Professor Guido FRANZOSO, M.D., Ph.D.
Imperial College London
A* STAR JOINT PhD PROGRAMME
PROJECT TITLE:
Cancer-selective targeting of the NF-ĸB pathway
BRIEF DESCRIPTION:
The interest of the laboratory is in the understanding of the regulation
and function of transcription factors of the NF-B family. These are
central coordinating regulators of immune and inflammatory
responses. They also promote cell survival by inhibiting apoptosis or
programmed cell death. In addition to exhibiting these important
physiological functions, the NF-κB pathway plays a crucial role in
oncogenesis. NF-B is aberrantly and stably activated in a wide
range of human cancers, where it promotes survival and malignancy
by upregulating survival genes. The paradigm of these cancers is
multiple myeloma (MM), an incurable malignancy of plasma cells.
Compelling genetic and biochemical evidence has established the
paramount importance of aberrant NF-B signalling in MM
pathogenesis and provided a strong rationale for therapeutically
targeting the NF-κB pathway in MM, as well as other cancers.
However, despite the pharmaceutical industry’s aggressive pursuit of
specific NF-κB inhibitors for treating a wide spectrum of malignant
and chronic inflammatory pathologies, including MM, no such
inhibitor has been clinically approved to this day, due to the
preclusive toxicities associated with the global suppression of NF-B.
The conundrum with conventional therapeutic NF-B-targeting
strategies has been how to achieve cancer-cell specificity, given the
ubiquitous nature and pleiotropic physiological functions of NF-κB,
such as functions in innate and adaptive immunity and inflammation.
Therefore, since a key pathogenetic activity of NF-B in MM and
other cancers is to induce genes that block apoptosis, and NF-B
signaling elicits highly tissue- and context-specific transcriptional
programs, we reasoned that an attractive alternative to globally
targeting NF-B would be to block the non-redundant, cancerspecific downstream effectors of the NF-B survival function; these
effectors, however, are not known.
Using an unbiased genetic screen, our group previously identified a
number of antiapoptotic genes that are transcriptionally regulated by
NF-B (1-7). More recently, we discovered that the complex formed
by the product of one of such genes with its partner kinase in the socalled, JNK pathway, is a key survival module downstream of NF-B
and, hence, a novel therapeutic target in MM (8). Further, by using a
drug-discovery strategy, we developed a corresponding
pharmacological inhibitor of this complex, named DTP3, which
effectively kills MM cells by inducing apoptosis and, importantly, at
the same time, completely lacks toxicity to normal cells (8). Due to
this cancer-selective target specificity, DTP3 displays potent
therapeutic activity against MM cells from patients and exceptionally
high cancer-cell selectivity, far superior to that of conventional NFB-targeting drugs, both in vitro and in vivo. These findings
uncovered a key mechanism for the pathological survival activity of
NF-B signalling in MM and provided an effective therapeutic
strategy, with no preclusive toxicity, for targeting the NF-B pathway
in a cancer-selective manner. Due to this property, this therapeutic
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Professor Guido FRANZOSO, M.D., Ph.D.
Imperial College London
strategy promises to be of profound benefit for patients with MM and,
beyond this, potentially, other cancers that rely on NF-B for survival.
The project has already received compelling validation in both human
and mouse models of MM. Therefore, it currently provides a
tremendous opportunity for the suitable Ph.D. candidate(s), within the
A*STAR-fellowship programme, to work on and contribute to such
exciting research, with ramifications both in the areas of basic biology
and of translational medicine. The broader project has received
support from a large programme grant from Cancer Research UK to
further investigate the role that NF-B plays via its target genes in
oncogenesis, and a large programme grant from the MRC to take the
therapeutic approach built on DTP3 forward into clinical trials, in
patients with advanced MM. The laboratory also accesses other
funds and works in conjunction with a spin-out company to develop
other drug molecules for indication in MM and, beyond this, in other
malignant and non-malignant, NF-B-driven pathologies.
Current areas of investigation and opportunity within this project for
the suitable A*STAR candidate(s) include:
1. Using established methodologies, to conduct a systematic genetic,
biochemical and bioinformatic analysis of cancer cell lines of different
tissues of origin and primary cancer cells from patients, as well as
cancer mouse models, in order to characterize other malignancies,
beyond MM, that depend on a similar NF-κB-mediated, pathological
mechanism for survival and may therefore be treated with DTP3.
2. Using the latest, state-of-the-art technology, including singlemolecule fluorescence imaging and dynamic NMR spectroscopy, to
conduct investigations into the interaction of DTP3 with its molecular
target, in order to further the mechanistic understanding of its mode
of therapeutic of action and, ultimately, of how it kills MM cells. The
project will also shed light on how similar mechanisms may be
exploited to therapeutically target other cancer-promoting kinases.
3. Using a multidisciplinary approach, to contribute to important
aspects of the clinical trial of DTP3 in patients with advanced MM, by
working towards the characterisation and validation of genetic
biomarkers to identify patient responder populations, the onset of
drug resistance, and patients at higher risk of rapid disease
progression, thereby offering to the candidate a unique opportunity to
contribute to translate cutting-edge basic research into a new and
effective therapy for treating patients with MM and, potentially, other
cancers.
BIBLIOGRAPHY:
1. De Smaele et al. 2001. Nature, 414: 308-313
2. Papa et al. 2004. Nat. Cell Biol., 6: 146-153
3. Pham et al. 2004. Cell, 119: 529-542
4. Pham et al. 2007. Mol. Cell. Biol., 27: 3920-3935
5. Papa et al. 2007. J. Biol. Chem., 282: 19029-19041
6. Papa et al. 2008. J. Clin. Invest., 118: 1911-1923
7. Mauro et al. 2011. Nat. Cell Biol. 13: 1272-1279
8. Tornatore et al. 2014. Manuscript submitted
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Professor Guido FRANZOSO, M.D., Ph.D.
PRE-REQUISITES:
Imperial College London
Enrolment in the A*STAR Ph.D. programme
Strong motivation and curiosity towards understanding the most
fundamental biological problems
Basic laboratory experience and knowledge of common molecular
and cellular biology techniques
Basic knowledge of molecular and cellular biology, as well as signal
transduction
Knowledge of research methods and statistical procedures
POTENTIAL PARTNERS: A*STAR Institute of Molecular Cell Biology (IMCB):
-
-
Discovery Research Division (DRD)

Prof. Byrappa Venkatesh / Prof. Sydney Brenner

Prof. Dmitry Bulavin

Prof. Vinay Tergaonkar

Dr. Ernesto Guccione

Dr. William F. Burkholder / Prof. Stephen Quake /
Prof. Yin Thai Chan
Infrastructure, Technology & Translational Division (ITTD)

Prof. Jayantha Gunaratne
A*STAR Genomic Institute of Singapore (GIS):

Prof. Qiang Yu
* Other Potential Partners will be given full consideration
CONTACTS:
Professor Guido Franzoso, M.D., Ph.D.
Chair of Signal Transduction and Inflammation
Head, Centre for Cell Signalling and Inflammation (CCSI)
Department of Medicine
Faculty of Medicine
Imperial College London
Commonwealth Research Building, Room 10N8
Du Cane Road
London W12 0NN
United Kingdom
Tel: +44 (0)20 3313 8421
Fax: +44 (0)20 8383 2788
E-mail: g.franzoso@imperial.ac.uk
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