The Caroline Foundation Fellowships (TCF)
RECIPIENTS OF THE CAROLINE FOUNDATION FELLOWSHIP
DR JAVIER SANCHEZ RAMIREZ
Dr. Javier Sánchez Ramírez graduated as a biochemist at the Faculty of Biology, Havana University. He worked at the two most prestigious Cuban research institutes: Center of Molecular Immunology and Center of Genetic Engineering and Biotechnology. In the latter, he worked in the Cancer Immunotherapy Group at the Department of Biomedical Research in the fields of Molecular Biology and Immunology, gai
ning his PhD in Biological Sciences. His work was focused in the development of therapeutic vaccine candidates for cancer treatment. Dr Sánchez Ramírez commences work with the Cancer Biotherapeutics group in DCU as The Caroline Foundation Research Fellow investigating the role of the immune system in HER2+ breast cancer.
DR DENIS COLLINS
Dr. Denis Collins completed his undergrad in Biochemistry at University College Cork in 2001. His PhD thesis was carried out in DCU. It examined the ability of tyrosine kinase inhibitors to modulate the activity of drug efflux
pumps involved in chemotherapy resistance in lung cancer. Dr. Collins held an IRCSET Enterprise Partnership Scheme Postdoctoral Fellowship from 2011-2013 examining the immune response to antibody therapies, spending six months working at Roche Diagnostics GmbH, Penzberg, Germany during this time. Dr. Collins went on to secure a Roche Postdoctoral Fellowship (RPF) from 2014-2017 that was carried out between the National Institute for Cellular Biotechnology (NICB), DCU and Roche Diagnostics GmbH in Germany. The RPF examined the impact of HER4 mutations on response to HER-family targeted therapies. Dr. Collins is currently a Caroline Foundation Research Fellow and runs the Cancer Biotherapeutics group at the NICB, DCU.
Biotherapeutics (biologics or biotech drugs) are at the forefront of modern cancer chemotherapy. Examples include the monoclonal antibodies Herceptin ®, Erbitux ® and Perjeta ® , the antibody drug conjugate Kadcyla ®, the immune checkpoint inhibitors Keytruda ®, Opdivo ® and Yervoy ®. These therapies are at the forefront of the effort to produce chemotherapy with potent and specific anti-cancer activity.
The goal of the Cancer Biotherapeutics programme is to fully exploit the potential of these exciting new drugs by generating treatment option rationale for cancers with an unmet clinical need such as metastatic HER2+ breast cancer, triple negative breast cancer, lung cancer and melanoma. Combinations of the biotherapeutics with existing small molecule inhibitors such as Tyverb ® and Nerlynx ® and chemotherapeutic agents like Taxotere ® are investigated. Projects utilise cutting-edge laboratory techniques, unique cancer cell line-based resistance models and patient material obtained from the translational component of clinical trials carried out in Ireland.
Our objectives are to:
- Understand the interplay between biotherapeutics and the immune system in order to find new therapeutic targets or potential synergistic combinations with existing or novel chemotherapies.
- Determine the underlying mechanisms of innate and acquired resistance to biotherapeutics that limit the efficacy of these drugs in the clinic.
- Identify patients that will most benefit from biotherapeutics through the analysis of patient-derived material from translational studies.
Current projects are examining:
- The effects of breast and lung cancer-indicated tyrosine kinase inhibitors (TKI) on the immune response to Herceptin ® and Perjeta ®.
- Examining novel combination strategies involving the TKI Nerlynx ® for the treatment of treatment refractory HER2+ breast cancer. An industry/academia collaboration with Puma Biotechnology, Inc.
- The role of immune cell-expressed PD-1 (an immune checkpoint targeted by Keytruda ® and Opdivo ®) in immune cell-mediated cytotoxicity in breast cancer patient samples.
- An assessment of the effects of chemotherapy on the plasma proteome of HER2+ breast cancer patients.
- The influence of HER-family mutations on response to HER-family-targeted biotherapeutics.
