Dr. Bishoy M. Faltas, director of bladder cancer research at the Englander Institute for Precision Medicine at Weill Cornell Medicine, the Gellert Family-John P. Leonard, M.D. Research Scholar and an assistant professor of medicine at Weill Cornell Medicine has been awarded a $4 million, seven-year MERIT grant from the National Cancer Institute (NCI) at the National Institutes of Health (NIH).
The “Method for Extending Research In Time” (MERIT) award provides investigators with ambitious scientific projects longer-term federal grant support. Unlike conventional grants, there is no application for the MERIT Award, but outstanding researchers who submit grant applications that receive the highest scores are nominated by the NCI.
“I am honored to receive this prestigious award that will allow us to pursue more high-risk, high-reward angles within our work. This gives us the stability to expand our research on APOBEC3 proteins, which drive mutations in bladder cancer, affecting our ability to treat patients with this disease,” said Dr. Faltas, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Preventing Drug Resistance in Bladder Cancer
Cancer cells are constantly changing, so treating cancer is like hitting a moving target. Too often a treatment starts out as effective, but then the tumor develops resistance to the drug, and it stops working. If researchers could block these genetic changes, they could potentially deliver a knockout blow, but how cancer cells evolve and acquire drug resistance is not well understood.
Dr. Faltas has been studying one of these pathways involving APOBEC3 enzymes that are produced widely in human cells and induce changes in DNA. Normally, this enzyme provides a defense against infecting retroviruses, such as HIV, causing mutations that inactivate the virus. Dr. Faltas and other researchers have found evidence that these enzymes are co-opted by some cancers, including bladder cancers, to boost their mutational rates—making it easier for them to evolve. Some of these mutations may contribute to the cancer’s ability to form drug resistance.
“We are taking a novel approach by studying these enzymes that are the drivers of cancer evolution,” said Dr. Faltas. “By understanding these processes, we aim to dismantle the very mechanisms that allow cancer cells to sidestep our treatments.”
His lab hopes to identify mutational profiles that can act as biomarkers that indicate which patients are more likely to develop resistance early. “Then, patients can be tested for these mutations in circulating tumor DNA and can we do something about them,” he explained. It may be possible to identify a drug that preemptively blocks resistance and combine it with existing therapies to boost its long-term efficacy.
Turning APOBEC Against Cancer Cells
APOBEC3 not only causes mutations but also double-stranded DNA breaks, which, left unrepaired, are fatal to the cell. In a second avenue of investigation, Dr. Faltas’s lab wants to take advantage of this vulnerability. “By pinpointing and then inhibiting the DNA repair pathways that cancer cells rely on to repair the DNA breaks caused by the APOBEC3 enzymes, we may be able to transform the cancer cells’ survival strategy into a self-destruction mechanism, turning a cellular survival mechanism into a fatal flaw for the cancer cell,” he said.
Since breast and lung cancers also have highly expressed APOBEC3 enzymes, this research area may be expanded to cancers beyond bladder cancer. This approach also has the potential advantage of allowing researchers a way to specifically target cancer cells with APOBEC3 activity while sparing healthy cells.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the profile for Dr. Bishoy Faltas.