WIMM PI
CURRICULUM VITAE
Personal data
Name
Valentine Macaulay
Nationality
UK
Email
valentine.macaulay@imm.ox.ac.uk
valentine.macaulay@oncology.ox.ac.uk
Present position
2001 - present
2003 - present
2008 - present
Honorary Consultant in Medical Oncology
University Research Lecturer
HEFCE Clinical Senior Lecturer
Previous appointments
2001 - 2008 Senior Clinical Research Fellow, Weatherall Institute of Molecular Medicine
Honorary Consultant in Medical Oncology, Churchill Hospital, Oxford
1995 - 2001
MRC Clinician Scientist, Institute of Molecular Medicine, Oxford
1993 - 1995
Registrar/Senior Registrar in Medical Oncology, Churchill Hospital, Oxford
1990 - 1993
Clinical Research Fellow/Honorary Senior Registrar, Chester Beatty, London
1985 - 1990
Clinical Research Fellow/Honorary Registrar, Inst. of Cancer Research Surrey
1984 - 1985
Registrar in Infectious Diseases, St George’s Hospital Tooting
1983 - 1984
Registrar in Medical Oncology, Royal Marsden Hospital London
1981 - 1983
SHO appointments: Medical Oncology (Charing Cross), General Medicine
(Kingston), Chest Medicine (Brompton), Neurology (Atkinson Morley’s)
1980 - 1981
House surgeon (Charing Cross), House physician (West Middlesex)
Research achievements
I became interested in insulin-like growth factor (IGF) signalling during research for my MD
thesis. Following a PhD with Alan Ashworth, I was awarded an MRC Clinician Scientist
Fellowship (1995-2001) and Cancer Research UK Senior Clinical Research Fellowship (20012006). These awards, together with a grant from the Molecular and Cellular Medicine Board of
the MRC (2007-2010), allowed me to establish a research group to study the role of IGFs in
cancer biology. My group focuses on the type 1 IGF receptor (IGF-1R), a receptor tyrosine
kinase that is widely expressed on normal tissues, and signals from the cell surface to promote
proliferation, invasion and cell survival. Initial studies characterized IGF-1R expression in
urological cancers, until recently my clinical speciality.
We showed that IGF-1R is
overexpressed in primary prostate cancers, further up-regulated on progression to metastatic
or androgen-independent disease, and detectable in prostate cancer bone metastases. We
also showed that IGF-1R expression is regulated at a transcriptional level by the von Hippel
Lindau (vHL) tumour suppressor, and IGF-1R up-regulation is detectable in clear cell renal
cancer, the common clinical type, in which vHL is frequently inactivated by mutation. Before
the availability of drugs to inhibit IGF-1R, we used IGF1R gene silencing to explore effects of
IGF-1R targeting, revealing that siRNA efficacy is influenced by secondary structure in the
target transcript (collaboration with Ed Southern). We then used these reagents to show that
IGF-1R depletion sensitises human and murine tumour cells to ionising radiation and DNA
damaging cytotoxic drugs, but not to drugs that kill cells without inducing DNA damage. These
findings contributed to the recognition of IGF-1R as an attractive cancer treatment target. I
have been Oxford PI for trials of IGF-1R therapeutics, firstly a humanised IGF-1R antibody in
combination with chemotherapy, and secondly an IGF-1R kinase inhibitor with erlotinib.
What are the Future Aims of Your Current Group?
We are taking three approaches to explore interactions of IGF-1R with the DNA damage
response, and to understand what makes tumours responsive or resistant to IGF-1R inhibitors.
First, we find that IGF-1R influences repair of DNA double strand breaks (DSBs), with evidence
for effects on both homologous recombination and non-homologous end-joining. These effects
appear to be independent of known IGF-1R roles in regulating cell cycle progression,
transcription and cell survival, and we speculate that IGF-1R inhibition influences loading of
repair proteins onto chromatin, and/or their post-translational modification. We are also
collaborating with Dr Gareth Bond (Ludwig Institute) to explore the significance of an IGF1R
SNP identified as the top hit in a screen for sequence variants associated with
chemoresistance.
