Professor Caroline Springer led a multidisciplinary team called Gene and Oncogene Targeting within the Division of Cancer Therapeutics at The Institute of Cancer Research (ICR). Her work focused on the discovery of a wide range of novel therapeutics.
After completing her PhD in biological chemistry at University College London, Professor Springer began work at the ICR on the novel ADEPT (antibody-directed enzyme prodrug therapy) treatment designed to target tumours selectively. The target tumour was colorectal carcinoma and this work led to four ADEPT clinical trials at Charing Cross, Royal Free and University College London Hospitals in London. Caroline also developed gene-directed enzyme prodrug therapy (GDEPT), a suicide gene therapy treatment that can be used in a wide range of cancer types. This work is now coming to fruition clinically with Professor Kevin Harrington in head and neck cancer.
Caroline investigated several different therapeutic approaches including research into lysyl oxidase inhibitors, an enzyme that is important in invasion and metastasis. The goal was to prevent and treat metastases in a range of tumour types in collaboration with Professor Richard Marais. A series of LOX inhibitors are now in late lead optimisation.
A key area of research was to discover panRAF inhibitors for use in melanoma and colorectal cancers in collaboration with Professor Richard Marais. The new drug target entered clinical trials at The Royal Marsden with Professor Gore and Dr James Larkin and Christie Hospitals in 2015.
Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk BM, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Hohloch J, Carragher N, Macleod K, Ashton G, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais R, Springer C.Cancer Cell. 2015 Jan 12;27(1):85-96.
BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno G, Zambon A, Niculescu-Duvaz D, Turajlic S, Hayes A, Gore M, Larkin J, Lorigan P, Cook M, Springer C, Marais R.Sci Signal. 2014 Mar 25;7(318):ra30. doi: 10.1126/scisignal.2004815.
Detection of the prodrug-activating enzyme carboxypeptidase G2 activity with chemical exchange saturation transfer magnetic resonance. Jamin Y, Eykyn TR, Poon E, Springer CJ, Robinson SP.Mol Imaging Biol. 2014 Apr;16(2):152-7. doi: 10.1007/s11307-013-0680-5.
Bacterial-directed enzyme prodrug therapy. Lehouritis P, Springer C, Tangney M.J Control Release. 2013 Aug 28;170(1):120-31. doi: 10.1016/j.jconrel.2013.05.005. Epub 2013 May 17. Review.
Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R.Cancer Discov. 2013 Feb;3(2):158-67. doi: 10.1158/2159-8290.CD-12-0386. Epub 2012 Dec 14.
Topical 5-fluorouracil elicits regressions of BRAF inhibitor-induced cutaneous squamous cell carcinoma.Viros A, Hayward R, Martin M, Yashar S, Yu CC, Sanchez-Laorden B, Zambon A, Niculescu-Duvaz D, Springer C, Lo RS, Marais R.J Invest Dermatol. 2013 Jan;133(1):274-6. doi: 10.1038/jid.2012.268. Epub 2012 Aug 16. No abstract available. Erratum in: J Invest Dermatol. 2013 Jun;133(6):1691.
Contrasting effects of sunitinib within in vivo models of metastasis.Welti JC, Powles T, Foo S, Gourlaouen M, Preece N, Foster J, Frentzas S, Bird D, Sharpe K, van Weverwijk A, Robertson D, Soffe J, Erler JT, Pili R, Springer CJ, Mather SJ, Reynolds AR.Angiogenesis. 2012 Dec;15(4):623-41. doi: 10.1007/s10456-012-9291-z. Epub 2012 Jul 28.
RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R.N Engl J Med. 2012 Jan 19;366(3):207-15. doi: 10.1056/NEJMoa1105358.
Small molecule inhibitors of BRAF in clinical trials.Zambon A, Niculescu-Duvaz I, Niculescu-Duvaz D, Marais R, Springer CJ.Bioorg Med Chem Lett. 2012 Jan 15;22(2):789-92. doi: 10.1016/j.bmcl.2011.11.060. Epub 2011 Dec 3. Review.
Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia.Packer LM, Rana S, Hayward R, O'Hare T, Eide CA, Rebocho A, Heidorn S, Zabriskie MS, Niculescu-Duvaz I, Druker BJ, Springer C, Marais R.Cancer Cell. 2011 Dec 13;20(6):715-27. doi: 10.1016/j.ccr.2011.11.004.