DR NICOLA GAYNOR
Dr Nicola Gaynor completed a bachelor’s degree in pharmacology in UCD in 2014. She then started her PhD project, supported by the Cancer Clinical Research Trust, in the National Institute for Cellular Biotechnology in Dublin City University. Nicola’s project investigated methods of improving the immune response against breast cancer. She completed her PhD at the start of 2019 and began a post-doctoral research project supported by the Caroline Foundation. As part of this research Nicola will be investigating how different features of the immune response could be used to predict whether or not a patient will respond to anti-cancer treatments.
DR MARIE PRENCIPE
Dr. Maria Prencipe was awarded her Degree in Biology with a major in Biochemistry and Molecular Biology from L’Aquila University, Italy. After 3 years as a research scientist in the research hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy, she moved to Ireland where she was awarded her PhD in Cancer Biology from University College Dublin, studying the mechanisms of resistance to taxane treatment in breast and ovarian cancer. As a postdoctoral fellow within the SFI funded Molecular Therapeutic for Cancer Ireland (MTCI) research cluster, she studied the molecular mechanisms of resistance to advanced prostate cancer treatments, identifying novel transcription factors as potential new therapies. She was awarded an Irish Cancer Society research fellowship in 2012 to carry on her work on transcription factors’ role in hormone-driven cancers such as prostate and breast cancer. Maria recently joined Professor John Crown’s research team as a senior research fellow. Her research interests focus on the mechanisms of resistance to hormone therapy in breast cancer with the goal of identifying novel and more effective treatments especially for triple negative breast cancer.
DR SARAH FOLEY
Dr Sarah Foley studied Biotechnology at the National University of Ireland, Galway (NUIG) where she was awarded Fist Class Honours. She then pursued a Ph.D in Biochemistry in NUIG focused on extraction of complex sugars from seaweed and investigation of their potential anti-cancer activities. After graduating, Sarah moved to Japan to begin work with a drug discovery company where her research involved drug metabolism and transport. She then moved to the U.K. to further her knowledge in this field working with drugs from various therapeutic areas. In 2018, she moved back to Ireland and took up a post-doctoral research position at UCD/SVUH. Having always had a keen interest in cancer biology, she was eager to find a position where she could work closely to clinical trials. The aim of her current project is to develop and validate a new targeted therapy for breast cancer, with a particular focus on triple-negative disease (TNBC).
DR ALYSON MURRAY
Dr. Alyson Murray obtained her PhD in Infection Biology from University College Dublin in 2013. She then began her career in cancer biology when she commenced her postdoctoral research in the lab of Professor Joe Duffy in St. Vincent’s Hospital, Dublin.
The research in Professor Joe Duffy’s lab is focussed on targeted therapies in breast cancer. In particular, Alyson is investigating the possible use of a synthetic form of vitamin D* for the treatment of breast cancer. There is increasing evidence that vitamin D may have a protective role in breast cancer, which Alyson is hoping to confirm as part of her research.
Collaborators include Professor John Crown, Professor Willliam Gallagher (UCD) and Dr Norma O’Donovan (DCU). Alyson has published in international peer reviewed journals along with collaborators from Cancer Research UK Cambridge Institute and The Institute of Cancer Research London. Alyson is also involved in the Irish Cancer Society Collaborative cancer research centre, BreastPredict (www.breastpredict.com).
Targeting the Vitamin D receptor as a potential treatment for breast cancer
The active form of vitamin D* is involved in a number of the body’s processes, most notably in the absorption of calcium. However, recent evidence implicates a deficiency in vitamin D in the formation and progression of cancer. Therefore we propose that vitamin D could have the potential to be used as a therapeutic agent in the treatment of cancer. The active form of vitamin D binds to the Vitamin D receptor (VDR) that is present on almost all cells of the body, including in the breast. When activated, this receptor then drives a number of reactions that can lead to a decrease in cancer cell growth, an increase in cancer cell death and a decrease in invasion and metastasis.
