The Institute of Cancer Research

PHD STUDENTSHIP PROJECT PROPOSAL

GUIDANCE
x This form must be completed and submitted electronically. Please do not submit a scanned document.
x This information will appear on www.icr.ac.uk to advertise the studentship if approved and funded. Please highlight in
yellow any confidential material that you wish to include in the funding proposal but that is not for public consumption.
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the project but not in the web text.
PROJECT DETAILS
Project Title: Targeting cancer metabolism as a novel therapeutic strategy
for breast cancers with PI3K/Akt activation
Short Project Title: Targeting metabolic vulnerabilities of breast cancers with PI3K/Akt
activation
(If main project title is >120 This title will be used on the main section of the website and on the iSAP shortlisting
characters including spaces) application.
FUNDING (only complete this section if this project already has full/partial funding)
Full-funding details (this must include stipend, fees and consumables)
including the source of funding:
This project is fully funded CRUK Grand Challenge award

This project is partly funded Part-funding details (Please set out how much you will provide, from what source,
and how much is additionally required; detailing consumables and stipend
payments):

SUPERVISORY TEAM
For further guidance and definitions of supervisory roles, please see the MPhil/PhD Code of Practice at
http://ispace.icr.ac.uk/corporate/departments/academicServices/Academic % 20Services % 20IADL/MPhil-
PhD % 20Code % 20of % 20Practice.docx
x The Primary Supervisor must hold IRS status, or else be a Career Development Faculty, an ICR Fellow or Associate
Honorary Faculty with an IRS Partner on the team. If there are two primary supervisors (only permitted where the terms
of the grant require this), at least one primary supervisor must have IRS status. There are a maximum of two primary
supervisors.
x The IRS Partner provides guidance and support to the Primary Supervisor as necessary in the carrying out of these
functions. The IRS Partner and the Back-up supervisor can be the same person, however if the IRS Partner is likely to be
heavily involved in the project a separate person should be appointed as a Back-up supervisor.
x The Associate Supervisor(s) – all students should also ideally have one or two Associate Supervisors who will be either a

Supervisor form 2015 Page 1 of 6

 member of Faculty, Faculty collaborator, a Senior Staff Scientist, or another appropriate staff member e.g. Staff Scientist,
Post-Doctoral Worker.
x The Backup Supervisor must always have IRS status.
x Supervisors are required to attend refresher training sessions at least every 5 years. Records of attendance on these
sessions will be reviewed by the Recruitment Committee in considering the allocation of studentships.
Primary Supervisor(s): George Poulogiannis

Associate Supervisor(s):
NA
Backup Supervisor:
(must have IRS status) Julian Downward

IRS Partner : Julian Downward

(only required where Primary is a CDF, Associate
Honorary Faculty or an ICR Fellow – see above)
Lead contact person for the project: George Poulogiannis

DIVISIONAL AFFILIATION
Primary Division: Cancer Biology

Primary Team: Signalling and Cancer Metabolism

Other Division (if applicable):

Other Team (if applicable)):

PROJECT PROPOSAL
x Note: This information will appear on www.icr.ac.uk to advertise the studentship if approved and funded.
Please highlight any confidential material that you wish to include in the funding proposal but that is not for
public consumption in yellow.
x Please reference by number within your proposal, using the Harvard system, and give appropriate references
for any pictures you submit. Please also ensure you proof-read the proposal carefully.

BACKGROUND TO THE PROJECT (up to 300 words)

More than half a million of the world’s women died from breast cancer (BC) in 2012, making it one of the leading
causes of cancer-related deaths in women across the world (Ferlay et al., 2015). The phosphatidylinositol 3-kinase
(PI3K)/Akt pathway represents a complex signalling network that integrates numerous upstream stimuli to
regulate diverse cellular processes, including cell growth, proliferation, survival, and migration (Manning and
Cantley, 2007). It is one of the most frequently activated pathways in BC, and in most cases its activation is driven
by oncogenic PIK3CA mutations or loss of PTEN function, which are most frequently detected in estrogen receptor
(ER) positive and basal-like BCs.
Multiple PI3K/Akt/mTOR pathway inhibitors have been tested in phase I-III clinical trials and although partially
better response has been noted in PIK3CA mutant early stage BCs, neither PTEN, nor PIK3CA status are associated
with anti-tumour response in patients with advanced BC (Mayer et al., 2014, Ma et al., 2016, Schmid et al., 2016).
In addition, activation of the PI3K/Akt pathway has been associated with resistance to endocrine, HER2-targetted
and cytotoxic therapies in breast cancer (Paplomata and O'Regan, 2013, Nahta, 2012), further supporting the

