Timeframe: 2023 – 2025
Goal: Evaluate selective inhibitors of polo-like kinase 1 (PLK1) for effectiveness in human models of FLC
Principal Investigator: Taran Gujral, PhD
Study overview: Abormal cell signaling by the DNAJ-PKAc fusion protein kinase drives the uncontrolled growth of fibrolamellar carcinoma. Thus far, however, drugs that inhibit the fusion kinase also block the activity of normal PKA in many noncancerous cells, leading to toxicity that precludes their use to treat FLC. FCF, therefore, has supported multiple efforts to identify “downstream” steps in the biochemical signaling cascade initiated by DNAJ-PKAc that might be inhibited in FLC cells without causing excessive side effects.
Dr. Gujral’s lab has been developing new patient-derived xenograft (PDX) and cell culture models from human FLC tumors to facilitate the search for effective targeted drugs against this cancer. IOn previous work, Dr. Gujral identified one “druggable” protein kinase, named polo-like kinase 1 (PLK1), as a particularly good candidate for FLC therapy among the several hundred kinases specified in the human genome. Biochemical studies suggested that the abnormal DNAJ-PKAc fusion kinase, but not normal PKA, associates with PLK1 in cellular structures called centrosomes, which are critical for cell division (mitosis). Because of its importance in the regulation of cell multiplication, PLK1 already has been considered a good candidate for targeted cancer therapy. The Gujral team found that a known inhibitor of PLK1 significantly decreased the survival of FLC cells in lab cultures. The compound also decreased the growth of human FLC tumors in mice lacking a competent immune system (PDX models).
The proposed grant funding will support the evaluation in human FLC models of selective inhibitors of PLK1 that are currently in clinical development for other cancers. The PLK1 inhibitors to be evaluated are Onvansertib (Cardiff Oncology) and Plogosertib, also known as CYC140 (Cyclacel). The biopharmaceutical companies that are developing these drugs have agreed to provide them for the proposed study. The targeted kinase inhibitors will be tested both by themselves and in combination with “classical” chemotherapeutic agents known to damage DNA. Because PLK1 is important in DNA repair as well as in cell division, the investigators predict that it will be possible to identify a drug combination with synergistic anti-cancer activity.
If favorable results are identified, the work has the potential to lead to clinical trial(s) against FLC.