chemotherapy-induced diarrhoea (a particularly nasty side effect from cancer treatment). Rachel has recently been appointed a Lecturer within the Discipline of Anatomical Sciences.
Rachel is member of the Multinational Association for Supportive Care in Cancer, International Mucositis Study Group, International Dysphagia Study Group, Clinical Oncology Society of Australia and the Australian Society for Medical Research. She is on the Scientific Organising Committee for the South Australian State Branch Local Scientific Meeting for the ASMR. Rachel has supervised 4 honours students (3 First Class; 1 Second Class) and is currently supervising 3 PhD Students, two of whom have been awarded NH&MRC Scholarships. In addition Rachel has supervised various undergraduate research projects for BHSc and BSc students. Since 2002 Rachel has published 34 papers, with a further 13 manuscripts either submitted or in the final stages of preparation (for full list of publications see attachment).

Expertise for Media Contact

Categories	Medicine and medical research
Expertise	mucositis; supportive care in cancer; side effects of cancer treatment
Notes	2003-current: Member of the Australian Society for Medical Research (ASMR) 2004-current: Member of the Multinational Association for Supportive Care in Cancer (MASCC) 2004-current: Member of the International Mucositis Study Group 2008: Member of the Clinical Oncology Society of Australia (COSA)
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Entry last updated: Sunday, 22 Nov 2009