Fred Hutchinson Cancer Center

2023

Development and Characterization of Patient-derived Models of Fibrolamellar Carcinoma

Goal: Evaluate selective inhibitors of polo-like kinase 1 (PLK1) for effectiveness in human models of FLC

Principal Investigator: Taran Gujral, PhD

Grant length: Two years

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.

2023

Therapeutic modulation of tumor-infiltrating T cell function in fibrolamellar carcinoma

Goals: Identifying factors in the tumor environment that impair immune responses to FLC and defining potentially effective immunotherapy strategies

Principal Investigators: Venu Pillarisetty, MD (University of Washington); and Kevin Barry, PhD (Fred Hutchinson Cancer Center)

Grant length: Two years

Study overview: Immunotherapy – harnessing patients’ immune systems to attack tumor cells – has become established as an exceptionally promising approach in cancer treatment. However, the few published studies of FLC to date have showed limited success of currently approved immunotherapies, such as immune checkpoint inhibitors. More promising results in FLC have been seen in (as of yet) unpublished laboratory tests and a clinical trial of a peptide vaccine targeting the cancer’s unique molecular driver. However, among patients who developed a strong immune response against the FLC driver, only a subset showed marked clinical benefit.

Prior work from Dr. Pillarisetty revealed characteristics of immune cells in the tumor environment indicating that their ability to find and kill cancer cells is suppressed in FLC. The main goal of the proposed research is to better understand factors responsible for this suppression, and to find ways to overcome the barriers and thereby fully unleash the therapeutic potential of immune cells against FLC. Certain classes of T lymphocytes, including some capable of directly killing cancer cells, are found within human FLC tumors. However, these immune cells may be sequestered away from cancer cells. Second, receptors on T cells do not multiply as much as in other tumor types suggesting that the immune system is not responding normally to immune triggers called antigens. Third, cytotoxic T cells—immune cells that can kill cancer cells—may be dysfunctional.

This project aim is to investigate how immunotherapy alters these attributes and thus may be employed to reverse the immunosuppression in FLC. The team will characterize the distribution of immune cells in relation to cancer cells and evaluate the proliferation of specific T cells after immunotherapy. They will use slices of FLC tumors from patients to test how combinations of immunotherapy influence the cancer-killing function of T cells. This work will focus on the roles of members of two broad classes of signaling molecules in the tumor microenvironment, known as cytokines and chemokines. These are secreted proteins that regulate inflammatory responses (cytokines) and control cell migration (chemokines). Finally, as an important resource for the field, they will develop a novel mouse model of FLC with an intact immune system to make studying the disease easier.

The ultimate goal is to learn how to create immune system treatments that can prolong patient survival or even cure FLC.