Secondly, we showed that IGF-1R undergoes ligand-induced translocation into the nucleus of
human tumour cells, and nuclear IGF-1R is associated with poor prognosis in renal cancer.
This suggests that nuclear IGF-1R influences tumour biology, and it may also have implications
for sensitivity to IGF-1R therapeutics. We are taking several approaches to understand the
function of IGF-1R in this newly-identified location. These include ChIP-seq to define DNAs
that are bound by nuclear IGF-1R, mass spectrometry (with Dr Eric O’Neill, Oncology, Oxford)
to identify nuclear IGF-1R binding partners, and expression of IGF-1Rs modified to influence
their subcellular localisation.
Finally, we performed siRNA screens for proteins whose depletion enhances sensitivity to IGF1R inhibition (with Alan Ashworth and Chris Lord, Breakthrough Breast Cancer, and Elaine
Kilgour, AstraZeneca). Validated screen hits include cell cycle regulators, DNA repair proteins,
and proteins with poorly characterised functions. We are investigating how these proteins
influence sensitivity to IGF-1R inhibition, defining their patterns of expression in clinical
cancers, including samples from patients treated with IGF-1R inhibitors, and exploring how to
convert these findings into clinically testable treatments.
How do These Aims Contribute to the Understanding and/or Management of Human
Disease?
These investigations will shed light on the contribution of IGF-1R to tumour biology, but the
over-riding aim is to enable effective use of IGF-1R inhibitors in cancer treatment. IGF-1R
inhibitors do have clinical activity, sometimes dramatic and durable, as monotherapy in
sarcomas and with chemotherapy or targeted agents in a subset of patients with common
cancers. However, encouraging Phase I/II activity has not yet translated to Phase III benefit in
unselected patients. To exploit this new class of drug, we need a better understanding of the
factors that regulate sensitivity to IGF-1R inhibition, and of the interactions between IGF-1R
signalling and other forms of cancer treatment.
We know from clinical trials and in vitro studies that IGF-1R deficient tumours are resistant to
IGF-1R inhibitors (ie lack of IGF-1R is a good negative predictor), but IGF-1R expression level
is a poor positive predictor of sensitivity. Preliminary clinical data suggest that nuclear IGF-1R
may influence sensitivity to IGF-1R therapeutics; we are testing this hypothesis via analysis of
clinical tumours (with Jean-Yves Blay, Lyon) and in vitro studies outlined above. We are also
testing cancers for candidate predictive biomarkers identified in our siRNA screen, and are
near to being able to use these tests to stratify patients in clinical trials. The screen approach
provides a route to rational design of combination therapy trials, using drugs that phenocopy
depletion of candidate resistance mediators. We are using xenograft models to test one such
combination, co-targeting a proximal WNT component (with Chris Lord, Breakthrough), and to
test effects of IGF-1R inhibition as a route to chemo-sensitisation (with Mark Middleton).
Thus the key aims are to understand what makes tumours responsive or resistant to IGF-1R
inhibition, to use this information to target these new drugs to potentially responsive patients,
and to select treatment combinations for clinical evaluation.
Lay summary of research
Many cancer patients develop secondary tumours that are treatable with chemotherapy or
radiotherapy but cannot be cured, and there is an urgent need for better treatments. Our work
focuses on IGF-1R, a protein found at high levels on the surface of many cancer cells. IGF-1R
helps cancer cells to grow, spread, and resist killing by cancer treatments including
radiotherapy and chemotherapy. These functions make IGF-1R an attractive target for cancer
treatment. IGF-1R blocking drugs are being tested in clinical trials; some patients respond
dramatically, but others show no response. At present we know little about what makes
tumours sensitive to IGF-1R blockers, nor how best to combine these drugs with other
treatments. We are taking three approaches to answer these important questions. Firstly, we
found that blocking IGF-1R makes cancer cells less able to repair DNA damage caused by
radiotherapy and many chemotherapy drugs. We are trying to figure out how IGF-1R does
this, so that we can exploit this effect in treatment. Secondly, we found that IGF-1R can move
from the cell surface into the nucleus of cancer cells. Patients whose cancers have a lot of
nuclear IGF-1R do not live as long as those whose cancers lack nuclear IGF-1R, suggesting
that nuclear IGF-1R makes cancers behave aggressively. We want to find out what IGF-1R is
doing in the nucleus of cancer cells, and whether this affects response to cancer treatments.
