Cancer Research - Europa

Keywords | Dependence receptors | apoptosis | tumour suppressor |
HERMIONE
Novel Anticancer Therapeutics based
on Modulation of Apoptosis through
Dependence Receptors
Summary
Receptors are usually seen as inactive unless bound by their
ligand. However, a new concept has emerged since 1998, by
which some receptors can in fact mediate two diff erent signalling
pathways, depending on the presence or absence of
their ligand. Studies of such receptors have indeed revealed
that, in the absence of ligand, signalling initiates an active
process leading to cell death via apoptosis, whereas programmed
cell death is inhibited in the presence of the
ligand. Therefore, expression of these receptors leads to
a state of cellular dependence on their respective ligands,
which is why they have been named ‘Dependence Receptors’
(DRs). The diff erent DRs trigger apoptosis in the
absence of ligand, suggesting that they may all act as regulators
of tumourigenesis. In addition, expression of DRs is
lost or decreased in many tumours, suggesting that they
act as tumour suppressors and that their loss represents
a selective advantage for tumour cells.
HERMIONE proposes that unravelling the link between different
DRs (DCC, UNC5H, KAI1 and RET), downstream
molecules and apoptosis will lead to the identifi cation of
new potential targets for anti-cancer drugs. The project will
provide a better understanding of the signalling pathways
acting downstream of DRs, observe the association of
mutations with the onset and progression of tumours
(grade, prognosis), and generate murine models in which
the apoptotic signalling of the DR is turned off to study the
implication of DRs in tumourigenesis in vivo. Through this,
HERMIONE will generate knowledge on DR-signalling pathways
involved in the apoptosis of tumoural cells (colorectal,
breast, thyroid and prostate cancers) and use the general
concept of Dependence Receptors to select and perform
pre-clinical testing of novel anti-cancer drugs.
Problem
Colorectal, breast and prostate cancer are among the commonest
forms of cancer in Europe. Breast cancer is the main
cause of death by cancer, killing over 400 000 women a year.
There is no effi cient treatment against metastatic breast
tumours and available anti-cancer treatments are imperfect,
therefore the probability of cure is not high. Existing treatments
are highly toxic to normal tissue and cause substantial
loss of life quality. Surgery, chemotherapy and radiotherapy
TREATMENT
are very invasive, and advanced stage cancer patients
treated with cytotoxic therapeutics are often subject to
debilitating side- eff ects. Therefore, there is a great need to
develop more precise therapeutics, to reduce side-eff ects
and improve the overall wellbeing of treated patients.
Aim
The aim of HERMIONE is to understand better how dysfunctions
in DR-signalling can lead to tumour formation and/or
progression. The generated knowledge will be applied to
the development of targeted drugs, to provide safer and
more eff ective treatments for patients.
The following models, by which DRs regulate tumour initiation,
progression and metastasis, can be surmised from
current knowledge on DR-signalling and illustrate the
project’s hypothesis that these receptors act as tumour suppressors
via their pro-apoptotic activity: in a normal context:
the receptor is bound by its ligand and induces a positive
signal (survival, diff erentiation, etc.). In the case of genetic
alteration leading to cell transformation and thus cell proliferation,
the concentration of ligand in the extracellular
environment becomes insuffi cient to bind all receptors.
In some cases, cells acquire the property to migrate into the
blood circulation and/or invade other tissues where the ligand
is absent. Unbound dependence receptors consequently
trigger apoptosis.
According to these models, a selective advantage for a tumour
cell would be to lose the death activity of DRs by mutation, to
curb their expression or to acquire autocrine expression of the
ligand. Therefore, Dependence Receptors appear to be original
targets for combating cancer and potential candidates to
be studied in the aim of developing novel cancer therapeutics.
In order to achieve this, proper understanding of
the way these receptors induce apoptosis, i.e. deciphering
the signalling pathways operating downstream, is of great
importance.
Expected results
• Understanding the fundamental phenomena:
• to yield better understanding of the signalling pathways
that act downstream of dependence receptors.
Understanding the way Dependence Receptors are
linked to the trigger of apoptosis will provide targets
for drug development;
• to analyse the status of DR/ligand pairs in human
tumourigenesis: is there a selective advantage to losing
expression of the receptor, gaining autocrine
expression of the ligand or losing death function by
mutation? From these studies, clear links between
DRs and tumour progression will be established,
thereby generating new markers for prognosis.
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