Parker_relayout_EU Urology 17/03/2010 12:02 Page 18
Prostate Cancer
castrate prostate cancer cell lines and in the human disease at a Insulin-like Growth Factor Receptor Signalling
higher frequency in castration-resistant as opposed to hormone- Activation of IGF-1R by IGF-1 or IGF-2 results in phosphorylation
naïve primary tumours.
68,72,73
In addition, HER-2/neu was shown to and membrane recruitment of insulin receptor substrate proteins
promote DNA binding and AR stability through activation of mitogen- and activation of intracellular signalling pathways, including PI3K
activated protein kinase (MAPK) and Akt, which could also bind and MAPK. The activated receptor is thus able to induce AR
directly to the receptor.
74,75
However, phase II clinical studies of signalling in the absence of AR ligand activation. IGF-1R expression
therapeutics targeting HER2 failed to demonstrate any clinical benefit, has been reported to alter as prostate cells progress from a normal
despite proven antitumour activity with the same dose and regimen to a malignant phenotype, and IGF-1R is implicated in resistance to
in other tumour types.
76–78
As it becomes increasingly evident that a therapy.
84
Targeting of IGF-1R signalling in pre-clinical tumour
significant proportion of CRPC remains driven by ligand activation of models has suppressed growth of prostate cancer cells, induced
the AR, the role of cross-talk between the HER kinase family and AR apoptosis in vitro and in vivo and sensitised cancer cells to
signalling must at best be of limited relevance. However, in the future conventional chemotherapeutic treatment and irradiation.
85
An
there may be a role for combination regimens that include IGF-1R-targeting monoclonal antibody is now being evaluated for
therapeutics targeting cross-talk pathways in patients in whom AR the treatment of CRPC.
86
signalling has been truly abrogated with CYP17 inhibitors and novel
anti-androgens, etc. Ongoing Challenges
It is envisaged that the next decade will result in significant
Phosphatase and Tensin Homologue and changes in the treatment of prostate cancer. As new and better
Phosphoinositide 3-kinase Signalling drugs targeting the AR are developed (see Table 1), patients may
The phosphoinositide 3-kinase (PI3K) pathway regulates many become truly AR-independent. Also, therapeutic targeting of ETS
key cellular processes. There is now overwhelming evidence genes or their downstream targets could achieve the antitumour
implicating the PI3K/AKT/mTOR pathway as a regulator in the effectivity of hormone therapies while sparing patients the adverse
malignant progression of prostate cancer. Functional loss of effects of androgen deprivation. A key challenge that remains to be
phosphatase and tensin homologue (PTEN) (which is the negative addressed is the identification of suitable surrogate end-points for
regulator of PI3K) is thought to occur in up to half of all prostate survival. PSA does not predict survival and therefore is not suitable
cancers and is associated with increased activation of AKT and the for evaluating response to drugs. Recently, the rate of the rise of
downstream kinase mTOR, which is involved in regulating protein PSA (PSA velocity) has been associated with the length of survival
synthesis. Loss of PTEN and increased AKT-1 phosphorylation is after treatment and may prove to be a suitable surrogate for
typically associated with higher Gleason grading, advanced stage and survival.
87
However, PSA secretion is driven by AR signalling, and
poorer prognosis.
79
new drugs that directly target AR signalling could be ineffective
treatments yet modulate PSA levels.
The PI3K pathway appears to be critical in the development of
CRPC. In vitro data suggest that over-expression and activation New technology allows the isolation and enumeration of circulating
of AKT can trigger prostate cancer androgen escape via altered tumour cells (CTCs) in patients with advanced prostate cancer. The
sensitivity and activation of AR.
80
The PI3K pathway therefore number of CTCs pre- and post-chemotherapy above and below a set
presents a number of attractive kinase targets for drug development. threshold is associated with survival in CRPC, and a decline in CTC
The first generation of PI3K inhibitors were limited by lack of potency, count with treatment is associated with an improvement in survival.
88
poor selectivity for the oncogenic class I PI3K isoforms and Dynamic-weighted magnetic resonance imaging and positron
unsuitable pharmaceutical properties. Newer-generation inhibitors emission scans using
18
F-fluoro-2-deoxy-D-glucose or
18
F-fluoro-
have improved pharmacological properties, appear highly selective 3’deoxy-3’-L-fluorothymidine may also be valuable tools to assess
and have demonstrated growth inhibition in vitro and in vivo. A CRPC and may allow early assessment of disease response. Overall,
number of these inhibitors are shortly to enter the clinic.
81
these surrogates could become primary end-points in efficacy trials,
thereby expediting future advances and drug approval. n
Preliminary data from these inhibitors show that the likely molecular
response is G1/S phase arrest, with no significant apoptosis. PI3K
Gerhardt Attard is a Clinical Lecturer at The Institute of
inhibitors may therefore be best used in combination with inhibitors
Cancer Research. His research focuses on the
of other survival signalling pathways, e.g. EGFR/ MEK/MAPK,
82
or discovery of novel biomarkers and therapeutics for
following treatment with cytotoxics. Similarly, a number of specific
castration-resistant prostate cancer. Dr Attard has
been at the vanguard of the development of
small-molecule inhibitors of AKT are in development and should
abiraterone acetate, a novel inhibitor of steroid
enter clinical trials shortly. Proof of principle that the PI3K pathway synthesis, for the treatment of prostate cancer.
can be targeted successfully for clinical use in cancer has been
demonstrated by the development of rapamycin analogues (CCI-779,
RAD-001) that inhibit the mTOR kinase and are now undergoing
Chris Parker is a Cancer Research UK Clinician
Scientist Fellow and a Senior Lecturer and Honorary
evaluation in phase II trials in CRPC. RAD-001 has been shown to
Consultant in Clinical Oncology at The Institute of
completely reverse the PIN phenotype in murine transgenic AKT
Cancer Research and The Royal Marsden Hospital. He
models. In addition, mTOR-dependent regulation of HIF1-
is also a member of several committees including the
α may
Department of Health (DoH) Prostate Cancer Advisory
produce an anti-angiogenic effect.
83
One of the main concerns
Group and the National Cancer Research Institute
regarding the use of mTOR inhibitors is the possibility of ‘negative
(NCRI) South of England Prostate Cancer Collaborative
feedback’ with activation of upstream targets such as insulin-like
Scientific Committee.
growth factor (IGF)1-R and p-AKT.
18
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