Finally, using a large-scale screen, we have identified a few proteins that make cancer cells
resistant to IGF-1R blockers. We can reverse this resistance using chemical drugs that block
the resistance proteins, suggesting possible combination treatments that can be tested in
clinical trials. The aim of our research is to understand the function of IGF-1R, to enable
effective use of IGF-1R blockers in cancer treatment.
Publications in last 5 years
Yuen J, Cockman M, Protheroe A, Sullivan M, Pugh C, Werner H, Macaulay VM The VHL
tumour suppressor inhibits expression of the IGF1R and its loss contributes to IGF1R
overexpression in human clear cell renal carcinoma. Oncogene 26: 6499-508, 2007.
Rochester MA, Patel N, Turney BW, Davies DR, Roberts IS, Crew J, Protheroe A, Macaulay
VM. The type 1 insulin-like growth factor receptor is over-expressed in bladder cancer.
BJU Int, 100: 1396-401, 2007.
Riedemann J, Sohail M, Macaulay VM. Dual silencing of the EGF and type 1 IGF receptors
suggests dominance of IGF signaling in human breast cancer cells. Biochem Biophys Res
Commun. 355:700-6, 2007.
Riedemann J, Takiguchi M, Sohail M, Macaulay VM. The EGF receptor interacts with the
type 1 IGF receptor and regulates its stability. Biochem Biophys Res Commun. 355:70714, 2007.
Rochester MA, Patel N, Turney BW, Davies DR, Roberts IS, Crew J, Protheroe A, Macaulay
VM. The type 1 insulin-like growth factor receptor is over-expressed in bladder cancer.
BJU Int, 100: 1396-401, 2007.
Yuen JSP and Macaulay VM. Targeting the type 1 insulin-like growth factor receptor as a
treatment for cancer. Expert Opinion in Therapeutic Targets 12: 589-603, 2008.
Chitnis MM, Yuen JSP, Protheroe AS, Pollak M, Macaulay VM. The Insulin-like Growth
Factor Pathway. Clin Cancer Res, 14: 6364-70, 2008.
Yuen JSP, Akkaya E, Wang Y, Takiguchi M, Peak, S, Sullivan M, Protheroe A, Macaulay
VM. Validation of the type 1 IGF receptor as a therapeutic target in renal cancer.
Molecular Cancer Therapeutics 8: 1448-59, 2009.
Brierley GV, Macaulay SL, Forbes BE, Wallace JC, Cosgrove LJ, Macaulay VM. Silencing of
the insulin receptor isoform A favors formation of type 1 insulin-like growth factor receptor
(IGF-IR) homodimers and enhances ligand-induced IGF-IR activation and viability of
human colon carcinoma cells. Endocrinology 151:1418-27, 2010.
Aleksic T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, Protheroe A,
Howarth M, Macaulay VM. The type I IGF receptor translocates to the nucleus of human
tumor cells. Cancer Res 70: 6412-9, 2010.
Pwint TP, Macaulay V, Roberts IS, Sullivan M, Protheroe A. An adult Xp11.2 translocation
renal carcinoma showing response to treatment with sunitinib. Urol Oncol 29:821-4, 2011.
Turney BW, Turner GDH, Brewster SF, Macaulay VM. Serial analysis of resected prostate
cancer suggests up-regulation of type 1 IGF receptor with disease progression. BJU Int
107:1488-99, 2011.
Bardella C, El-Bahrawy M, Frizzell N, Adam J, Ternette N, Hatipoglu E, Howarth K,
O'Flaherty L, Roberts I, Turner G, Taylor J, Giaslakiotis K, Macaulay VM, Harris AL,
Chandra A, Lehtonen HJ, Launonen V, Aaltonen LA, Pugh CW, Mihai R, Trudgian D,
Kessler B, Baynes JW, Ratcliffe PJ, Tomlinson IP, Pollard PJ. Aberrant succination of
proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of
mutation status.. J Pathol. 225: 4-11, 2011.
