Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity inKRASwild-type tumors

Abstract

Pancreatic cancer (PC) is largely refractory to existing therapies used in unselected patient trials, thus emphasizing the pressing need for new approaches for patient selection in personalized medicine. KRAS mutations occur in 90% of PC patients and confer resistance to epidermal growth factor receptor (EGFR) inhibitors (e.g., panitumumab), suggesting that KRAS wild-type PC patients may benefit from targeted panitumumab therapy. Here, we use tumor tissue procured by endoscopic ultrasound-guided fine-needle aspirate (EUS-FNA) to compare the in vivo sensitivity in patient-derived xenografts (PDXs) of KRAS wild-type and mutant PC tumors to panitumumab, and to profile the molecular signature of these tumors in patients with metastatic or localized disease. Specifically, RNASeq of EUS-FNA-derived tumor RNA from localized (n = 20) and metastatic (n = 20) PC cases revealed a comparable transcriptome profile. Screening the KRAS mutation status of tumor genomic DNA obtained from EUS-FNAs stratified PC patients into either KRAS wild-type or mutant cohorts, and the engraftment of representative KRAS wild-type and mutant EUS-FNA tumor samples into NOD/SCID mice revealed that the growth of KRAS wild-type, but not mutant, PDXs was selectively suppressed with panitumumab. Furthermore, in silico transcriptome interrogation of The Cancer Genome Atlas (TCGA)-derived KRAS wild-type (n = 38) and mutant (n = 132) PC tumors revealed 391 differentially expressed genes. Taken together, our study validates EUS-FNA for the application of a novel translational pipeline comprising KRAS mutation screening and PDXs, applicable to all PC patients, to evaluate personalized anti-EGFR therapy in patients with KRAS wild-type tumors.

Circulating cell-free mitochondrial DNA levels in Parkinson’s disease are influenced by treatment

“…The identification of circulating cell-free mitochondrial DNA (ccf-mtDNA) in 2000 [1], prompted a wave of studies assessing the utility of ccf-mtDNA as a biomarker of disease [2][3][4][5][6][7], detection of cancers [8][9][10][11][12] and susceptibility to comorbidities during HIV infection [13,14].…”

Needle Biopsy Adequacy in the Era of Precision Medicine and Value-Based Health Care

“…200 Adequacy is high only if multiple passes are performed and, for FNAB, if the samples evaluated immediately by ROSE. [201][202][203] However, EUS needle biopsy has advantages over open biopsy to sample chemotherapy-naïve tumors and to provide material for genomic analysis, for example KRAS mutations 204 and immunophenotype analysis. 205 Against the significant hazards of open biopsy, inadequacy rates of EUS needle biopsy can be tolerated.…”

AGA White Paper: Optimizing Endoscopic Ultrasound–Guided Tissue Acquisition and Future Directions

“…For EUS-FNB specimen prepared by formalin-fixed, paraffinembedded, a 95% success rate for NGS is expected when samples have a tissue volume of 1.2 cm 2 and at least 5 ng/mL of analyzable DNA. 49 Although much of the initial work on EUS-TA has focused on NGS and is the focus of this paper, numerous additional methods, such as RNA and microRNA sequencing, [59][60][61][62] use of fluorescence in situ hybridization, 63,64 identification of protein and immune markers, the creation of tumor organoids, [65][66][67][68] and low cost whole-exome sequencing are emerging. Of these methods, the ability to create organoids, which are in vitro 3-dimensional tissue models, is particularly promising.…”

“…RNA sequencing has been shown to potentially aid in distinguishing adenocarcinoma from benign pancreatic masses 59 and in determining response to chemotherapy. 62 Similarly, microRNA analyses may aid in not only in achieving a diagnosis, but also in predicting prognosis and identifying tumor susceptibility to chemotherapeutic agents in pancreatic ductal adenocarcinomas. 60,61 Another important recent advance has been the creation of murine and human pancreatic organoids from normal and malignant pancreatic tissue.…”