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Kidney Cancer PDOXs reveal patient-specific pro-malignant effects of antiangiogenics and its molecular traits

ABSTRACT: An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address this we developed an extensive series of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) that represent inter-patient heterogeneity. In specific tumors antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species-discriminative RNA-sequencing identified a tumor cell-specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion-annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro-invasive subtype of Ren-PDOXs. Validation in an independent series of 15 antiangiogenic-treated patients confirmed that pre-treatment ALDH1A3 can significantly discriminate patients with pro-aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.

SUBMITTER: Lidia Moserle

PROVIDER: S-SCDT-EMM-2019-11889P | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background Validity is the ability of an instrument to measure what it claims to measure. It means the degree to which the empirical evidence supports the trustworthiness of interpretations based on the calculated scores. The hematological malignancy (HM) specific patient reported outcome measure (HM-PRO), is a newly developed instrument for use in daily clinical practice as well as in research. This study, provides the evidence for construct validity of the HM-PRO, specifically focusing on the convergent and divergent validity compared to the other established instruments used in hematology. Methods This validation study adopted a prospective cross-sectional design where a heterogeneous group of patients diagnosed with different HMs and different disease state were recruited. A total of 905 patients were recruited from seven secondary care hospitals in the UK and online through five patient organizations. Patients were asked to complete the HM-PRO and other cancer specific PRO’s, FACT-G and EORTC QLQ C-30. Data analysis was performed using IBM SPSS 23 statistical software. Results A total of 486 males (53.7%) and 419 females (46.3%), with a mean age of 64.3 (± 12.4) years and mean time since diagnosis of 4.6 ( ± 5.2) were recruited. The total score of Part A of the HM-PRO highly correlated with the five functional scales of the EORTC QLQ-C30 (Physical = ?0.71, Role = ?0.72, Emotional = ?0.64, Cognitive = ?0.58, Social = ?0.74—p < 0.001). With respect to correlation with FACT-G, the total score of Part A of the HM-PRO highly correlated with Physical (?0.74), Emotional (?0.57), Functional (?0.66) domains and overall score of FACT-G (?0.74). Similarly, the total score of Part B of the HM-PRO highly correlated with three symptoms scales of EORTC QLQ-C30 (Fatigue scale = ?0.74, Nausea and Vomiting = ?0.52, Pain = ?0.59—p < 0.001) and individual symptom items (Dyspnea = 0.51, Insomnia= 0.43, Appetite loss = 0.54—p < 0.001). Conclusion The construct validity evidence presented in this research is a testimony to the HM-PRO’s ability to measure HRQoL issues which it intends to measure. This is of utmost importance when a PRO is used in routine clinical practice so that the interpretation of the scores or response to an individual item is understood by the clinicians/nurses as intended by the patients.

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Kidney Cancer PDOXs reveal patient-specific pro-malignant effects of antiangiogenics and its molecular traits

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