Macaulay VM, Middleton MR, Eckhardt SG, Juergens RA, Rudin, CA, Manukyants A, Gogov
S, Poondru S, Gedrich R, Gadgeel SM. Phase I study of OSI-906, dual tyrosine kinase
inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) in
combination with erlotinib (E) in patients with advanced solid tumors. J Clin Oncol 29:
3098, 2011.
Blick C, Hall P, Pwint T, Al-Terkait F, Crew J, Powles T, Macaulay V, Munro N, Douglas D,
Kilbey N, Protheroe A, Chester JD. Accelerated methotrexate, vinblastine, doxorubicin,
and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive
transitional cell carcinoma of the bladder. Cancer 118: 3920-7, 2012.
Turney BW, Kerr, M, Chitnis, MM, Lodhia K, Wang, Y, Riedemann, R, Rochester, MA, Protheroe
AS, Brewster SF, Macaulay VM. Depletion of the type 1 IGF receptor delays repair of
radiation-induced DNA double strand breaks. Radiotherapy and Oncology 103: 492-9,
2012.
Macaulay VM, Middleton MR, Protheroe AS, Tolcher A, Dieras V, Sessa C, Bahleda R, Blay JY, LoRusso P, Mery-Mignard D, Soria J-C. Phase I study of humanized monoclonal
antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R),
administered in combination with anticancer therapies to patients with advanced solid
tumors. Annals of Oncology 24: 784-91, 2013.
Chitnis MC, Lodhia KA, Aleksic T, Gao S, Protheroe AS, Macaulay VM. IGF-1R inhibition
enhances radiosensitivity and delays double-strand break repair by both non-homologous
end-joining and homologous recombination. Oncogene, epub 4 Nov 2013.
Dsh homolog DVL3 mediates resistance to IGF-1R inhibition. Gao S, Bajrami I, Verrill C,
Konde A, Aleksic T, Asher R, Han C, Allen P, Bailey D, Feller S, Kashima T, Athanasou N,
Blay J-Y, Schmitz S, Machiels J-P, Upile N, Jones TM, Thalmann GN, Middleton MR,
Ashworth A, Lord CJ, Macaulay VM. Under review at Cancer Discovery.
The following manuscripts are in preparation for submission.
Ramcharan R, Watson A, Margison G, Middleton MR, Macaulay VM. IGF-1R inhibition
influences processing of replication-associated DNA double-strand breaks and induces
schedule-dependent sensitization of human melanoma to temozolomide. Awaiting
approval of Pharma collaborators for manuscript submission.
Lodhia K, Gao S, Aleksic T and Macaulay VM. RAD51 mediates resistance to IGF-1R
inhibition in PTEN wild-type prostate cancer cells. Submission will await acceptance of
Shan Gao’s publication (above) describing results of siRNA screens, initial hit validation,
interrogation of DVL3.
Aleksic T, Browning L, Turley H, Woodward M, Ansorge O, Middleton MR, Macaulay VM.
Durable response to combined IGF-1R:EGFR inhibition in chordoma with exclusively
nuclear IGF-1R. Awaiting final immunohistochemical analysis.
Macaulay VM, Middleton MR, Eckhardt SG, Juergens RA, Rudin, CA, Manukyants A, Gogov
S, Poondru S, Gedrich R, Gadgeel SM. Phase I study of OSI-906, dual tyrosine kinase
inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) in
combination with erlotinib (E) in patients with advanced solid tumors. Presented by V
Macaulay at ASCO 2010, 2011; final data analysis completed, I have signed off the
Clinical Study Report, plan for submission of manuscript Q2 2014.
Ten key publications
Hellawell GO, Turner GDH, Davies DR, Poulsom R, Brewster SF, Macaulay VM. Expression
of the type 1 insulin-like growth factor receptor is upregulated in primary prostate cancer
and commonly persists in metastatic disease. Cancer Research, 62: 2942-50, 2002.
Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM, Macaulay VM.
The efficacy of small interfering RNAs targeting the type 1 IGF receptor is influenced by
secondary structure in the IGF1R transcript. J Biol Chem 278: 15991-15997, 2003.