The research performed in our lab is looking at the use of vitamin D as a treatment for breast cancer. We have screened a large panel of breast cancer cells, which includes all of the different breast cancer subgroups, for the response to vitamin D exposure. We saw a response to treatment in all subgroups and could calculate the concentration of VD that would be required to reduce the growth by 50%. This concentration indicated the most responsive cells. The Estrogen receptor positive cells responded best to treatment, followed by the HER2 group and finally the triple negative cells.
In order to utilize vitamin D in a patient, you would need to ensure the concentrations prescribed are low enough to avoid hypercalcaemia but still maintain the anti-cancer properties. To try overcome this we have been researching the effects of a synthetic form of vitamin D. This has been shown to require much lower doses to reduce the growth of cancerous cells. Part of our research is involved in thoroughly comparing the actions of both the natural and the synthetic forms of vitamin D, and determining the method of action.
In a clinical environment vitamin D would likely be given in conjunction with another treatment. So, to test the benefits of this we are looking at the effect of vitamin D on the growth of breast cancer cells when treated alongside a number of chemotherapy and hormonal agents. One notable discovery so far, is that we can see a response to the estrogen receptor targeting agent Tamoxifen in the triple negative cells. We are currently exploring many avenues to discover both how this is happening and how it may be exploited in a clinical environment.
DR NORMA O’DONOVAN
Dr Norma O’Donovan obtained her PhD from University College Cork in 1998, and conducted her postdoctoral training in University Hospital Bern, Switzerland. She subsequently returned to Ireland as a postdoctoral scientist in St. Vincent’s Hospital, Dublin, and also spent some time working with the Health Research Board. Since 2004, she has been employed as a Senior Scientist at the National Institute for Cellular Biotechnology (www.nicb.ie) in Dublin City University.
Her research focusses on targeted therapies for cancer, in particular breast cancer and melanoma. She is also involved in the Science Foundation Ireland funded Strategic Research Cluster, Molecular Therapeutics for Cancer Ireland (www.mtci.ie) and Breast-Predict, an Irish Cancer Society Collaborative Cancer Research Centre. Dr O’Donovan has published 44 research articles in international peer reviewed journals and is an active member of the All-Ireland Cooperative Oncology Research Group (www.icorg.ie), participating in several breast cancer clinical trials.
Update from Dr Norma O’Donovan | July 2015
We are currently testing seven different drugs which may provide new therapy options for patients with specific types of breast cancer and melanoma. We have recently tested three targeted therapies for HER2 positive breast cancer and showed that the three drugs together produced a greater effect on HER2 positive breast cancer cells in the lab, than each of the drugs alone or a combination of two of the drugs.
The results of this research will be presented at the annual meeting of the European Society of Medical Oncology in September 2015.
Update on Dr Norma O’Donovan’s Research | October 2014
There are currently 9 breast cancer clinical trials open in Ireland (run by ICORG, www.icorg.ie) – St Vincent’s are participating in all of these trials
- In addition to supporting the clinical trials team at St Vincent’s, CCRT also supports lab research in St Vincent’s, UCD, RCSI and DCU.
- The Caroline Foundation supports a senior scientist, Norma O’Donovan, at Dublin City University. Dr O’Donovan is supervising a team of 9 cancer researchers at the National Institute for Cellular Biotechnology, DCU (4 of the 9 are funded partly/fully by CCRT, ccrt.ie) – the team includes postgraduate students, postdoctoral scientists and a research assistant.
The focus of the research is on developing new targeted therapies for cancer and identifying biomarkers to help determine which drugs will benefit individual patients. For example, by studying how tumour cells become resistant to current therapies they can identify new targets and test new treatments that may overcome drug resistance. The group are currently testing 6 new drugs in breast cancer cells in the lab and performing biomarker tests on patient samples from 2 breast cancer clinical trials. The drugs which produce the most promising results in the lab will be progressed into clinical trials in breast cancer patients.