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need for novel therapeutic interventions.
A hallmark of oncogenesis is the observation that cancer cells often restructure their metabolism in an atypical
manner, the most famous example being the Warburg effect, where glucose is metabolized to lactate despite
oxygen’s presence (Warburg, 1956). Activation of PI3K/Akt promotes glycolysis (Deprez et al., 1997, Gottlob et al.,
2001, Kohn et al., 1996, Rathmell et al., 2003) and stimulates de novo lipogenesis through direct phosphorylation
and activation of ACL (Berwick et al., 2002) and mTORC1-mediated activation of SREBF (Porstmann et al., 2008).
Importantly, recent data from our laboratory also indicate that oncogenic mutations in PIK3CA induce significant
metabolic changes, some of which are shared and others that are functionally distinct from those driven by PTEN
loss, opening up opportunities to investigate the mechanistic basis underlying potential metabolic vulnerabilities
of a substantial fraction of BCs.

PROJECT AIMS (up to 5 bullet points)

This project focuses on gaining a mechanistic understanding of the metabolic reprogramming events conferred by
activating mutations in PIK3CA and/or loss of PTEN in breast cancer. We propose to address the following Aims:
Aim1: Deconstruct the metabolic phenome conferred by the activation of PI3K/Akt signalling in breast cancer.
Objective 1. Characterisation of cellular metabolism conferred by oncogenic mutations in PIK3CA and/or loss of
PTEN in vivo.
Objective 2. Recovery of tumour phenotypes in PDX and organoid models and assessment of their in vivo
relevance.
Aim 2: Targeting metabolic vulnerabilities of breast cancers with PI3K/Akt activation.
Objective 3. Interrogate mechanism/s responsible for metabolic vulnerabilities in breast cancers with PI3K/Akt
activation.
Objective 4. Investigate the biological relevance of our findings to inform novel therapeutic strategies.

RESEARCH PROPOSAL (max. 1000 words) Please provide information on the approaches to be used and the
expected outcomes.

Our hypothesis is that breast cancers with constitutive activation of the PI3K/Akt pathway conferred by loss of
PTEN or activating PIK3CA mutations have a number of metabolic Achilles heels that can be targeted directly by
drugs inhibiting critical metabolic regulators such as MCT1/4, GLS and/or indirectly through inhibition of co-
dependent pathways such as DNA repair, and PI3K/Akt. Mechanistic exploration of their metabolic restructurings
can assist with the development of novel targets for drug development and the identification of combinatorial
drug regimens. This together with parallel efforts to identify robust molecular diagnostic assays that could predict
BCs with PI3K/Akt activation based on their metabolic signatures will be the cornerstone of designing clinical trials
capable of treating a substantial fraction of BC patients.
This project is part of the CRUK Grand Challenge Award funded program that aims to map the entire molecular
make-up of tumours using the latest technologies in high-throughput mass spectrometry imaging. The first
objective of this study will be to identify specific metabolite profiles associated with the activation of the PI3K/Akt
pathway driven by oncogenic mutations in PIK3CA (E545K and H1047R) and/or loss of PTEN. This will be achieved
by performing mass-spec metabolomics profiling of human primary breast cancers followed by extensive genomic
profiling of the metabolically distinct sub-regions e.g. by next generation sequencing (NGS) and expression
microarrays with the focus to unveil novel gene alterations-metabolic phenotype interactions that are associated
with the activation of the PI3K/Akt pathway. This analysis will be further expanded in breast tumours obtained

