Lymphoma Diffuse Large B-cell Clinical Trial
Official title:
ProLyPhy-GEP : Pesticide Associated Lymphomas: Expression of Treatment Resistance Genes
Lymphomagenesis is partially known, and some risk factor are identified like those inducing
immune deficiencies: chronic exposure to HIV, immune suppressor therapies or commun variable
immunodeficiency. Parts of the mechanisms leading to NHL development after pesticide exposure
are the disruption of immune surveillance against cancer cell. Pro-oncogenic action of
metabolites is the most important mechanisms of action for pesticides. Thus, pesticides are
metabolized in pro-oxidant compounds disturbing the redox homeostasis in the haematopoietic
and immune cells precursors, promoting proliferation and survival, and inducing DNA breaks.
Some of them induce direct DNA breaks and non-conform reparation, leading to activation of
oncogenes; and other induces transcription factors for oncogenic signalling pathways. DNA
reparation and adaptation to a higher ROS level are associated with resistance against
cytotoxic chemotherapy treatment with induction of detoxification mechanism by tumour cells.
That DNA repair pathways, which are targeted by chemotherapy could also explain a part of
chemo-resistance. It was therefore suggested that DLBCL dependence to specific DNA repair
pathways could be targeted to hamper repair of intrinsic DNA damage occurring during
B-lymphoma cells proliferation or to increase DNA damage induced by chemotherapy.
Occupational exposure to pesticides is associated with higher incidence of non-Hodgkin
lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) The relative risk for NHL
after occupational exposure to pesticide is 1.5 to 3, with little variation according to NHL
subtypes. DLBCL is one of the most frequent subtypes of NHL and characterized by aggressive
presentation. DLBCL is treated by chemotherapy based on anthracyclines combined with an
anti-CD20 monoclonal antibody allowing complete response and long term remission in 65-70% of
patients. The response rate to treatment and clinical outcome is depending of the DLBCL
subtype. There are 3 of them depending of the cell of origin (germinal centre B cell or
activated B cell), and the anatomical location (primary mediastinal) identified by molecular
gene expression profile. The activated B cell subtype have a worse outcome.
Lymphomagenesis is partially known, and some risk factor are identified like those inducing
immune deficiencies: chronic exposure to HIV, immune suppressor therapies or commun variable
immunodeficiency. Parts of the mechanisms leading to NHL development after pesticide exposure
are the disruption of immune surveillance against cancer cell. Pro-oncogenic action of
metabolites is the most important mechanisms of action for pesticides. Thus, pesticides are
metabolized in pro-oxidant compounds disturbing the redox homeostasis in the haematopoietic
and immune cells precursors, promoting proliferation and survival, and inducing DNA breaks.
Some of them induce direct DNA breaks and non-conform reparation, leading to activation of
oncogenes; and other induces transcription factors for oncogenic signalling pathways. DNA
reparation and adaptation to a higher ROS level are associated with resistance against
cytotoxic chemotherapy treatment with induction of detoxification mechanism by tumour cells.
That DNA repair pathways, which are targeted by chemotherapy could also explain a part of
chemo-resistance. It was therefore suggested that DLBCL dependence to specific DNA repair
pathways could be targeted to hamper repair of intrinsic DNA damage occurring during
B-lymphoma cells proliferation or to increase DNA damage induced by chemotherapy.
The investigators hypothesize that actions of pesticides on DNA and redox homeostasis are
critical events during lymphomagenesis. We supposed that specific mechanisms of DNA repair
and antioxidant defences induced by pesticides exposure are implicated in the
chemo-resistance in DLBCL patients.
There might be a negative impact of professional exposure to pesticide on treatment response.
In this search, the investigators will explore a comprehensive view of both lymphomagenesis
and adverse prognosis of pesticide-exposed DLBCL. The investigators plan to analyse the
molecular profile of B-lymphoma cells from pesticide-exposed patients, to better understand
biological mechanisms underlying lymphomagenesis as well as chemotherapy resistance
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Terminated |
NCT02898870 -
Occupational Exposure to Pesticides in the Prognosis of Lymphomas
|
N/A |