Projectdetails
!!Description
Multiple Myeloma (MM) is a plasma cell malignancy, growing in the bone marrow (BM). Typical MM-related signs and
symptoms include bone lesions, anemia, hypercalcemia, renal failure and recurrent infections. It is the second most common
blood cancer, with 40000 people being diagnosed yearly in Europe. The treatment of MM has improved over the last 10 years,
with a median survival of 8-9 years. However, the vast majority of MM patients eventually relapses and becomes refractory to
all therapies, due to the development of drug resistance. The BM environment plays an important role in this evolution,
protecting the tumor cells from conventional treatments and supporting their growth. MM and BM stromal cells communicate
with each other through several mechanisms, including the secretion of small vesicles, formed inside cells, termed exosomes.
We have previously demonstrated that exosomes play a significant role in the MM-supportive processes in the BM, including
the development of drug resistance. Blocking exosome-mediated cellular interactions might therefore limit the protective
effect of the BM. However, effective strategies to ‘neutralize’ exosomes are currently lacking. We have recently uncovered a
role for a characteristic MM marker, CD138/syndecan, and its direct interactor, syntenin, in the biogenesis as well as the uptake
of (protumoral) exosomes. Moreover, together with drug designers and chemists, we have developed small cell-permeant
compounds binding with high affinity and specificity to syntenin, inhibiting this pathway.
In this project we now aim to evaluate the efficacy of the syntenin inhibitors in controlling MM development and drug
resistance. We will investigate whether blocking syntenin-syndecan interactions influences exosome secretion and/or uptake
and is capable of neutralizing the pro-tumoral effects of the MM BM environment. We will use both 2D and 3D culture systems
to study the effects of the inhibitors in vitro and we will test the inhibitors in vivo in preclinical mouse models. Finally, we will
validate these inhibitors with patient material and evaluate whether their efficacy might be predicted using a companion test
measuring exosomal syntenin levels in the blood.
The proposed project will underscore the impact of syntenin-dependent BM-derived exosomes on MM cells and potentially
deliver a novel treatment strategy for MM patients
symptoms include bone lesions, anemia, hypercalcemia, renal failure and recurrent infections. It is the second most common
blood cancer, with 40000 people being diagnosed yearly in Europe. The treatment of MM has improved over the last 10 years,
with a median survival of 8-9 years. However, the vast majority of MM patients eventually relapses and becomes refractory to
all therapies, due to the development of drug resistance. The BM environment plays an important role in this evolution,
protecting the tumor cells from conventional treatments and supporting their growth. MM and BM stromal cells communicate
with each other through several mechanisms, including the secretion of small vesicles, formed inside cells, termed exosomes.
We have previously demonstrated that exosomes play a significant role in the MM-supportive processes in the BM, including
the development of drug resistance. Blocking exosome-mediated cellular interactions might therefore limit the protective
effect of the BM. However, effective strategies to ‘neutralize’ exosomes are currently lacking. We have recently uncovered a
role for a characteristic MM marker, CD138/syndecan, and its direct interactor, syntenin, in the biogenesis as well as the uptake
of (protumoral) exosomes. Moreover, together with drug designers and chemists, we have developed small cell-permeant
compounds binding with high affinity and specificity to syntenin, inhibiting this pathway.
In this project we now aim to evaluate the efficacy of the syntenin inhibitors in controlling MM development and drug
resistance. We will investigate whether blocking syntenin-syndecan interactions influences exosome secretion and/or uptake
and is capable of neutralizing the pro-tumoral effects of the MM BM environment. We will use both 2D and 3D culture systems
to study the effects of the inhibitors in vitro and we will test the inhibitors in vivo in preclinical mouse models. Finally, we will
validate these inhibitors with patient material and evaluate whether their efficacy might be predicted using a companion test
measuring exosomal syntenin levels in the blood.
The proposed project will underscore the impact of syntenin-dependent BM-derived exosomes on MM cells and potentially
deliver a novel treatment strategy for MM patients
Acroniem | ANI374 |
---|---|
Status | Actief |
Effectieve start/einddatum | 1/01/24 → 31/12/27 |
Flemish discipline codes in use since 2023
- Oncology not elsewhere classified
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