R01CA279487

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.

University Of Texas Health Science Center At Houston

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.310 - Trans-NIH Research Support

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Houston, Texas 77030 United States

Single Zip Code

NIH Directors Transformative Research Awards (R01 Clinical Trial Optional) (RFA-RM-21-017)

Amendment Since initial award the total obligations have increased 447% from $663,143 to $3,626,716.