Method of prognosticating and determining the efficiency of bet inhibitor for treating cancer (in particular pancreatic adenocarcinoma)
Pancreatic ductal adenocarcinoma (PDAC) is one of the 15 most lethal cancers, and a major public issue since there are approximately 230 000 new PDAC cases per year worldwide with approximately the same number of death.
Like other malignant diseases, PDAC results from a complex combination of genetic, epigenetic, and environmental factors which gives rise to a particularly heterogeneous disease in terms of symptoms, predisposition to early metastasis and therapeutic responses. This heterogeneity highlights the necessity to stratify patients with the goal of predicting better responses to therapies.
The present technology explores the frequently deregulated c-MYC oncogene pathway to identify potential markers for patient stratification, c-MYC known to behave as a cancer driver gene for PDAC.
The technology relates to an in vitro or ex vivo method for determining the efficiency of a compound modulating the c-MYC oncogene activity, in particular BET proteins inhibitor, for treating cancer (preferentially pancreatic adenocarcinoma). It relates also to an in vitro or ex vivo method for prognosticating such a cancer.
The method of invention is based on MYC associated transcriptomic expression signature, comprising the steps of :
- a) measuring the expression level of at least one marker gene selected from a group consisting of 10 MYC target genes: CDC20, KPNA2, PLK1, SRM, RFC4, MCM2, RUVBL2, MAD2L1, CCT4 and CAD, specific of Myc-high pathway;
- b) measuring the expression level of at least one marker gene selected from a group consisting of 6 genes: VSIG2, BCL2L15, RAB25, TXNIP, CTSE and ERN2, specific of Myc-low pathway;
- c) determining from said measurement, if the MYC pathway is activated or not in said cancer; and prognosticating said cancer from the determination and measurement obtained;
- d) determining the efficiency of the compound (BET proteins inhibitor) on the c-MYC oncogene activity for treating cancer (PDAC) of human.
– MYC-dependent RNAs signatures can be used for classifying distinct PDAC subtypes ;
– MYC-high PDX are sensitive to growth inhibition by the BET inhibitor JQ1:
The transcriptome of 55 patient‐derived xenografts (PDX) show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC‐high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC‐low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC‐high group and six transcripts increased in the MYC‐low group. We validated the ability of these markers panel to identify MYC‐high patient‐derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC‐high patients are more sensitive to JQ1 treatment compared to MYC‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis.
– The method of the invention is validated on a second BET inhibitor drug candidate by using PDX and organoids;
– POC on Biopsy Derived Pancreatic Organoids:
Pancreatic tumor organoids can mimic very tightly the behavior of corresponding primary tumor in the patient. They are composed only by the epithelium compartment and show a typical cancerous pancreatic gland organization/polarization and function (e.g. mucins production). The team has optimized the production of organoids directly from PDAC EUS-FNA biopsies (Biopsy Derived Pancreatic Organoid) and after a few days of growth the material become almost without other cellular contamination (only 2 weeks). Based on this method, the team is able to produce organoids from both resectable and non-resectable tumor who give a clear outlook of PDAC tumors heterogeneity. These organoids are a well-cleaned source of materials for extracting, in small quantities but pure, RNA, DNA, proteins etc. by using standards approaches developed for small amounts of material. Thus, we have already validated on 20 organoids the determination of the specific MYC signature to select tumors sensitive to BET inhibitor. Results obtained using these macromolecules corroborate tightly those obtained from using PDX.
The technology can address a compound selected from a group consisting of :
– (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-30 6-yl)acetate,
– OTX015/MK-8628, TEN-010, ZEN-3365, ABBV-075, INCB-54329, GS-5829 to
select tumors sensitive on these drugs.
In addition to prognostication of the outcome of patients PDAC, this technology may improve the future management of these patients by the distinction of subgroups of pancreatic tumors (stratification) and the prediction of their response to therapies based on BET inhibitors