TCRF
Funded Research

Polo-like kinase 4 (PLK4) regulates duplication of each cell’s centrosome, which facilitates movement of duplicated chromosomes to opposite poles in dividing cells. Without two centrosomes cells cannot divide; hence preventing cancer cell duplication. We have also found that PLK4 controls a final step in cell division, known as cytokinesis. We are part of a research collaboration that has developed a new drug, CFI-400945, which inhibits PLK4 activity. Our proposal seeks support to identify biomarkers that predict which cancers cannot complete cell division when PLK4 function is inhibited and which cancers, like normal cells, can complete cell division.

Despite decades of extensive studies in cancer research, cancer is still the number 2 leading cause of death in the United States. The major problem is that individual cancers display distinct genetic abnormalities, and none of the known treatments and their combination can effectively deal with these abnormalities. We have recently created a mutant DNA repair protein that irreversibly binds to cancer cell-specific DNA errors during cancer growth, leading to cell death. This application aims to develop this mutant DNA repair protein into an effective drug for cancer therapy.

Liver cancer is the second most common cause of cancer death worldwide, but the sole FDA-approved drug for liver cancer prolongs life for only 2-3 months and has significant side effects. While most anti-cancer drugs have a single target, we are investigating a novel drug, SF1126, that simultaneously targets two proteins (PI3K and BRD4) that are overactive in liver cancer, and our experiments demonstrate that it is efficacious and well tolerated. We are studying the mechanism whereby SF1126 kills liver cancer cells and are actively pursuing the use of dual PI3K/BRD4 inhibitors in clinical trials in liver cancer patients.

Sponsor: Donald L. Durden, MD, PhD

Epithelial ovarian cancers (OC) are highly lethal tumors, but treatment options are limited, largely because our poor understanding of the biology of OC development has hindered the development of new drugs. Recent investigations in our laboratory and others identified the PAX8 gene as a major driver of OC, regulating the expression of key genes to promote tumorigenesis. The goal of this proposal is to understand how DNA mutations impact PAX8-dependent control of target gene expression to promote cancer development. The idea is that by understanding pathways upstream of cancer gene expression we can identify much-needed new therapeutic targets for OC.

Sponsor: Ben Berman, PhD

DI82 is a new potential chemotherapy drug which can kill cancer cells by preventing them from making new DNA. The project will look at drug levels in the blood, tumor, and other parts of the body using an imaging machine (PET). The drug will be tested in mice in combination with two other drugs to determine how well they work together to kill tumor cells. This information will be used in a model to predict how much drug to give patients in future human studies.

Sponsor: Caius Radu, MD

With scientific excellence and an ambitious vision, the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute is giving hope to patients with mesothelioma. With Tower’s support, Cedars-Sinai team members will collaborate across disciplines to investigate how mesothelioma begins, how it grows, and how to halt its progression. Team members will conduct research that spans the continuum – from novel laboratory explorations, to translational experiments, to clinical trials that test the safety and efficacy of new interventions for the prevention and treatment in humans. Clinical scientists and basic scientists will submit proposals and, after a rigorous peer-review process by the multi-disciplinary committee, a winning project(s) will be selected.

Despite remarkable improvements in treatment options, development of endocrine resistance is one reason that breast cancer is the second most frequent cause of cancer death in women. In most cases, estrogen receptor (ER) is present in these resistant tumors, and in many ER continues to regulate tumor growth. This project aims to develop a new clinical-translational strategy to address this challenge and promote patient survival. Dr. Pietras plans to develop a new generation of selective ER downregulators (termed SERDs) with the proper biologic/pharmacologic profile to be used as therapeutics for endocrine-sensitive and -resistant cancers in clinic.

PARP inhibitors are promising new drugs for a subset of breast and ovarian cancers. However, as single agents PARP inhibitors show little activity in triple-negative breast cancer (TNBC). Dr. Koefler will use a TNBC cell model to evaluate the effect of single gene mutations on the response to PARP inhibition. Mutations conferring sensitivity will be further tested in cell lines, animal models, and TNBC patients. Based on our findings, Dr. Koefler will develop an assay to evaluate PARP sensitivity in clinical samples. The study will provide valuable insights that can be translated into biomarkers for patient selection, and new drug combination therapies.

Advanced prostate cancer is a deadly disease with limited treatment options. Two members of the Myc family of cancer genes named c-Myc and N-Myc are active in the main types of lethal prostate cancer – castration-resistant prostate adenocarcinoma and small cell neuroendocrine prostate cancer. In this work, Dr. Lee will clarify the biologic functions of c-Myc and N-Myc in two unique prostate cancer models developed from normal human prostates. Dr. Lee will take advantage of these models of advanced prostate cancer to find new therapies and evaluate a promising inhibitor that directly targets the activity of N-Myc in cancer cells.

Mentor: Owen N. Witte, MD

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and new treatment approaches are urgently needed. Immunotherapy has emerged as a safe and effective treatment for certain solid tumors, however the development of effective immunotherapies for AML requires a better understanding of the mechanisms by which leukemia evades the immune system. AML is associated with selective dysregulation of antigen presenting cells (APCs), which are a vital component of anti-tumor immune responses. The study will investigate mechanisms by which leukemia cells interfere with APC development with the goal of identifying novel immunotherapeutic targets in AML.

Mentor: Gay M. Crooks, MD