Development of a precision medicine platform for circadian based therapeutics in pancreatic cancer

Abstract
Pancreatic ductal adenocarcinoma (PDA) is among the most fatal of all cancers, and is on track to become the
second-leading cause of cancer-related death in the US by 2030. There is significant heterogeneity among PDA
tumors, mitigating the effectiveness of conventional chemotherapy and highlighting the need for more
individualized approaches to treatment. Personalized medicine (PM) strategies, which take tumor and/or patient-
specific data into account when deciding on a course of treatment, have shown great promise within the context
of many different types of cancers in recent preclinical and clinical studies. However, most PM approaches rely
on molecular profiling data that require relatively large samples of tumor tissue. Unlike other cancers in which
surgical resection is standard-of-care, PDA patients rarely undergo surgery at diagnosis. In the absence of
upfront surgery in the majority of PDA patients, access to sufficient tumor tissue for comprehensive molecular
and drug profiling in PDA is limited. Patient-derived organoids (PDOs) represent a unique opportunity to
circumvent this limitation. Patient-derived organoids can be successfully established from the scant tissue
collected during endoscopic biopsies, which are routine in PDA diagnosis. Moreover, such organoids can
recapitulate the phenotype of their tissue of origin and can predict patient drug response in clinic. The primary
goal of the current proposal is to establish pre-clinical predictors of tumor-specific circadian clock dynamics and
chronotherapeutic efficacy using normal human pancreas tissue, well characterized PDA cell lines and patient-
specific biopsy-based PDOs. Specifically, we will: (1) characterize baseline molecular rhythms and clock
dynamics in the normal human pancreas over 24 hours; (2) determine the role of PDA cancer events in tumor
clock perturbations and patient survival and (3) validate the use of molecular and drug response profiling data
from PDOs to inform time-based drug treatment (“chronotherapy”) strategies. Altogether, these studies will help
advance the use of tumor specific circadian profiles in clinical settings, with particular implications for bringing
more individualized and targeted time/circadian-based strategies to PDA patients.

Grant Number: 4R01CA279487-04
NIH Institute/Center: NIH
Principal Investigator: Faraz Bishehsari