Rochester MA, Riedemann J, Hellawell GO, Brewster SF, Macaulay VM. Silencing of the
IGF1R gene enhances sensitivity to DNA damaging agents in both PTEN wild-type and
mutant human prostate cancer. Cancer Gene Therapy 12: 90-100, 2005.
Yeh A, Bohula E, Macaulay VM Human melanoma cells expressing activated BRAF remain
susceptible to IGF1R targeting by small interfering RNA. Oncogene, 25: 6574-81, 2006.
Yuen J, Cockman M, Protheroe A, Sullivan M, Pugh C, Werner H, Macaulay VM The VHL
tumour suppressor inhibits expression of the IGF1R and its loss contributes to IGF1R
overexpression in human clear cell renal carcinoma. Oncogene 26: 6499-508, 2007.
Yuen JSP, Akkaya E, Wang Y, Takiguchi M, Peak, S, Sullivan M, Protheroe A, Macaulay
VM. Validation of the type 1 IGF receptor as a therapeutic target in renal cancer.
Molecular Cancer Therapeutics 8: 1448-59, 2009.
Aleksic T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, Protheroe A,
Howarth M, Macaulay VM. The type I IGF receptor translocates to the nucleus of human
tumor cells. Cancer Res 70: 6412-9, 2010.
Turney BW, Kerr, M, Chitnis, MM, Lodhia K, Wang, Y, Riedemann, R, Rochester, MA, Protheroe
AS, Brewster SF, Macaulay VM. Depletion of the type 1 IGF receptor delays repair of
radiation-induced DNA double strand breaks. Radiotherapy and Oncology 103: 492-9,
2012.
Macaulay VM, Middleton MR, Protheroe AS, Tolcher A, Dieras V, Sessa C, Bahleda R, Blay JY, LoRusso P, Mery-Mignard D, Soria J-C. Phase I study of humanized monoclonal
antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R),
administered in combination with anticancer therapies to patients with advanced solid
tumors. Annals of Oncology 24: 784-91, 2013.
Chitnis MC, Lodhia KA, Aleksic T, Gao S, Protheroe AS, Macaulay VM. IGF-1R inhibition
enhances radiosensitivity and delays double-strand break repair by both non-homologous
end-joining and homologous recombination. Oncogene, epub 4 Nov 2013.
Markers of Esteem
2003 - current
University Research Lecturer
2006 - current
Member of Advisory Boards for development of IGF-1R inhibitors
(Sanofi-Aventis, Pfizer, Roche, OSI Pharmaceuticals; now Astellas).
2008
FRCP
2012 - current
Invited to serve as member of the Scientific Program Committee of
ASCO on the Tumor Biology track.
Appointed to Executive Committee, Department of Oncology
Selected invited lectures:
‘Targeting IGF-1R as treatment for cancer’ AACR/EORTC/NCI Molecular Targets and Cancer
Therapeutics, San Francisco October 2007
‘Biology of the type 1 IGF receptor’ Targeted Anticancer Therapies, Bethesda March 2008
‘IGF-1R as a target in human cancer’ Insulin and Cancer Workshop, Dusseldorf Oct 2008
‘IGF-1R: signaling cross-talk’ IGF Gordon Conference, Ventura March 2009
‘IGF biology’ Molecular Therapeutics of Cancer Research Conference, Stanford July 2009
‘IGF1R inhibitors: rational combinatorial strategies’ Targeted Anticancer Therapies, Bethesda
March 2010
‘Molecular Drug Targets: IGF-1R’, MSD Oncology Summit, Lisbon, October 2011.
‘Nuclear translocation of the IGF receptor’, ICE/ENDO 2014 International Congress of
Endocrinology, Chicago, June 2014.
Current and recent grants
Prostate Cancer UK (G2012-25)
05/13 - 04/14
£ 55,335
Breast Cancer Campaign (2012NovemberPR46)
01/13 - 12/14
£109,021
Research Capacity Funding (OUH Joint R&D Committee)
04 /13 - 03/14
£ 46,224
Rosetrees Trust (JS16/A475)
10/13 – 09/14
£ 10,000