Characterizing and Targeting a Novel Dependency of Aneuploid Cancer Cells on the Mitotic Checkpoint
Abstract
Our DNA is packed into chromosomes, and each chromosome comprises two chromosome arms. The normal cells of our bodies contain two sets of 23 chromosomes, one inherited from each of our parents. When cells divide, their chromosomes are segregated into the daughter cells – one copy of each chromosome goes to each daughter cell. However, errors can occur in this process, leading to gains or losses of specific chromosomes or chromosome arms. Such errors usually have severe detrimental consequences, and cells with altered chromosome number (a state known as “aneuploidy”) are therefore naturally eliminated from our tissues. Remarkably, however, cancer cells can tolerate changes in chromosome number, and some of these changes are even beneficial for their survival and proliferation. In fact, changes in chromosome number are so common in cancer that they are considered to be a “hallmark” of the disease. As cancer cells are almost invariably aneuploid, whereas healthy cells (almost) always have a normal number of chromosomes, there is an enormous potential therapeutic value in identifying drugs that selectively eliminate aneuploid cells. Such drugs have not been yet identified; however, mostly because of the limitations of existing model systems to study this phenomenon. The goal of the current project is to apply an innovative approach to tackle this challenge. We aim to study whether aneuploid cells uniquely depend on a cellular mechanism that regulates chromosome segregation and whether this vulnerability can be harnessed therapeutically. If successful, this unique approach can be used to identify and validate additional cellular vulnerabilities that are associated with aneuploidy. By identifying, validating, and characterizing cellular vulnerabilities associated with aneuploidy in cancer cells, the study will expose a new class of cancer vulnerabilities. As we will study the sensitivity of the cells to drugs that are currently in clinical trials, our results will be readily translatable. Moreover, our study may suggest that aneuploidy could be used as a “biomarker,” a molecular indicator of patients’ response, thus improving patient stratification. The findings will be of particular relevance to several types of cancers that are highly aneuploid, such as colorectal, stomach, pancreatic, and bladder cancers. 90% of solid tumors are aneuploid, and therefore 90% of cancer patients may ultimately benefit from this work. This study, therefore, has the potential to affect mission readiness for active duty military, Veterans, their family members, and other military beneficiaries. Dr. Ben-David is a new Assistant Professor at Tel-Aviv University. The award will allow Dr. Ben-David to advance his career at the forefront of cancer research by: (a) providing him with the opportunity to be the first to identify, validate, and characterize a unique cellular vulnerability of aneuploid cancer cells; (b) allowing him to expand the set of experimental techniques used in his lab; and (c) deepen his professional relationships with leaders in the field of aneuploidy research and with other cancer researchers at Tel-Aviv University. The Career Guide proposed for this project is Dr. Angelika Amon from MIT, who is one of the world’s greatest experts on cancer aneuploidy. Dr. Ben-David is expected to benefit considerably from his interactions with Dr. Amon.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010552
Entities
People
- Uri Ben-David
Organizations
- Tel Aviv University
- United States Army