Dr. Ronnekleiv-Kelly’s Lab

Our Goals

1. To understand how disruption of the circadian clock contributes to carcinogenesis and a more aggressive cancer phenotype in pancreas cancer.
2. To determine how the DNAJB1-PRKACA fusion oncogene drives cancer formation to identify novel therapies for the spectrum of cancers caused by this gene fusion.

Our Projects

1. We have developed a novel platform to evaluate individual patient tumors (PDAC) and identify which patient PDAC harbors a disrupted circadian clock (BMAL1 suppressed) versus intact circadian clock. Those tumors with a disrupted clock and BMAL1 suppression portend a far worse prognosis. We use patient cancer-derived xenograft models, patient cancer-derived organoids and syngeneic mouse models to understand how BMAL1 silencing and circadian disruption occurs in human PDAC for prognostic and therapeutic avenues.
2. We have identified CDK7 as a therapeutic target in DNAJB1-PRKACAdriven cancer. We are using patient cancer-derived models and engineered cell lines to identify top candidate drugs targeting CDK7, and advanced molecular techniques to determine why DNAJB1-PRKACA cancer cells are so susceptible to CDK7 inhibitor therapy. This has led to informed combination therapies that may be applied as a translational approach. We are also evaluating other cancer subtypes that are sensitive to CDK7 inhibitor therapy.
3. We have constructed a conditional immune competent model of DNAJB1-PRKACA driven carcinoma that mimics human IOPN-associated carcinomas of the pancreas and bile duct. Using this model system, we aim to understand how the DNAJB1-PRKACA transformed cells remodel the tumor microenvironment to yield a permissive, desmoplastic stroma and invasive carcinoma development.
4. We have identified the orphan monocarboxylate transporter, SLC16A14, as strongly linked to DNAJB1-PRKACA. SLC16A14 may play a key metabolic role in the cancer cells, and we are working towards understanding the structure of this protein as well as transport substance and function in DNAJB1-PRKACA expressing cells (i.e., de-orphanization).

Make a Donation

Support the Dr. Ronnekleiv-Kelly Research Lab through the UW-Madison Department of Surgery. Philanthropic gifts make a tremendous difference in advancing groundbreaking research.