Background: Mortality in patients with high-risk and recurrent endometrial cancer (EC) is high since treatment options are limited, and tumors are extremely chemoresistant. In this study, we unveil the possible impact of molecular ITH in treatment response in EC; and we incorporate the molecular ITH of the tumor in the definition of a personalized medicine for EC patients.
Methods: Patient-derived xenograft (PDX) models were generated from 32 different tumor areas of a total of 13 EC patients. PDX tumors and a patient counterpart were analyzed by whole exome sequencing (WES) to unveil single nucleotide variation (SNV) and copy number variation (CNV) alterations. A bioinformatic pipeline was conducted to find the best candidate’s drugs targeting the specific mutated genes of each tumor area. Viability assays were performed to assess the efficacy of the selected drugs in organoids derived from patient-derived xenograft (PDX) organoids and mice models representing ITH.
Results: All EC models presented molecular ITH. A subset of the most relevant altered tumor drivers and pathogenic genes were used to select drugs targeting specific ITH genes or homogenously altered genes in the primary tumor. Targeted drugs and standard chemotherapy were tested in deep and superficial areas of two EC patients using their PDXOs. A relevant difference between the IC50 of both areas (50 µM vs 12 µM) was encountered when assessing the efficacy of the Geldanamycin, which is a HSP90 inhibitor, targeting the ITH alteration of the deep area of one patient.
Conclusions: We have established a workflow for the identification of specific drugs targeting the molecular ITH in EC. Our preliminary results indicate that ITH might have an important role in treatment response.