Project Details

Description

Personnel: I completed a Ph.D. degree in Molecular Biology in 2009 focusing on the study of the epigenetic regulation of microRNAs and other non-coding RNAs in cancer. I then moved to the laboratory of Dr. Lowe to work on hepatocellular carcinoma (HCC). My academic training has allowed me to obtain extensive theoretical and practical knowledge in the fields of liver cancer, cellular senescence, and shRNA screens, and I am therefore well equipped to identify novel combination therapies for HCC. My mentor, Dr. Friedman, is the Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai. He has performed pioneering work studying the underlying causes of liver fibrosis associated with chronic liver disease, which affects millions worldwide and constitutes the main risk factor for HCC development. His unique knowledge of liver biology will greatly contribute to the success of the proposed project. I will also collaborate with Dr. Hoshida, who has vast experience in transcriptional profiling of HCC and has recently established a sophisticated method for ex vivo culture of HCC samples directly from patients.Career Development: This Career Development Award will provide me with support to identify novel combination therapies for liver cancer during the first years of my tenure-track appointment. This grant will allow me to address important mechanistic and translational questions pertaining liver cancer and develop the required skills to establish myself as an emerging leader in liver cancer research.Research: Background: HCC is one of the most aggressive types of cancer, and it represents the second leading cause of cancer-related mortality in the United States. The multi-kinase inhibitor sorafenib was recently approved as the first systemic treatment for patients with advanced HCC, suggesting that targeted therapies could be beneficial in this cancer. However, cancer therapy is often hampered by reduced drug activity or the rapid emergence of drug resistance, and as a consequence, treatment with single agents tends to fail. It is therefore clear that the successful clinical management of liver cancer will entail the use of drug combinations.Objective/Hypothesis: The objective of this project is to identify target genes whose inhibition increases the performance of palbociclib, a selective inhibitor of CDK4/6 that shows limited toxicity and is amenable to combination therapy. Our central hypothesis is that palbociclib could be successfully used in combination with other drugs for HCC treatment.Specific Aims: We propose two interrelated but distinct specific aims to identify combination therapies with palbociclib for HCC. By performing a sophisticated shRNA screen in combination with palbociclib, we will identify genes whose inhibition increases the therapeutic efficacy of palbociclib (Aim 1). By using palbociclib-resistant cell lines and by combining transcriptional profiling with RNAi screening, we will dissect novel mechanisms of resistance to palbociclib and design strategies to overcome it (Aim 2).Study Design: Aim 1: We will perform an shRNA screen in combination with palbociclib to identify genes whose inhibition synergizes with palbociclib treatment. We will then validate our candidate drug targets in vitro, in vivo, and ex vivo. To facilitate the rapid translation of our results into the clinic, we will use an established shRNA library that targets genes whose protein products can be inhibited by available compounds. Aim 2: We will perform transcriptional profiling (RNA-seq) of palbociclib-resistant cell lines, which will inform potential mechanisms of resistance to palbociclib. We will then identify resistance-related genes by performing an shRNA screen in the resistant cell lines.Military Relevance: The incidence of HCC is increasing in the United States, especially within the US Military and US Veterans community. Among the main risk factors for HCC development, we find alcohol consumption, hepatitis B and C infection, obesity, and male gender, all of which are over-represented in the US Military and US Veterans community. Here, we will identify effective combination therapies with palbociclib, a novel CDK4/6 inhibitor that has shown unprecedented results in breast cancer, is well tolerated, and is currently tested in a clinical trial for advanced HCC. These studies are very likely to improve the life of Americans citizens in general and US Military and Veterans in particular.Impact: By identifying compounds that act synergistically with palbociclib and/or overcome resistance to palbociclib, we will improve the treatment options of liver cancer patients and our understanding on liver cancer biology. Moreover, the identification of novel mechanisms of resistance to palbociclib will uncover predictive biomarkers of drug response in HCC and facilitate patient selection. This work will enhance our understanding of liver cancer biology and liver cancer treatment.

StatusFinished
Effective start/end date30/09/1629/09/19

Funding

  • Congressionally Directed Medical Research Programs: $610,200.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.