PAY-IF RESEARCH FUND

Coordination of transcription and translation in the maintenance of prolonged cell-cycle arrest

The Rockefeller University

Total Award Amount: $217,500

 

About 1 in 8 women in the United States will develop breast cancer in their lifetime. While treatment strategies continue to evolve with new information and research, the most aggressive forms of this cancer (metastatic tumors) evolve as well, making drug resistance a perpetual challenge in deadliest stages of disease. Currently the standard approach for treating metastatic breast cancers that remain responsive to hormones is a dual tactic: one drug blocks the estrogen receptors that signal cancer cells to grow and multiply and another drug reinforces this by preventing the passage of a checkpoint required for division. Together this can result in tumor cell death, shift cells into a dormant state known as quiescence, or force cancer cells permanently out of the cell cycle into a state of senescence. The differences between response are not fully understood and some ~70-80% of patients develop resistance within 3 years, making it imperative that we uncover the factors behind these incongruities.

 

In this study, I plan to investigate non-genetic means of resistance; in other words, I will look for mistakes in how cancer cells read the information encoded in DNA (epigenetics), rather than strictly looking for mistakes in the code itself (genetics). Much of our genetic code is normally packaged in a very precise manner, such that different cell types with different functions only have access to the portions they need. In cancers these rules become blurred; cancer cells co-opt regions of the genome that should be inactive and shut down other regions responsible for activating defense measures. My plan is to identify these dysfunctional networks that underlie differential drug response, then test novel compounds that can shift the tumor cells towards favorable outcomes.

 

To do this I will use pre-clinical breast cancer models to generate high-dimensional datasets that map the molecular responses: 1) at multiple levels of genetic regulation, 2) over a month of time, 3) across thousands of individual cells, 4) with different drug combinations. After determining factors that appear to be involved in creating resistant tumor cells, I will attempt to shut down these dysfunctional networks by synthesizing molecules that target the problematic proteins by capturing them and tagging them for disposal, using enzymes that inherently exist within our cells. Finally, I will explore a process in gene regulation that is commonly overlooked, the actual synthesis of proteins from RNA messages. Less is known about how dysregulation of this process impacts disease outcomes, including in breast cancer and drug response; however, given the importance of this biological step in all aspects of life, it likely plays a critical function that may help to explain the discrepant outcomes we observe across patients.

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Uncovering the consequences of chromosome arm aneuploidies in tumorigenesis

Columbia University Medical Center

Total Award Amount: $792,000 (partially funded in 2023)

 

Genetic information is carried in DNA on 46 chromosomes in each human cell. Cancer is characterized by genetic changes, including mutations in individual genes. However, more than 90% of tumors also have cells with an incorrect number of chromosomes. The exact role of these chromosome changes in tumor formation is an unanswered question in cancer biology because it is challenging to directly induce in the lab the same chromosome changes that occur in cancer. To address this, our research uses a new technology called “CRISPR” that allows us to cut chromosomes at specific locations. With this technology, our lab is able to study the effects of specific large chromosome changes that occur in types of lung, throat, and esophageal cancers with a focus on a piece of chromosome 3.

 

Here, our experiments will uncover the interaction between these changes and three tumor features: immune cell invasion, cancer cell evolution and tumor formation. We previously found that changes in chromosome 3 caused more immune cell invasion into a tumor. Our work here will determine how this happens and whether we can use this information to predict which patients will respond to immunotherapy. In our second aim, we will uncover how cells with these chromosome 3 changes adapt and evolve. Lastly, we will study how chromosome 3 changes affect tumor cell development and metastasis. A better understanding of how chromosomal changes affect these features of cancer will be crucial for designing new cancer treatments.