Function and therapeutic targeting of 3’UTR-dependent protein localization (UDPL) in cancer

Our research enables us to inhibit specific functions of a protein and not the whole protein. This is only possible because we are not targeting a sequence within the protein but within the mRNA that generates the protein. The knowledge that 3’UTRs regulate protein localization and function allows us to specifically inhibit the oncogenic functions of CD47 while preserving its tumor-suppressor function. Ultimately, we hope that this approach can be used to treat patients.

Christine Mayr, MD, PhD, is an Assistant Member of the Cancer Biology and Genetics Program at Memorial Sloan Kettering Cancer Center and an Assistant Professor at Weill Cornell Medical College. Dr. Mayr received her MD from Free University, Berlin and her PhD from Humboldt University, Berlin, Germany. After a few years of Residency in the Department of Hematology-Oncology at the LMU Munich and a fellowship in tumor immunology, she joined David Bartel’s laboratory at the Whitehead Institute (Massachusetts Institute of Technology) in Cambridge, MA as a postdoctoral fellow. She found that loss of 3’ untranslated regions (3’UTRs) can activate oncogenes. She showed that loss of 3’UTR sequence can occur through genetic aberrations such as chromosomal translocations. Later, she found that loss of 3’UTR sequence can also occur through gene-regulatory events that do not require changes in the DNA sequence, including the widespread 3’UTR shortening by alternative cleavage and polyadenylation that occurs in cancer. In July 2009, she was recruited to the Cancer Biology and Genetics Program of MSKCC where she studies the function and regulation of alternative 3’UTRs. In her own laboratory she found that alternative 3’UTR isoform expression is highly cell type-specific and that 3’UTRs can regulate protein localization and protein function. For her work she received the Kimmel Scholar Award and the Damon Runyon-Rachleff Innovation Award.

Proteins carry out the majority of functions in cells by interacting with other proteins, yet only 1% of the genome encodes the information that is necessary to make them. Before a protein is made in a cell, a copy of the gene that encodes this information is made. We found earlier that this gene copy can contain either a little or a lot of the adjacent sequence.

"Winning the Pershing Square Sohn Prize allows us to transform a very basic finding in biology into an innovative treatment option for cancer patients."

We recently discovered that the amount of adjacent sequence that was included when the gene copy was made determines the interaction partners of the protein. For example, if the protein is made from a gene copy with a little of the adjacent sequence, the information about the protein interaction partners is not included. As a result, a protein can be part of different protein complexes and can fulfill different functions. This can have very important consequences because a single protein can have cancer-promoting and cancer-inhibiting functions through different interaction partners. So far, all cancer drugs can only inhibit proteins, but, if a protein has positive and negative functions in cancer, treatment with the drug may result in a mixed outcome. CD47 is one such protein with positive and negative functions for cancer, with at least five different cancer-promoting functions. We found a way to exclusively inhibit CD47 with cancer-promoting functions all at once. In this proposal we will examine the idea of inhibiting specific functions of a protein. Since half of all human genes encode proteins that have the potential to have different functions, if this is successful, this will open up new avenues for cancer treatment.