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from mice with mammary-specific mutations in PIK3CA or deletion of PTEN. In parallel, we will aim to generate a
collection of breast cancer patient-derived xenografts (PDXs) and derive matched organoid models, aiming at
recovering distinct metabolic phenotypes in pre-clinical models for genetic and pharmacological inhibition
screening. The comparison of GEMMS with organoids/PDXs and clinical samples will allow us to make an
assessment on model stability and heterogeneity and establish appropriate models for understanding the therapy
sensitivity pattern of PI3K/Akt activated breast cancers in vivo.
The second aim of this project is to identify metabolic vulnerabilities of breast cancers with PI3K/Akt activation
and is based on the mechanistic exploration of key metabolic properties identified in these tumours and whether
they are dictated by lipid phosphatase/kinase and Akt-dependent and independent functions. In relevant
organoid and cell line models we will test if unique metabolic signatures can be rescued by targeting various
nodes of the PI3K/Akt signalling pathway e.g. BKM120 (Pan-W/ï< ]vZ] ]š}Œ•U ' ìõðí ~W/ï<rlw ]vZ] ]š}Œ•U z>óíõ
~W/ï<r ]vZ] ]š}Œ•U • òðôî v d'yîî ~W/ï<t ]vZ] ]š}Œ••U D<îîìò v '^<òõìòõï ~W v-Akt inhibitors), and mTOR
inhibitors (Rapamycin and Torin). To further explore the mechanistic basis behind the observed changes in the
context of PTEN, we will investigate the metabolic signatures of PTEN null MCF10A cells expressing GFP, WT PTEN,
š oÇš] ooÇ ]v Œš íîð^U o]‰] ~'íîõ • v ‰Œ}š ]v ‰Z}•‰Z š • ~zíïô>• uµš vš• }( Wd EX This work will uncover
and biochemically dissect the signalling nodes that contribute in the metabolic restructurings of PI3K/Akt
activated cancers and identify novel metabolic vulnerabilities both in terms of genetically/pharmacologically
manipulating key metabolic enzymes and/or modifying tumour diet. Such therapeutic interventions will be tested
across all available PDO and representative PDX models with or without PTEN loss or oncogenic PIK3CA mutations
alone and/or in combination with inhibition of co-dependent pathways.
This project will deliver insight into major questions that are applicable across cancer research. We will establish
the broader metabolic wiring of breast cancers and better determine the plasticity of the tumour metabolism
across a variety of pre-clinical models. We will identify the metabolic vulnerabilities conferred by the activation of
the PI3K/Akt pathway and elucidate the metabolic biomarkers that govern the response to known therapeutic
regimes. In doing so we will establish the pivotal metabolic features (tumour or microenvironment dependencies
– and whether they can be targeted therapeutically). These results will prove invaluable information for drug
target identification and repurposing into clinical trials.

LITERATURE REFERENCES (Please use the Harvard system of referencing and provide up to 10 key references)

BERWICK, D. C., HERS, I., HEESOM, K. J., MOULE, S. K. & TAVARE, J. M. 2002. The identification of ATP-
citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem, 277, 33895-900.
DEPREZ, J., VERTOMMEN, D., ALESSI, D. R., HUE, L. & RIDER, M. H. 1997. Phosphorylation and activation of
heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling
cascades. J Biol Chem, 272, 17269-75.
FERLAY, J., SOERJOMATARAM, I., DIKSHIT, R., ESER, S., MATHERS, C., REBELO, M., PARKIN, D. M.,
FORMAN, D. & BRAY, F. 2015. Cancer incidence and mortality worldwide: sources, methods and major
patterns in GLOBOCAN 2012. Int J Cancer, 136, E359-86.
GOTTLOB, K., MAJEWSKI, N., KENNEDY, S., KANDEL, E., ROBEY, R. B. & HAY, N. 2001. Inhibition of early
apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial
hexokinase. Genes Dev, 15, 1406-18.
KOHN, A. D., SUMMERS, S. A., BIRNBAUM, M. J. & ROTH, R. A. 1996. Expression of a constitutively active Akt

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 Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J
Biol Chem, 271, 31372-8.
MA, C. X., LUO, J., NAUGHTON, M., ADEMUYIWA, F., SURESH, R., GRIFFITH, M., GRIFFITH, O. L.,
SKIDMORE, Z. L., SPIES, N. C., RAMU, A., TRANI, L., PLUARD, T., NAGARAJ, G., THOMAS, S., GUO,
Z., HOOG, J., HAN, J., MARDIS, E., LOCKHART, C. & ELLIS, M. J. 2016. A Phase I Trial of BKM120
(Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive
Metastatic Breast Cancer. Clin Cancer Res, 22, 1583-91.
MANNING, B. D. & CANTLEY, L. C. 2007. AKT/PKB signaling: Navigating downstream. Cell, 129, 1261-1274.
MAYER, I. A., ABRAMSON, V. G., ISAKOFF, S. J., FORERO, A., BALKO, J. M., KUBA, M. G., SANDERS, M. E.,
YAP, J. T., VAN DEN ABBEELE, A. D., LI, Y., CANTLEY, L. C., WINER, E. & ARTEAGA, C. L. 2014.
Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in
estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J
Clin Oncol, 32, 1202-9.
NAHTA, R. 2012. Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance. Curr Med
Chem, 19, 1065-75.
PAPLOMATA, E. & O'REGAN, R. 2013. New and emerging treatments for estrogen receptor-positive breast
cancer: focus on everolimus. Ther Clin Risk Manag, 9, 27-36.
PORSTMANN, T., SANTOS, C. R., GRIFFITHS, B., CULLY, M., WU, M., LEEVERS, S., GRIFFITHS, J. R.,
CHUNG, Y. L. & SCHULZE, A. 2008. SREBP activity is regulated by mTORC1 and contributes to Akt-
dependent cell growth. Cell Metab, 8, 224-36.
RATHMELL, J. C., FOX, C. J., PLAS, D. R., HAMMERMAN, P. S., CINALLI, R. M. & THOMPSON, C. B. 2003. Akt-
directed glucose metabolism can prevent Bax conformation change and promote growth factor-
independent survival. Mol Cell Biol, 23, 7315-28.
SCHMID, P., PINDER, S. E., WHEATLEY, D., MACASKILL, J., ZAMMIT, C., HU, J., PRICE, R., BUNDRED, N.,
HADAD, S., SHIA, A., SARKER, S. J., LIM, L., GAZINSKA, P., WOODMAN, N., KORBIE, D., TRAU, M.,
MAINWARING, P., GENDREAU, S., LACKNER, M. R., DERYNCK, M., WILSON, T. R., BUTLER, H.,
EARL, G., PARKER, P., PURUSHOTHAM, A. & THOMPSON, A. 2016. Phase II Randomized Preoperative
Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole
Alone in Patients With Estrogen Receptor-Positive Breast Cancer. J Clin Oncol.
WARBURG, O. 1956. On the origin of cancer cells. Science, 123, 309-14.

CANDIDATE PROFILE
Note: the ICR’s standard minimum entry requirement is a relevant undergraduate Honours degree (First or 2:1)
Pre-requisite qualifications of applicants: BSc in Cell Biology/Biochemistry or equivalent subject
e.g. BSc or equivalent in specific subject area(s)
Intended learning outcomes: x Attain strong knowledge in breast cancer biology,
Please provide a bullet point list (maximum of PI3K/Akt signalling and cancer metabolism.
seven) of the knowledge and skills you expect the x Obtain training in generating and handling breast cancer
student to have attained on completion of the PDX and PDO models.
project. x Acquire strong expertise in metabolomics and
bioinformatics.
x Analyse NGS data and assess how tumour metabolism can
be exploited in anticancer therapies and/or
diagnosis/prognosis in vitro and in vivo.

ADVERTISING DETAILS

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Project suitable for a student with a background Biological Sciences
in:
Physics or Engineering
(Please tick all categories that apply – your project will
be advertised under all selected categories) Chemistry
Maths, Statistics or Epidemiology
Computer Science
Keywords: 1. Molecular Biology PhD London
Please provide 4-6 words/short phrases that potential 2. Cancer metabolism
students may type into search engines (e.g. Google) to
search for PhDs similar to yours – e.g. ‘cancer 3. Breast cancer
predisposition genes’, ‘physics PhD London’ etc. 4. PI3K/Akt activation
5.
6.

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